for Journals by Title or ISSN
for Articles by Keywords
help
  Subjects -> CHEMISTRY (Total: 881 journals)
    - ANALYTICAL CHEMISTRY (54 journals)
    - CHEMISTRY (616 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (43 journals)
    - ORGANIC CHEMISTRY (48 journals)
    - PHYSICAL CHEMISTRY (71 journals)

CHEMISTRY (616 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Hybrid Journal   (Followers: 43)
ACS Chemical Neuroscience     Hybrid Journal   (Followers: 21)
ACS Combinatorial Science     Hybrid Journal   (Followers: 23)
ACS Macro Letters     Hybrid Journal   (Followers: 25)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 41)
ACS Nano     Hybrid Journal   (Followers: 279)
ACS Photonics     Hybrid Journal   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Hybrid Journal   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 7)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Open Access   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 67)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 21)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 24)
Advances in Environmental Chemistry     Open Access   (Followers: 5)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Polymer Science     Hybrid Journal   (Followers: 44)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 20)
American Journal of Chemistry     Open Access   (Followers: 30)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 167)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 243)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 32)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 2)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Hybrid Journal   (Followers: 357)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 10)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Biomacromolecules     Hybrid Journal   (Followers: 21)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 131)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 86)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 70)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 10)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 20)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 74)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Chemical Reviews     Hybrid Journal   (Followers: 190)
Chemical Science     Open Access   (Followers: 25)
Chemical Technology     Open Access   (Followers: 26)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 7)
Chemistry - A European Journal     Hybrid Journal   (Followers: 159)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Open Access   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 43)
Chemistry of Materials     Hybrid Journal   (Followers: 258)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 12)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access   (Followers: 1)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 4)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 6)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  

        1 2 3 4 | Last

Journal Cover
Bioorganic & Medicinal Chemistry Letters
Journal Prestige (SJR): 0.81
Citation Impact (citeScore): 3
Number of Followers: 86  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3159 journals]
  • Graphical abstract TOC
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s):
       
  • Synthesis, structure and bioactivity of primary sulfamate-containing
           natural products
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Prashant Mujumdar, Silvia Bua, Claudiu T. Supuran, Thomas S. Peat, Sally-Ann PoulsenHere we report the synthesis of natural products (NPs) 5′-O-sulfamoyl adenosine 1 and 5′-O-sulfamoyl-2-chloroadenosine 2. As primary sulfamates these compounds represent an uncommon class of NPs, furthermore there are few NPs known that contain a NS bond. Compounds 1 and 2 were evaluated for inhibition of carbonic anhydrases (CA), a metalloenzyme family where the primary sulfamate is known to coordinate to the active site zinc and form key hydrogen bonds with adjacent CA active site residues. Both NPs were good to moderate CA inhibitors, with compound 2 a 20–50-fold stronger CA inhibitor (Ki values 65–234 nM) than compound 1. The protein X-ray crystal structures of 1 and 2 in complex with CA II show that it is not the halogen-hydrophobic interactions that give compound 2 a greater binding energy but a slight movement in orientation of the ribose ring that allows better hydrogen bonds to CA residues. Compounds 1 and 2 were further investigated for antimicrobial activity against a panel of microbes relevant to human health, including Gram-negative bacteria (4 strains), Gram-positive bacteria (1 strain) and yeast (2 strains). Antimicrobial activity and selectivity was observed. The minimum inhibitory concentration (MIC) of NP 1 was 10 µM against Gram-positive Staphylococcus aureus and NP 2 was 5 µM against Gram-negative Escherichia coli. This is the first time that NP primary sulfamates have been assessed for inhibition and binding to CAs, with systematic antimicrobial activity studies also reported.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of novel N-phenylbutanamide derivatives
           as KCNQ openers for the treatment of epilepsy
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Shaoning Yang, Dingqiang Lu, Pingkai OuyangKCNQ (Kv7) has emerged as a validated target for the development of novel anti-epileptic drugs. In this paper, a series of novel N-phenylbutanamide derivatives were designed, synthesized and evaluated as KCNQ openers for the treatment of epilepsy. These compounds were evaluated for their KCNQ opening activity in vitro and in vivo. Several compounds were found to be potent KCNQ openers. Compound 1 with favorable in vitro activity was submitted to evaluation in vivo. Results showed that compound 1 owned significant anti-convulsant activity with no adverse effects. It was also found to posses favorable pharmacokinetic profiles in rat. This research may provide novel potent compounds for the discovery of KCNQ openers in treating epilepsy.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and antibacterial properties of
           pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): David H. McGarry, Ian R. Cooper, Rolf Walker, Catherine E. Warrilow, Mark Pichowicz, Andrew J. Ratcliffe, Anne-Marie Salisbury, Victoria J. Savage, Emmanuel Moyo, John Maclean, Andrew Smith, Cédric Charrier, Neil R. Stokes, David M. Lindsay, William J. KerrAccording to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of thiomannosides, potent and orally active FimH
           inhibitors
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Jitendra A. Sattigeri, Malvika Garg, Pragya Bhateja, Ajay Soni, Abdul Rehman Abdul Rauf, Mahendrakumar Gupta, Mahesh S. Deshmukh, Tarun Jain, Nidhi Alekar, Tarani Kanta Barman, Paras Jha, Tridib Chaira, Ramesh B. Bambal, Dilip J. Upadhyay, Takahide NishiFimH is a type I fimbrial lectin located at the tip of type-1 pili of Gram-negative uropathogenic Escherichia coli (UPEC) guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small molecule inhibitor is considered as a promising new therapeutic alternative to treat urinary tract infections caused by UPEC. Herein, we report that compounds having the S-glycosidic bond (thiomannosides) had improved metabolic stability and plasma exposures when dosed orally. Especially compound 5h showed the potential to inhibit biofilm formation and also to disrupt the preformed biofilm. And compound 5h showed prophylactic effect in UTI model in mice.Graphical abstractGraphical abstract for this article
       
  • Squaramides as novel class I and IIB histone deacetylase inhibitors for
           topical treatment of cutaneous t-cell lymphoma
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Jean-François Fournier, Yushma Bhurruth-Alcor, Branislav Musicki, Jérome Aubert, Michèle Aurelly, Claire Bouix-Peter, Karinne Bouquet, Laurent Chantalat, Marion Delorme, Bénédicte Drean, Gwenaelle Duvert, Nicolas Fleury-Bregeot, Blanche Gauthier, Karine Grisendi, Craig S. Harris, Laurent F. Hennequin, Tatiana Isabet, Florence Joly, Guillaume Lafitte, Corinne MilloisA series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.Graphical abstractGraphical abstract for this article
       
  • Pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety as
           potential antiviral agents
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Yan-Yan Wang, Fang-Zhou Xu, Yun-Ying Zhu, Baoan Song, Dexia Luo, Gang Yu, Shunhong Chen, Wei Xue, Jian WuA series of pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety were synthesized, characterised, and evaluated for their activity against tobacco mosaic virus (TMV). Biological assays indicated that several of the derivatives exhibited significant activity against TMV. In particularly, compounds 5y and 5aa displayed excellent inactivating activity against TMV, with half maximal effective concentration (EC50) values of 70.3 and 53.65 μg/mL, respectively, which were much better than that of ribavirin (150.45 μg/mL), and 5aa was superior to ningnanmycin (EC50 = 55.35 μg/mL). Interactions of compounds 5y and 5aa with TMV coat protein (TMV-CP) were investigated using microscale thermophoresis and molecular docking. Compounds 5y and 5aa displayed strong binding capability to TMV-CP with dissociation constant (Kd) values of 22.6 and 9.8 μM, respectively. These findings indicate that pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base may be potential antiviral agents.Graphical abstractA series of pyrazolo[3,4-d]pyrimidine derivatives containing Schiff base was synthesized. Compounds 5y and 5aa exhibited excellent antiviral activity against TMV. The interaction mode of 5y and 5aa with TMV-CP was conducted through molecular docking and microscale thermophoresis (MST) techniques.Graphical abstract for this article
       
  • Synthesis and antimicrobial activity of β-carboline derivatives with
           N 2-alkyl modifications
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Kenji Suzuki, Itsuki Nomura, Masayuki Ninomiya, Kaori Tanaka, Mamoru Koketsuβ-Carbolines constitute a vast group of indole alkaloids and exhibit various biological actions. The objective of this study was to investigate the structure–activity relationships of β-carboline derivatives on in vitro inhibitory effects against clinically relevant microorganisms. A series of β-carboline dimers and their N2-alkylated analogues were therefore prepared and evaluated for their antimicrobial effects. Among these, a dimeric 6-chlorocarboline N2-benzylated salt exerted potent activity against Staphylococcus aureus at MICs of 0.01–0.05 μmol/mL. Our work highlights that N1-N1 dimerization and N2-benzylation significantly enhanced the antimicrobial effects of compounds.Graphical abstractGraphical abstract for this article
       
  • The synthetic chalcone derivative 2-hydroxy-3′,5,5′-trimethoxychalcone
           induces unfolded protein response-mediated apoptosis in A549 lung cancer
           cells
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Ha-Na Gil, Dongsoo Koh, Yoongho Lim, Young Han Lee, Soon Young ShinThe synthetic chalcone derivative 2-hydroxy-3′,5,5′-trimenthoxyochalcone (named DK-139) exhibits anti-inflammatory and anti-tumor invasion properties. However, effects of DK-139 on tumor cell growth remain unknown. In the present study, we evaluated the inhibitory activity of DK-139 against human lung cancer cells. Treatment with DK-139 inhibited clonogenicity in various lung cancers and stimulated the caspase cascade, leading to the apoptosis of A549 lung cancer cells. To investigate the mode of action of DK-139-induced apoptosis, we analyzed the effect of DK-139 on the endoplasmic reticulum (ER) stress response. DK-139 increased expression of ER stress sensors, including p-PERK, GRP78/BiP, and IRE1α. IRE1α-regulated XBP-1 mRNA splicing and PERK-induced ATF4 expression was also upregulated following DK-139 treatment. In addition, expression levels of the pro-apoptotic transcription factor CHOP and its downstream target Bim, which is involved in mitochondria-mediated apoptosis, were increased by DK-139 treatment. These results suggest that DK-139 triggers caspase-mediated apoptosis via the ER stress-activated unfolded protein response (UPR) pathway. We propose that the synthetic chalcone derivative DK-139 may be used as a potential agent for the prevention and/or treatment of human lung cancer.Graphical abstractGraphical abstract for this article
       
  • Polyamine-containing etoposide derivatives as poisons of human type II
           topoisomerases: Differential effects on topoisomerase IIα and IIβ
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Alexandria A. Oviatt, Jissy A. Kuriappan, Elirosa Minniti, Kendra R. Vann, Princess Onuorah, Anna Minarini, Marco De Vivo, Neil OsheroffEtoposide is an anticancer drug that acts by inducing topoisomerase II-mediated DNA cleavage. Despite its wide use, etoposide is associated with some very serious side-effects including the development of treatment-related acute myelogenous leukemias. Etoposide targets both human topoisomerase IIα and IIβ. However, the contributions of the two enzyme isoforms to the therapeutic vs. leukemogenic properties of the drug are unclear. In order to develop an etoposide-based drug with specificity for cancer cells that express an active polyamine transport system, the sugar moiety of the drug has been replaced with a polyamine tail. To analyze the effects of this substitution on the specificity of hybrid molecules toward the two enzyme isoforms, we analyzed the activity of a series of etoposide-polyamine hybrids toward human topoisomerase IIα and IIβ. All of the compounds displayed an ability to induce enzyme-mediated DNA cleavage that was comparable to or higher than that of etoposide. Relative to the parent drug, the hybrid compounds displayed substantially higher activity toward topoisomerase IIβ than IIα. Modeling studies suggest that the enhanced specificity may result from interactions with Gln778 in topoisomerase IIβ. The corresponding residue in the α isoform is a methionine.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of Complex I inhibitor R419 and its
           derivatives as anticancer agents in HepG2 cells
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Yaping Huang, Geng Sun, Pengfei Wang, Rui Shi, Yanchun Zhang, Xiaoan Wen, Hongbin Sun, Caiping ChenIn this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50 = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50 = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.Graphical abstractIn this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50 = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50 = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.Graphical abstract for this article
       
  • The improvement of lysosome targetability with oligoethyleneoxy chains
           linked benzo[a]phenoxazine
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Wei-Jin Zhu, Jin-Yun Niu, Ru Sun, Yu-Jie Xu, Jian-Feng GeIn order to improve lysosome targetability of probes, fluorescent probes based on benzo[a]phenoxazine attaching different length oligoethyleneoxy chains were designed and prepared. Probes 2a–c containing N-pyridineium-3-yl exhibited almost ON-OFF near-infrared emission responses at 697–701 nm from pH 2.8 to 7.2, and the calculated pKa values of 2a–c were 4.90, 4.92 and 5.03 respectively. More importantly, fluorescent imaging experiments indicated that probes 2a–c were all lysosome biomarkers for Ges-1 and HeLa cells, which was because the introduction of oligoethyleneoxy groups improved the biocompatibility of probes, so that the probes 2a–c were better transported to lysosomes via the endocytosis pathway of the cells. Moreover, the probe 2a was selected as a representative, which not only showed good reversibility and selectivity, but used to successfully image lysosomal pH increases induced by chloroquine.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of a [18F]formyl–Met–Leu–Phe derivative: A
           positron emission tomography imaging probe for bacterial infections
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Hiroyuki Kimura, Saki Yamauchi, Hidekazu Kawashima, Kenji Arimitsu, Yusuke Yagi, Yuji Nakamoto, Kaori Togashi, Masahiro Ono, Hideo SajiThe tripeptide formyl–Met–Leu–Phe (fMLF) is a prototype of N-formylated chemotactic peptides for neutrophils owing to its ability to bind and activate the G protein-coupled formyl peptide receptor (FPR). Here, we developed an 18F-labeled fMLF derivative targeting FPR as a positron emission tomography (PET) imaging probe for bacterial infections. The study demonstrates that the fMLF derivative fMLFXYk(FB)k (X = Nle) has a high affinity for FPR (Ki = 0.62 ± 0.13 nM). The radiochemical yield and purity of [18F]fMLFXYk(FB)k were 16% and>96%, respectively. The in vivo biodistribution study showed that [18F]fMLFXYk(FB)k uptake was higher in the bacterial infected region than in the non-infected region. We observed considerably higher infection-to-muscle ratio of 4.6 at 60 min after [18F]fMLFXYk(FB)k injection. Furthermore, small-animal PET imaging studies suggested that [18F]fMLFXYk(FB)k uptake in the bacterial infected region was clearly visualized 60 min after injection.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide
           derivatives containing fused ring moieties
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Apeng Wang, Guocheng Huang, Bin Wang, Kai Lv, Hongjian Wang, Zeyu Tao, Mingliang Liu, Huiyuan Guo, Yu LuWe report herein the design, synthesis and antimycobacterial activity of 3,5-dinitrobenzamide derivatives containing fused ring moieties. Results reveal that many of the target compounds have considerable in vitro antitubercular activity. Especially, N-((2-(4-fluorophenyl)/N-((2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquilin-6-yl)methyl)-3,5-dinitrobenzamides 18a and 20e exhibit potent MIC values of 0.056–0.078 μg/mL against both drug-sensitive Mycobacterium tuberculosis (MTB) H37Rv strain and two clinically isolated multidrug-resistant MTB (MDR-MTB) strains, opening a new direction for further SAR studies.Graphical abstractGraphical abstract for this article
       
  • Discovery of potent, highly selective covalent irreversible BTK inhibitors
           from a fragment hit
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Hui Qiu, Lesley Liu-Bujalski, Richard D Caldwell, Ariele Viacava Follis, Anna Gardberg, Andreas Goutopoulos, Roland Grenningloh, Jared Head, Theresa Johnson, Reinaldo Jones, Igor Mochalkin, Federica Morandi, Constantin Neagu, Brian ShererBruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of novel thiadiazole-thiazolone hybrids as potential
           inhibitors of the human mitotic kinesin Eg5
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Samukelisiwe Pretty Khathi, Balakumar Chandrasekaran, Sivanandhan Karunanidhi, Chuin Lean Tham, Frank Kozielski, Nisar Sayyad, Rajshekhar KarpoormathA novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2 µM and 20.2 µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.Graphical abstractGraphical abstract for this article
       
  • Preclinical comparison study between [18F]fluoromethyl-PBR28 and its
           deuterated analog in a rat model of neuroinflammation
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Byung Seok Moon, Jae Ho Jung, Hyun Soo Park, Marialessandra Contino, Nunzio Denora, Byung Chul Lee, Sang Eun KimWe designed and synthesized deuterium-substituted [18F]fluoromethyl-PBR28 ([18F]1-d2) as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability. The comparison studies between [18F]fluoromethyl-PBR28 ([18F]1) and its deuterate analog ([18F]1-d2) were investigated in terms of in vitro binding affinity, lipophilicity and in vivo stability. In addition, the accuracies of both radioligands were determined by comparing the PET imaging data in the same LPS-induced neuroinflammation rat model. Both aryloxyanilide analogs showed similar lipophilicity and in vitro affinity for TSPO. However, [18F]1-d2 provided significantly lower femur uptake than [18F]1 (1.5 ± 1.2 vs. 4.1 ± 1.7%ID/g at 2 h post-injection) in an ex vivo biodistribution study. [18F]1-d2 was also selectively accumulated in the inflammatory lesion with the binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND = 3.17 ± 0.48), in a LPS-induced acute neuroinflammation rat model, comparable to that of [18F]1 (BPND = 2.13 ± 0.51). These results indicate that [18F]1-d2 had higher in vivo stability, which resulted in an enhanced target-to-background ratio compared to that induced by [18F]1.Graphical abstractThe comparison studies of brain PET between [18F]fluoromethyl-PBR28 ([18F]1) and its deuterate analog ([18F]1-d2) were investigated in the same LPS-induced neuroinflammation rat model as a novel translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability.Graphical abstract for this article
       
  • Design, characterization, and in vitro antiproliferative efficacy of
           gemcitabine conjugates based on carboxymethyl glucan
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Lu Ma, Yuancai Chen, Xude Wang, Mingzhou Xiong, Yuanyuan Sun, Xiaoshu Zhang, Yuqing ZhaoGemcitabine (GEM) is widely used in clinical practice in the treatment of cancer and several other solid tumors. Nevertheless, the antitumor effect of GEM is partially prevented by some limitations including short half life, and lack of tumor localizing. Carboxymethyl glucan (CMG), a carboxymethylated derivative of β-(1-3)-glucan, shows biocompatibility and biodegradability as well as a potential anticarcinogenic effect. To enhance the antiproliferative activity of GEM, four water soluble conjugates of GEM bound to CMG via diverse amino acid linkers were designed and synthesized. 1H NMR, FT IR, elementary analysis and RP-HPLC chromatography were employed to verify the correct achievement of the conjugates. In vitro release study indicated that conjugates presented slower release in physiological buffer (pH 7.4) than acidic buffer (pH 5.5) mimicking the acidic tumor microenvironment. Moreover, A549, HeLa and Caco-2 cancer cell lines were used to evaluate the in vitro cytotoxicity of conjugates and the results showed that binding GEM to CMG significantly enhanced antiproliferative activity of GEM on A549 cells. Therefore, these conjugates may be potentially useful as a delivery vehicle in cancer therapy and worthy of further study on structure-activity relationship and antiproliferative activity in vitro and in vivo, especially for lung tumor.Graphical abstractGraphical abstract for this article
       
  • Synthesis and antimicrobial studies of hydrazone derivatives of
           4-[3-(2,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid and
           4-[3-(3,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): A.A. Zakeyah, J. Whitt, C. Duke, D.F. Gilmore, D.G. Meeker, M.S. Smeltzer, M.A. AlamMicrobial resistance to antibiotics is an unresolved global concern, which needs urgent and coordinated action. One of the guidelines of the Centers for Disease Control and Preventions (CDC) to combat antibiotic resistance is the development of new antibiotics to treat drug-resistant bacteria. In our effort to find new antibiotics, we report the synthesis and antimicrobial studies of 30 new pyrazole derivatives. These novel molecules have been synthesized by using readily available starting materials and benign reaction conditions. Some of these molecules have shown activity with MIC values as low as 0.78 µg/mL against four bacterial strains; Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Acinetobacter baumannii. Furthermore, active molecules are non-toxic to mammalian cell line.Graphical abstract for this articleGraphical abstractGraphical abstract for this article
       
  • Structure-based design, synthesis, and evaluation of structurally rigid
           donepezil analogues as dual AChE and BACE-1 inhibitors
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Moustafa T. Gabr, Mohammed S. Abdel-RaziqA new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10–13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7 nM) and BACE-1 inhibition (IC50 value of 13.1 nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.Graphical abstractStructurally rigid donepezil hybrid as a potent dual AChE/BACE-1 inhibitor.Graphical abstract for this article
       
  • Diazirine-containing tag-free RNA probes for efficient RISC-loading and
           photoaffinity labeling of microRNA targets
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Kosuke Nakamoto, Yukihiro Akao, Yoshihito UenoWe designed and synthesized a photo-reactive and tag-free RNA probe for the identification of microRNA (miRNA) targets. To synthesize the RNA probe, we designed a novel nucleoside analog 1-O-[3-ethynyl-5-(3-trifluoromethyl-3H-diazirine-3-yl)]benzyl-β-d-ribofuranose containing aryl trifluoromethyl diazirine and ethynyl moieties. The RNA probe containing this analog was observed to form crosslinks with complementary RNA by UV irradiation and was rapidly tagged by Cu-catalyzed azide alkyne cycloaddition (CuAAC). In addition, the tag-free and photo-reactive miRNA-145 probe showed comparable gene silencing activity to that of unmodified miRNA-145. Therefore, miRNA probes containing the nucleoside analog are promising candidates for the identification of target mRNAs of miRNAs.Graphical abstractGraphical abstract for this article
       
  • Expanding chemical space of DNA-binding molecules with three base-binding
           units
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Yuki Yagi, Haruo Aikawa, Takeshi Yamada, Kazuhiko NakataniA new molecule NC3-3 designed to expand chemical space of parent molecule NCD by adding the third base-binding unit was reported. NC3-3 bound to the G-G mismatch in the 5′-CGG-3′/5′-CGG-3′ motif but not to that in 5′-GGC-3′/5′-GGC-3′. This binding selectivity is similar to that reported for NCD. Fluorimetric screening of NCD and NC3-3 to dsDNA library containing yGw/xGz motifs showed that NC3-3 still kept the sequence selectivity as we observed for NCD-binding. The third naphthyridine heterocycle in NC3-3 affected the mode of the binding, but a little effect on the sequence selectivity.Graphical abstractGraphical abstract for this article
       
  • New lead elements for histamine H3 receptor ligands in the
           pyrrolo[2,3-d]pyrimidine class
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Christian Espinosa-Bustos, Annika Frank, Sandra Arancibia-Opazo, Cristian O. Salas, Angelica Fierro, Holger StarkThis work describes the microwave assisted synthesis of twelve novel histamine H3 receptor ligands. They display pyrrolo[2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R and H4R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro and in docking studies. The combination of a rigidized H3R warhead and the pyrrolo[2,3-d]pyrimidine scaffold resulted in selective activity at the H3 receptor with a pKi value of 6.90 for the most potent compound. A bipiperidine warhead displayed higher affinity than a piperazine or morpholine motif, while a naphthyl moiety in the arbitrary region increased affinity compared to a phenyl derivative. The compounds can be starting points for novel, simply synthesized histamine H3 receptor ligands.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of panaxatriol derivatives as Na+, K+-ATPase
           inhibitors
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Qiong Wu, Peng Chen, Guangzhong Tu, Meng Li, Bowen Pan, Yan Guo, Jinbi Zhai, Hongzheng FuPanaxatriol, a triterpene bearing a steroid-like structure similar to cardiac glycosides, was presumed to share the same bioactivity with cardiac glycosides, and may be a potential Na+, K+-ATPase inhibitor. In this paper, a series of panaxatriol derivatives were synthesized and evaluated for Na+, K+-ATPase inhibitory activities. The results of biological tests showed that more than half of the synthesized derivatives presented increased inhibitory activities compared with panaxatriol. Of these compounds, 13a with a 3, 4-seco skeleton showed the most potent inhibitory activity, which was equal to that of the standard drug digoxin. To understand the binding mode of the most active compound, molecular docking study of 13a with Na+, K+-ATPase was conducted. Therefore, 13a may serve as a new lead compound for the development of novel Na+, K+-ATPase inhibitors.Graphical abstractGraphical abstract for this article
       
  • Lipid accumulation inhibitory activities of novel isoxazole-based
           
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Rongmao Qiu, Guoshun Luo, Xinyu Li, Fan Zheng, Haolin Li, Jin Zhang, Qidong You, Hua XiangIn continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.Graphical abstractGraphical abstract for this article
       
  • Development of a new thiol-reactive prosthetic group for site-specific
           labeling of biomolecules with radioactive iodine
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Ha Eun Shim, Sajid Mushtaq, Lee Song, Chang Heon Lee, Hyosun Lee, Jongho JeonIn this report, we describe the radiosynthesis of a new thiol-targeting prosthetic group for efficient radioactive iodine labeling of biomolecules. Radioiodination using the precursor 3 was performed to obtain 125I-labeled tetrazole 4b with high radiochemical yield (73%) and radiochemical purity. Using the radiolabeled 4b, a single free cysteine containing peptide and human serum albumin were labeled with 125I in modest-to-good radiochemical yields (65–99%) under mildly reactive conditions. A biodistribution study of [125I]7 in normal ICR mice exhibited lower thyroid uptake values than those of 125I-labeled human serum albumin prepared via a traditional radiolabeling method. Thus, [125I]7 could be employed as an effective radiotracer for molecular imaging and biodistribution studies. The results clearly demonstrate that 4b has the potential to be effectively implemented as a prosthetic group in the preparation of radiolabeled biomolecules.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s):
       
  • Recent advances in peptidomimetics antagonists targeting estrogen receptor
           α-coactivator interaction in cancer therapy
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Weirong Qin, Mingsheng Xie, Xuan Qin, Qi Fang, Feng Yin, Zigang LiEstrogen receptor α (ERα) is a crucial target for ERα positive breast cancer treatment. Previous drug discovery efforts were focused on developing inhibitors that targeted the canonical ligand binding pockets of the ligand binding domain (LBD) of ERα. However, significant percentage of patients developed cancer relapse with drug-resistance. ERα peptidomimetic modulators have been considered as promising treatments for drug resistant breast cancers as they are targeting ERα-coactivator interacting interface instead of the ligand binding pocket of ERα. Herein, we reviewed the recent development of ERα peptidomimetics antagonists.Graphical abstractGraphical abstract for this article
       
  • Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering
           ahead
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Emanuela Martino, Giuseppe Casamassima, Sonia Castiglione, Edoardo Cellupica, Serena Pantalone, Francesca Papagni, Marta Rui, Angela Marika Siciliano, Simona CollinaCancer still represents a “nightmare” worldwide, causing annually millions of victims. Several antiproliferative molecules are currently used as drugs market and offer a pharmaceutical opportunity for attenuating and treating tumor manifestations. In this context, natural sources have a relevant role, since they provide the 60% of currently-used anticancer agents. Among the numerous natural products, acting via different mechanisms of action, microtubule-targeting agents (MTAs) have a high therapeutic potential, since they disrupt the abnormal cancer cell growth, interfering with the continuous mitotic division. Vinca alkaloids (VAs) are the earliest developed MTAs and approved for clinical use (Vincristine, Vinblastine, Vinorelbine, Vindesine, and Vinflunine) as agents in the treatment of hematological and lymphatic neoplasms. Here, we review the state-of-art of VAs, discussing their mechanism of action and pharmacokinetic properties and highlighting their therapeutic relevance and toxicological profile. Additionally, we briefly disclosed the technological approaches faced so far to ameliorate the pharmacological properties, as well as to avoid the drug resistance. Lastly, we introduced the recent advances in the discovery of new derivatives.Graphical abstractGraphical abstract for this article
       
  • Recent applications of machine learning in medicinal chemistry
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s): Jane Panteleev, Hua Gao, Lei JiaIn recent decades, artificial intelligence and machine learning have played a significant role in increasing the efficiency of processes across a wide spectrum of industries. When it comes to the pharmaceutical and biotechnology sectors, numerous tools enabled by advancement of computer science have been developed and are now routinely utilized. However, there are many aspects of the drug discovery process, which can further benefit from refinement of computational methods and tools, as well as improvement of accessibility of these new technologies. In this review, examples of recent developments in machine learning application are described, which have the potential to impact different parts of the drug discovery and development flow scheme. Notably, new deep learning-based approaches across compound design and synthesis, prediction of binding, activity and ADMET properties, as well as applications of genetic algorithms are highlighted.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 September 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 17Author(s):
       
  • Design and Synthesis of Tetrahydropyridopyrimidine Based Toll-Like
           Receptor (TLR) 7/8 Dual Agonists
    • Abstract: Publication date: Available online 16 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): David C. McGowan, Florence Herschke, Mourad D. Khamlichi, Mari Luz Rosauro, Sara M. Pérez Benedicto, Frederik Pauwels, Bart Stoops, Vineet Pande, Annick Scholliers, Bertrand Van Schoubroeck, Wendy Mostmans, Kris Van Dijck, Tine Thoné, Helen Horton, Gregory Fanning, Tim H.M. Jonckers, Pierre RaboissonIn a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.Graphical abstractGraphical abstract for this article
       
  • Identification of potent RORβ modulators: Scaffold variation
    • Abstract: Publication date: Available online 16 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Christelle Doebelin, Rémi Patouret, Ruben D. Garcia-Ordonez, Mi Ra Chang, Venkatasubramanian Dharmarajan, Scott Novick, Anthony Ciesla, Sean Campbell, Laura A. Solt, Patrick R. Griffin, Theodore M. KameneckaWe sought to develop RORβ-selective probe molecules in order to investigate the function of the receptor in vitro and in vivo and its role in the pathophysiology of disease. To accomplish this, we modified a potent dual RORβ/RORγ inverse agonist from the primary literature with the goal of improving selectivity for RORβ vs RORγ. Truncation of the Western portion of the molecule ablated activity at RORγ and led to a potent series of RORβ modulators. Continued exploration of this series investigated alternate replacement cores for the aminothiazole ring. Numerous suitable replacements were found during the course of our SAR investigations and are reported hereinGraphical abstractGraphical abstract for this article
       
  • New piperidine-based derivatives as sigma receptor ligands. Synthesis and
           pharmacological evaluation
    • Abstract: Publication date: Available online 15 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Daniele Zampieri, Maurizio Romano, Renzo Menegazzi, Maria Grazia MamoloThe sigma receptor (σR) family has been considered mysterious for a long time. In fact, the σ2R subtype has been cloned only recently, revealing its identity as TMEM97, a NPC1-binding protein involved in cholesterol biosynthesis and implicated in the pathogenesis of cancer and neurologic disorders. With the aim of developing new chemical entities gifted with σR affinity, herein we report the design and synthesis of new piperidine-based alkylacetamide derivatives with mixed affinity towards both σ1 and σ2R subtypes.Graphical abstractGraphical abstract for this article
       
  • Discovery of novel spiro[chromane-2,4’-piperidine] derivatives as potent
           and orally bioavailable G-protein-coupled receptor 119 agonists
    • Abstract: Publication date: Available online 15 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Tomoaki Koshizawa, Toshiharu Morimoto, Gen Watanabe, Tomoaki Fukuda, Nao Yamasaki, Sumihiko Hagita, Yoshikazu Sawada, Ayumu Okuda, Kimiyuki Shibuya, Tadaaki OhgiyaHerein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4’-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC50 = 369 nM, Emax = 82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC50 = 54 nM, Emax = 181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3 mg/kg in a dose-dependent manner.Graphical abstractGraphical abstract for this article
       
  • Development of a New Doubly-Labeled Fluorescent Ceramide Probe for
           Monitoring the Metabolism of Sphingolipids in Living Cells
    • Abstract: Publication date: Available online 15 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yabin Wang, Junya Kasahara, Kazuyuki Yamagata, Hiroyuki Nakamura, Toshihiko Murayama, Noriyuki Suzuki, Atsushi NishidaA new ceramide analog, 1, containing two fluorescent dyes, NBD in the N-acyl part and KFL5 in the alkyl part, was synthesized. The fluorescence from both NBD and KFL5 was detected in living cells in a time-dependent manner. A multi-wavelength fluorescence detector was used to detect ceramide metabolites including sphingosine, sphingosine-1-phosphate, glucosylceramide, and sphingomyelin, which are connected to the fluorescent dyes, simultaneously in a single TLC plate.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of small molecule-conjugated photoaffinity nanoprobes
           for a streamlined analysis of binding proteins
    • Abstract: Publication date: Available online 14 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kaori Sakurai, Amane Kato, Kensuke AdachiWe designed and synthesized a set of photoaffinity nanoprobes, which multivalently display a small molecule ligand and a photoreactive group on gold nanoparticles. Due to the typically hydrophobic nature of these two functional groups, a hydrophilic spacer was additionally introduced to co-functionalize the nanoprobes to maintain their dispersibility in aqueous buffer solutions. Photoaffinity labeling studies using the nanoprobes composed of different ratios of three functional groups showed that including high density of the spacer group attenuates crosslinking efficiency. Comparative analysis of the reactivity among three major photoreactive groups suggested that unlike in the context of conventional photoaffinity probes, arylazide group enables the most selective crosslinking of a model small molecule binding protein.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “A cascade synthesis, in vitro cholinesterases inhibitory
           activity and docking studies of novel Tacrine-pyranopyrazole
           derivatives” [Bioorg. Med. Chem. Lett. 28 (14) (2018) 2481–2484]
    • Abstract: Publication date: Available online 14 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Chamseddine Derabli, Imen Boualia, Ahmed B. Abdelwahab, Raouf Boulcina, Chawki Bensouici, Gilbert Kirsch, Abdelmadjid Debache
       
  • Novel inhibitors of As(III) S-adenosylmethionine methyltransferase (AS3MT)
           identified by virtual screening
    • Abstract: Publication date: Available online 14 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Roland W. Bürli, Huijun Wei, Glen Ernst, Abigail Mariga, Ian M. Hardern, Kara Herlihy, Alan J. Cross, Steven S. Wesolowski, Hongming Chen, Ronald D.G. McKay, Daniel R. Weinberger, Nicholas J. Brandon, James C. BarrowDue to increased interest in As(III) S-adenosylmethionine methyltransferase (AS3MT), a search for chemical probes that can help elucidate function was initiated. A homology model was built based on related enzymes, and virtual screening produced 426 potential hits. Evaluation of these compounds in a functional enzymatic assay revealed several modest inhibitors including an O-substituted 2-amino-3-cyano indole scaffold. Two iterations of near neighbor searches revealed compound 5 as a potent inhibitor of AS3MT with good selectivity over representative methyltransferases DOT1L and NSD2 as well as a representative set of diverse receptors. Compound 5 should prove to be a useful tool to investigate the role of AS3MT and a potential starting point for further optimization.Graphical abstractGraphical abstract for this article
       
  • New β-lactam – Tetramic acid hybrids show promising
           antibacterial activities
    • Abstract: Publication date: Available online 17 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Philip T. Cherian, Martin N. Cheramie, Ravi K.R. Marreddy, Dinesh M. Fernando, Julian G. Hurdle, Richard E. Leeβ-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25 μg/mL and 3.13 μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ2 cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.Graphical abstractGraphical abstract for this article
       
  • The design, synthesis, and evaluation of organic dithienopyrrole-based
           D-π-A dyes for use as sensitizers in photodynamic therapy
    • Abstract: Publication date: Available online 17 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shinichiro Fuse, Keisuke Matsumura, Miori Takizawa, Shinichi Sato, Hiroyuki NakamuraDithienopyrrole-based organic dyes that combine an electron-donating moiety (D), a π-conjugated bridge moiety (π), and an electron-accepting moiety (A) were designed and synthesized in short steps by previously developed one-pot Suzuki-Miyaura coupling approach. Absorption wavelengths of the dyes were readily tuned by altering the D and A moieties. The use of a strongly electron-withdrawing cyanopyridone acceptor enabled NIR absorption. A synthesized sensitizer, 2j, exerted potent phototoxicity mainly via a Type I mechanism in cells. A nitrogen atom in the dithienopyrrole ring serves as a connecting point for the introduction of functional building blocks that can improve the properties of sensitizers, which makes this D-π-A sensitizer a valuable template for the further development of sensitizers.Graphical abstractGraphical abstract for this article
       
  • Effective cancer therapy based on selective drug delivery into cells
           across their membrane using receptor-mediated endocytosis
    • Abstract: Publication date: Available online 11 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Toshihiko TashimaCancer is one of the major causes of death globally. The current treatment options are insufficient, leading to unmet medical needs in cancer treatment. Off-target side effects, multidrug resistance, selective distribution to cancerous tissues, and cell membrane permeation of anti-cancer agents are critical problems to overcome. There is a method to solve these problems by using receptor-mediated endocytosis (RME). It is well known that proteins such as integrin, HER2, EGFR, or other cancer biomarkers are specifically overexpressed on the surface of target cancer cells. By taking advantage of such specific receptors, payloads can be transported into cells through endocytosis using a conjugate composed of the corresponding ligands connected to the payloads by an appropriate linker. After RME, the payloads released by endosomal escape into the cytoplasm can exhibit the cytotoxic activity against cancer cells. Cell-penetrating peptides (CPPs), tumor-homing peptides (THPs), and monoclonal antibodies (mAbs) are utilized as ligands in this system. Antibody drug conjugates (ADCs) based on RME have already been used to cure cancer. In addition to the canonical conjugate method, nanocarriers for spontaneous accumulation in cancer tissue due to enhanced permeability and retention (EPR) effect are extensively used. In this review, I introduce the possibilities and advantages of drug design and development based on RME for the treatment of cancer.Graphical abstractGraphical abstract for this article
       
  • Introduction
    • Abstract: Publication date: Available online 10 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Matthew D. Disney, Kim D. Janda
       
  • Hemin-incorporated nanoflowers as enzyme mimics for colorimetric detection
           of foodborne pathogenic bacteria
    • Abstract: Publication date: Available online 10 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Kui-Yu Wang, Sheng-Jun Bu, Chuan-Jing Ju, Chang-Tian Li, Zhong-Yi Li, Ye Han, Cheng-You Ma, Cheng-Yu Wang, Zhuo Hao, Wen-Sen Liu, Jia-Yu WanRapid, sensitive and point-of-care detection of foodborne pathogenic bacteria is essential for food safety. In this study, we found that hemin-concanavalin A hybrid nanoflowers (HCH nanoflowers), as solid mimic peroxidase, could catalyze oxidation of 2,2’-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) in the presence of H2O2 to a green-colored product. HCH nanoflowers, integrating the essential functions of both biological recognition and signal amplification, meet the requirements of signal labels for colorimetric immunoassay of bacteria. In view of the excellent peroxidase mimetic catalytic activity of HCH nanoflowers, a colorimetric biosensing platform was newly constructed and applied for sensitive detection of foodborne Escherichia coli O157:H7 (E.coli O157:H7). The corresponding detection limits was as low as 4.1 CFU/mL with wide linear ranges (101−106 CFU/mL).Graphical abstractGraphical abstract for this article
       
  • Inhibition of the LOX enzyme family members with old and new ligands.
           Selectivity analysis revisited
    • Abstract: Publication date: Available online 6 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): István Hajdú, József Kardos, Balázs Major, Gabriella Fabó, Zsolt Lőrincz, Sándor Cseh, György DormánLysyl oxidase (LOX) enzymes as potential drug targets maintain constant attention in the therapy of fibrosis, cancer and metastasis. In order to measure the inhibitory activity of small molecules on the LOX enzyme family members a fluorometric activity screening method was developed. During assay validation, previously reported non-selective small inhibitor molecules (BAPN, MCP-1, thiram, disulfiram) were investigated on all of the major LOX enzymes. We confirmed that MCP-1, thiram, disulfiram are in fact pan-inhibitors, while BAPN inhibits only LOX-like enzymes (preferably LOX-like-protein-2, LOXL2) in contrast to the previous reports. We measured the LOX inhibitory profile of a small targeted library generated by 2D ligand-based chemoinformatics methods. Ten hits (10.4% hit rate) were identified, and the compounds showed distinct activity profiles. Potential inhibitors were also identified for LOX-like-protein-3 (LOXL3) and LOX-like-protein-4 (LOXL4), that are considered as emerging drug targets in the therapy of melanoma and gastric cancer.Graphical abstractGraphical abstract for this article
       
  • Discovery and structure-activity-relationship study of novel imidazole
           cyclopropyl amine analogues for mutant isocitric dehydrogenase 1 (IDH1)
           inhibitors
    • Abstract: Publication date: Available online 4 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Qiangang Zheng, Ziqi Chen, Huixin Wan, Shuai Tang, Yan Ye, Yuan Xu, Lei Jiang, Jian Ding, MeiyuGeng, Min Huang, Ying HuangThe discovery and optimization of imidazole cyclopropyl amime analogues as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, moderate liver microsome stability and PK properties.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of 4-chloro-2H-thiochromenes
           featuring nitrogen-containing side chains as potent antifungal agents
    • Abstract: Publication date: Available online 19 June 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Dan-Jiao Wang, Zhuang Hou, Hang Xu, Ran An, Xin Su, Chun GuoA series of 4-chloro-2H-thiochromenes featuring nitrogen-containing side chains were designed, synthesized and tested in vitro for their antifungal activities. The results of preliminary antifungal tests showed that most target compounds exhibited good inhibitory activities against Candida albicans, Cryptococcus neoformans, Candida tropicalis. Notably, compounds 10e and 10y showed most potent activity in vitro against a variety of fungal pathogens with low MICs. Meanwhile, low cytotoxicity on mammalian cells has been observed for compounds 10e and 10y in the tested concentrations by the MTT assay. Therefore, the 4-chloro-2H-thiochromenes with nitrogen-containing groups provide new lead structures in the search for novel antifungal agents.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of an 18F-labeled boramino acid analog of
           aminosuberic acid for PET imaging of the antiporter system xC −
    • Abstract: Publication date: Available online 8 June 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Milena Čolović, Etienne Rousseau, Zhengxing Zhang, Joseph Lau, Chengcheng Zhang, Hsiou-Ting Kuo, Hua Yang, Paul Schaffer, François Bénard, Kuo-Shyan LinIn this study, we synthesized 18F-ASu-BF3, a close boramino acid analog of 5-[18F]fluoro-aminosuberic acid (18F-ASu), via 18F-19F isotope exchange reaction and evaluated its potential for imaging with positron emission tomography (PET). 18F-ASu-BF3 was stable in mouse plasma and taken up into PC3 prostate cancer cells via the system xC− amino acid transporter. The continuous use of isoflurane for anesthesia during dynamic imaging acquisition slowed down the excretion of 18F-ASu-BF3 and enabled visualization of PC3 tumor xenografts in mice. In contrast, no tumor visualization was observed from static images of 18F-BF3-ASu due to its rapid renal excretion mediated in part by the organic anion transporter. Our data indicate that the pharmacokinetics of amino acids could be altered after being converted into their boramino acid analogs. Therefore, care should be taken when using the boramino acid strategy to design and prepare 18F-labeled tracers for imaging amino acid transporters/receptors with PET.Graphical abstractGraphical abstract for this article
       
  • Nav1.7 inhibitors for the treatment of chronic pain
    • Abstract: Publication date: Available online 12 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Steven J. McKerrall, Daniel P. Sutherlin The voltage gated sodium channel Nav1.7 plays an essential role in the transmission of pain signals. Strong human genetic validation has motivated extensive efforts to discover potent, selective, and efficacious Nav1.7 inhibitors for the treatment of chronic pain. This digest will introduce the structure and function of Nav1.7 and highlight the wealth of recent developments on a diverse array of Nav1.7 inhibitors, including optimization of their potency, selectivity, and PK/PD relationships.Graphical abstractGraphical abstract for this article
       
  • Discovery and biological activity of computer-assisted drug designed Akt
           pathway inhibitors
    • Abstract: Publication date: Available online 9 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nne E. Uko, Osman F. Güner, Lillie M.A. Barnett, Diane F. Matesic, J. Phillip Bowen The P13K/Akt pathway is a growth-regulating cellular signaling pathway that is over-activated in numerous human cancers. A novel series of Akt pathway inhibitors were identified using iterative pharmacophore modeling, energy-based calculations, and property predictions of known Akt inhibitors. Inhibitory effects on activation of Akt and growth of human neoplastic cells are reported. Results show variable inhibitory effects of three selected compounds on Akt phosphorylation at a key activation site, and on proliferation of tumorigenic cells. We identify one lead compound with potent inhibitory activity on both human carcinoma cell proliferation and Akt activation.Graphical abstractGraphical abstract for this article
       
  • Novel Fluorescence Probes based on the Chalcone Scaffold for In vitro
           Staining of β-Amyloid Plaques
    • Abstract: Publication date: Available online 8 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hiroyuki Watanabe, Hideo Saji, Masahiro Ono The β -amyloid (A β) plaque is one of the neuropathological hallmarks in the Alzheimer’s disease brain. The detection of A β plaques with fluorescent probes is useful for preclinical studies of Alzheimer’s disease. In this study, we developed four novel fluorescence probes based on chalcone scaffold. In an in vitro binding study, all FCH derivatives showed moderate binding affinity for A β (1-42) aggregates (Ki = 72 – 113 nM). The fluorescence intensities of FCH-3 and FCH-4 dramatically changed in the presence of A β (1-42) aggregates (6.7 and 14.2 fold), but the changes of FCH-1 and FCH-2 were minor (2.0 and 2.4 fold). In a fluorescence staining study using Tg2576 mouse brain sections, FCH-3 and FCH-4 clearly visualized A β plaques, but FCH-1 and FCH-2 did not stain. Taken together, all FCH derivatives could bind to A β aggregates, but only FCH-3 and FCH-4 may be useful fluorescence probes for in vitro staining of A β plaques.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s):
       
  • Novel highly selective inhibitors of ubiquitin specific protease 30
           (USP30) accelerate mitophagy
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Arthur F. Kluge, Bharat R. Lagu, Pranab Maiti, Mahaboobi Jaleel, Michael Webb, Jyoti Malhotra, Ashley Mallat, P. Akhila Srinivas, James E. Thompson Mitophagy is one of the processes that cells use to maintain overall health. An E3 ligase, parkin, ubiquitinates mitochondrial proteins prior to their degradation by autophagasomes. USP30 is an enzyme that de-ubiquitinates mitochondrial proteins; therefore, inhibiting this enzyme could foster mitophagy. Herein, we disclose the structure–activity relationships (SAR) within a novel series of highly selective USP30 inhibitors. Two structurally similar compounds, MF-094 (a potent and selective USP30 inhibitor) and MF-095 (a significantly less potent USP30 inhibitor), serve as useful controls for biological evaluation. We show that MF-094 increases protein ubiquitination and accelerates mitophagy.Graphical abstractGraphical abstract for this article
       
  • Studies directed toward the asialoglycoprotein receptor mediated delivery
           of 5-fluoro-2′-deoxyuridine for hepatocellular carcinoma
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Lorena Rico, Michael E. Østergaard, Melanie Bell, Punit P. Seth, Stephen Hanessian The anticancer nucleoside 5-fluoro 2′-deoxyuridine-5′-phosphate (5-FdU-P) was attached via an amide chain linker to a triantennary GalNAc cluster as a means to deliver the drug to hepatic cells that recognize the amino sugar units.Graphical abstractGraphical abstract for this article
       
  • Synthesis of novel imidazopyridines and their biological evaluation as
           potent anticancer agents: A promising candidate for glioblastoma
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Dilek Güçlü, Burak Kuzu, İsrafil Tozlu, Filiz Taşpınar, Hande Canpınar, Mehmet Taşpınar, Nurettin Menges Novel imidazopyridine derivatives were synthesized according to a very simple protocol and then subjected to cytotoxicity testing against LN-405 cells. Two of the compounds exhibited antiproliferative effects on LN-405 cells at 10 and 75 µM and were selected as lead compounds for further study. Safety experiment for lead compounds on WS1 was carried out and IC50 values were calculated as 480 and 844 µM. LN-405 cell line were incubated with the lead compounds and then tested for DNA damage by comet assay and effects on cell cycle using flow cytometry. The results of these two tests showed that both lead compounds affected the G0/G1 phase and did not allow the cells to reach the synthesis phase. The log BB (blood–brain barrier) and Caco-2 permeability of the synthesized molecules were calculated and it was shown that imidazopyridine derivatives taken orally are likely to pass through gastrointestinal membrane and the blood–brain barrier.Graphical abstractGraphical abstract for this article
       
  • Discovery and characterization of
           N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold
           as mGlu4 positive allosteric modulators that mitigate CYP1A2 induction
           liability
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Darren W. Engers, Sean R. Bollinger, Julie L. Engers, Joseph D. Panarese, Megan M. Breiner, Alison Gregro, Anna L. Blobaum, Joanne J. Bronson, Yong-Jin Wu, John E. Macor, Alice L. Rodriguez, Rocio Zamorano, P. Jeffrey Conn, Craig W. Lindsley, Colleen M. Niswender, Corey R. Hopkins Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).Graphical abstractGraphical abstract for this article
       
  • Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of
           JAK2 and histone deacetylase 6 (HDAC6)
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Lianbin Yao, Pondy Murugappan Ramanujulu, Anders Poulsen, Sten Ohlson, Brian W. Dymock Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41 pM and a sub-nanomolar IC50 against HDAC6 of 200 pM. Binding models show a good fit into both JAK2 and HDAC6.Graphical abstractGraphical abstract for this article
       
  • Fluorescent-fipronil: Design and synthesis of a stable conjugate
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Adriano Aloisi, Adrien Franchet, Dominique Ferrandon, Alberto Bianco, Cécilia Ménard-Moyon Fipronil is a phenyl pyrazole molecule widely used across the world as both insecticide and veterinary drug. The main goal of this work was to synthesize a fluorescently labeled fipronil derivative for cellular imaging without affecting its intrinsic properties. We selected fluorescein as fluorescent probe and we investigated different strategies for stable chemical ligation between both entities, such as thiourea and direct peptide bond. While thiourea bond displayed low stability, direct peptide bond was difficult to achieve due to problems of steric hindrance. The best result was obtained by conjugation using click chemistry, which allowed to obtain fipronil stably labeled with the fluorescent probe.Graphical abstractGraphical abstract for this article
       
  • Design and synthesis of bridged piperidine and piperazine isosteres
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Gaëtan Maertens, Oscar M. Saavedra, Vito Vece, Miguel A. Vilchis Reyes, Sofiane Hocine, Esat Öney, Bertrand Goument, Olivier Mirguet, Arnaud Le Tiran, Philippe Gloanec, Stephen Hanessian We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.Graphical abstractGraphical abstract for this article
       
  • ROCK inhibitors 3: Design, synthesis and structure-activity relationships
           of 7-azaindole-based Rho kinase (ROCK) inhibitors
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Upul K. Bandarage, Jingrong Cao, Jon H. Come, John J. Court, Huai Gao, Marc D. Jacobs, Craig Marhefka, Suganthi Nanthakumar, Jeremy Green Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.Graphical abstractGraphical abstract for this article
       
  • ROCK inhibitors 2. Improving potency, selectivity and solubility through
           the application of rationally designed solubilizing groups
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Huai Gao, Craig Marhefka, Marc D. Jacobs, Jingrong Cao, Upul K. Bandarage, Jeremy Green Solubilizing groups have been frequently appended to kinase inhibitor drug molecules when solubility is insufficient for pharmaceutical development. Such groups are usually located at substitution sites that have minimal impact on target activity. In this report we describe the incorporation of solubilizing groups in a class of Rho kinase (ROCK) inhibitors that not only confer improved solubility, but also enhance target potency and selectivity against a closely related kinase, PKA.Graphical abstractGraphical abstract for this article
       
  • Phosphorus-containing isothiocyanate-derived mercapturic acids as a useful
           alternative for parental isothiocyanates in experimental oncology
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Mateusz Psurski, Łukasz Janczewski, Marta Świtalska, Anna Gajda, Tomasz M. Goszczyński, Jarosław Ciekot, Łukasz Winiarski, Józef Oleksyszyn, Joanna Wietrzyk, Tadeusz Gajda A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled 31P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mercapturic acids synthesis from the parental isothiocyanates was confirmed. All compounds were evaluated as highly active antiproliferative agents in vitro in human colon cancer cell lines (LoVo and its doxorubicin-resistant subline LoVo/DX). The cell cycle progression and caspase-3 activity analyses revealed compounds moderate activity as apoptosis inducers and their poor influence on cell cycle progression in the LoVo cells. Our results confirm that isothiocyanate-derived mercapturic acids present a reasonable alternative for the parental compounds, and can replace them in the future studies on isothiocyanates potential as anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, X-ray studies, and biological evaluation of novel BACE1
           inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Arun K. Ghosh, Koena Ghosh, Margherita Brindisi, Emma K. Lendy, Yu-Chen Yen, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D. Mesecar We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.Graphical abstractA series of BACE1 inhibitors incorporating bicyclic isoxazoline carboxamides as the P3 ligands is described. An X-ray crystal structure of 3a-bound BACE1 provided insight into the ligand-binding site interactions.Graphical abstract for this article
       
  • Discovery of novel selective GPR120 agonists with potent anti-diabetic
           activity by hybrid design
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Ren Sheng, Liu Yang, Yanchun Zhang, Enming Xing, Rui Shi, Xiaoan Wen, Heyao Wang, Hongbin Sun GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50 = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications.Graphical abstractGraphical abstract for this article
       
  • Highly selective anthraquinone-chalcone hybrids as potential antileukemia
           agents
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Tatjana Stanojković, Violeta Marković, Ivana Z. Matić, Milan P. Mladenović, Nina Petrović, Ana Krivokuća, Miloš Petković, Milan D. Joksović A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway. Treatment of K562 cells with each of these four compounds caused decrease in the expression levels of MMP2, MMP9, and VEGF, suggesting their anti-invasive, antimetastatic and antiangiogenic properties. The compounds 6g and 6v downregulated expression levels of miR-155 in K562 cells, while compounds 6e and 6u upregulated miR-155 levels in treated cells, in comparison with control cells. The structure-based 3-D QSAR models for 6f, 6e, 6i and 6l describe pro-apoptotic activity against caspase-3.Graphical abstractGraphical abstract for this article
       
  • Inducing protein-protein interactions with molecular glues
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Ye Che, Adam M. Gilbert, Veerabahu Shanmugasundaram, Mark C. Noe The drugable proteome is limited by the number of functional binding sites that can bind small molecules and respond with a therapeutic effect. Orthosteric and allosteric modulators of enzyme function or receptor signaling are well-established mechanisms of drug action. Drugs that perturb protein-protein interactions have only recently been launched. This approach is more difficult due to the extensive contact surfaces that must be perturbed antagonistically. Compounds that promote novel protein-protein interactions promise to dramatically expand opportunities for therapeutic intervention. This approach is precedented with natural products (rapamycin, FK506, sanglifehrin A), synthetic small molecules (thalidomide and IMiD derivatives) and indisulam analogues.Graphical abstractGraphical abstract for this article
       
  • Recent progress in human telomere RNA structure and function
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s): Yan Xu Human telomeric DNA is transcribed into telomeric RNA in cells. Telomeric RNA performs the fundamental biological functions such as regulation and protection of chromosome ends. This digest highlights the human telomere RNA G-quadruplex structures, telomere RNA functions, G-quadruplex-binding small molecules, and future prospects.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC continued
    • Abstract: Publication date: 15 August 2018Source: Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 15Author(s):
       
  • Design, synthesis, and activity evaluation of novel erythropoietin mimetic
           peptides
    • Abstract: Publication date: Available online 3 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Siliang Feng, Shaohua Chang, Lingdi Yan, Huajin Dong, Xiaoyu Xu, Chenhong Wang, Yuanjun Liang, Keliang Liu The approval of the erythropoietin (EPO) mimetic peptide drug peginesatide in 2012 was a breakthrough for the treatment of secondary anemia. However, due to severe allergic reactions, peginesatide was recalled a year later. In this study, 12 novel peptides were designed and synthesized by substituting specific amino acids of the monomeric peptide in peginesatide, with the aim of obtaining new EPO mimetic peptides with higher activities and lower side effects than the parent compound. Their cell proliferation activities were evaluated, and the structure-activity relationships were analyzed. Five compounds had equal cell proliferation activity to the control peptide. Among them, one compound showed a higher in vivo activity than the control peptide, with no obvious side effects.Graphical abstractGraphical abstract for this article
       
  • 2,4-Diamino-6-methylpyrimidines for the potential treatment of
           Chagas’ Disease
    • Abstract: Publication date: Available online 3 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Michael G Thomas, Manu De Rycker, Ignacio Cotillo Torrejon, John Thomas, Jennifer Riley, Daniel Spinks, Kevin D Read, Tim J Miles, Ian H Gilbert, Paul G Wyatt Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8-10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification a suitable lead for further optimisation.Graphical abstractGraphical abstract for this article
       
  • Amelioration of mechanism-based inactivation of CYP3A4 by a H-PGDS
           inhibitor
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Roy J Vaz, Yi Li, Mark Munson, Michael Elliot, Sukanthini Thurairatnam This work describes the rational amelioration of mechanism-based inactivation (MBI) of Cytochrome P450 (CYP) 3A4 in a human hematopoietic prostaglandin D synthase (hH-PGDS) inhibitor (cpd 1). We utilized metabolism reports in order to check if patterns in the metabolism of 1 and similar compounds by CYP3A4 could be deciphered. Then we used structure based design, first modifying the CYP3A4 crystal structure (pdb code: 4NY4) by adding an oxyferryl moiety to the heme, followed by validating the modified structure to obtain the 1’ and 4 position oxidation products of midazolam and then recapitulating the metabolism patterns deciphered previously for 1 and analogs. We checked if the pattern deciphered could lead to a putative reactive moiety. Finally we used the docking pose of 1 into this model of the modified CYP3A4 crystal structure to guide transformation of 1 into MBI-free H-PGDS inhibitors.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of a series of novel GPR40
           agonists containing nitrogen heterocyclic rings
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Zhaozhu Sun, Tian Zhou, Xuan Pan, Ying Yang, Yi Huan, Zhiyan Xiao, Zhufang Shen, Zhanzhu Liu A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituded phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR miceGraphical abstractGraphical abstract for this article
       
  • Monoterpene’s multiple free radical scavenging capacity as compared with
           the radioprotective agent cysteamine and amifostine
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yoshimi Sueishi, Risako Nii Monoterpenes are major active components of lavender, thyme, and mint. The X-ray radioprotective activity of pure monoterpenes is attributed to their scavenging ability against active species, but so far no firm evidence has been demonstrated. The objective of this study is to quantitatively determine antioxidant abilities of monoterpenes and collate it with radioprotective activity. Using multiple free-radical scavenging (MULTIS) method, we have determined the scavenging abilities of monoterpenes (linalool, thymol, and menthol) against six active species. A previous study has shown that the monoterpene linalool is a radioprotector for cellular systems, therefore, its scavenging ability was compared with known radioprotective agents such as cysteamine and amifostine. Results indicated that the monoterpene menthol but not linalool is a potent scavenger of reactive oxygen species and its scavenging magnitude is comparable to cysteamine and amifostine. This paper is first to show a correlation between ROS scavenging ability and radioprotective action.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological activity investigation of azole and quinone
           hybridized phosphonates
    • Abstract: Publication date: Available online 2 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yagya Prasad Subedi, Madher N. Alfindee, Jaya P. Shrestha, Greg Becker, Michelle Grilley, Jon Y. Takemoto, Cheng-Wei Tom Chang Phosphonates, azoles and quinones are pharmacophores found in bioactive compounds. A series of phosphonates conjugated to azoles and quinones with variable carbon chain lengths were synthesized in 3-4 steps with good yield. Antifungal assay of these compounds showed that ethyl protected phosphates have excellent inhibitory activity against phytopathogenic fungus Fusarium graminearum, and the free-base phosphates have good activity against human pathogenic fungi Aspergillus flavus and Candida albicans. Structure- activity relationship (SAR) studies showed activity increases with longer carbon chain length between phosphonate and anthraquinone analogs consisting of azole and quinone moieties. These newly synthesized compounds also have mild antibacterial activities to Gram positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytotoxicity analysis of these compounds against HeLa cells reveals that the phosphoric acid analogs are less toxic compared to ethyl protected phosphonates. Three leads compounds have been identified with prominent antifungal activity and low cytotoxicity.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and antifungal evaluation of novel pyrazole carboxamides
           with diarylamines scaffold as potent succinate dehydrogenase inhibitors
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Aigui Zhang, Jingya Zhou, Ke Tao, Taiping Hou, Hong Jin Sixteen novel pyrazole carboxamides with diarylamines scaffold were designed, synthesized and characterized in detail via 1H NMR, 13C NMR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani, Fusarium oxysporum, Phytophthora infestans and Fusarium graminearum. Among them, compound 1c exhibited the highest antifungal activities against R. solani in vitro with EC50 value of 0.005 mg/L, superior to the commercially available fungicide fluxapyroxad (EC50 = 0.033 mg/L). And compound 1c (IC50 = 0.034 mg/L) showed higher inhibition abilities against succinate dehydrogenase than fluxapyroxad (IC50 = 0.037 mg/L). This study suggests that compound 1c could be regarded as a potential succinate dehydrogenase inhibitor.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of oxime-functionalized
           nitrofuranylamides as novel antitubercular agents
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Yi-Lei Fan, Jian-Bing Wu, Xing Ke, Zhong-Ping Huang A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.Graphical abstractA series of novel oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b which were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, also demonstrated great potency against drug-resistant clinical isolates, suggesting they may serve as new and promising candidates for further anti-TB drug discovery.Graphical abstract for this article
       
  • Evaluation of 4-phenylamino-substituted naphthalene-1,2-diones as tubulin
           polymerization inhibitors
    • Abstract: Publication date: Available online 1 August 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Honghao Yang, Baijiao An, Xingshu Li, Wei Zeng A series of 4-phenylamino-substituted naphthalene-1,2-dione derivatives were prepared and evaluated as effective antiproliferative agents. MTT assays showed that the compounds with a methyl group on the nitrogen linker exhibited potent antiproliferative activities against human cancer cells. The mechanistic study revealed that these compounds could induce mitochondrial depolarization, which resulted in intracellular ROS production, and they also acted as tubulin polymerization inhibitors. Moreover, the typical compound could arrest A549 cells in the G2/M phase, resulting in cellular apoptosis and induced mitotic arrest in A549 cells through disrupting microtubule dynamics.Graphical abstractGraphical abstract for this article
       
  • New Series of 3,5-Disubstituted Tetrahydro-2H-1,3,5-thiadiazine Thione
           (THTT) Derivatives: Synthesis and Potent Antileishmanial Activity
    • Abstract: Publication date: Available online 31 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nuzhat Arshad, Jamshed Hashim, Irfanullah, Muhammad Ali Minhas, Javeria Aslam, Tahira Ashraf, Syeda Zehra Hamid, Tahseen Iqbal, Shumaila Javed Four series of heterocyclic compounds, namely, tetrahydro-2H-1,3,5-thiadiazine thione derivatives were synthesized in good to excellent yields and were screened for their in vitro antileishmanial activities against Leishmania major (promastigotes). Most of the compounds showed significant antileishmanial activity within the range of IC50 = 15.48-39.36 μM when compared with standard pentamidine (IC50 = 14.95 μM). The structure–activity relationship showed that N-3 and N-5 substituents have a key role against leishmanicidal activity. The ester analogues (series B) were found to have a 1.5 to 5-fold reduced activity compared to their acidic counterparts. Cytotoxicity against mammalian mouse fibroblast 3T3 cells was also evaluated and compared between the acid and its ester analogue. The reduction of antileishmanial activity and loss of toxicity in the newly developed THTT ester derivative indicates that these compounds can be used as a template study for the production of effective antileishmanial ester prodrugs.Graphical abstractGraphical abstract for this article
       
  • Novel, potent, selective and brain penetrant vasopressin 1b receptor
           antagonists
    • Abstract: Publication date: Available online 31 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Hervé Geneste, Swati Bhowmik, Marcel M. van Gaalen, Wilfried Hornberger, Charles W. Hutchins, Astrid Netz, Thorsten Oost, Liliane Unger Herein we report the discovery of a novel oxindole-based series of vasopressin 1b (V1b) receptor antagonists. Introducing a substituted piperazine moiety and optimizing the southern and the northern aromatic rings resulted in potent, selective and brain penetrant V1b receptor antagonists. Compound 9c was found to be efficacious in a rat model of anti-depressant activity (3mg/kg, ip). Interestingly, both moderate terminal half-life and moderate bioavailability could be achieved despite sub-optimal microsomal stability.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Challenges in the development of an M4 PAM preclinical
           candidate: The discovery, SAR, and biological characterization of a series
           of azetidine-derived tertiary amides” [Bioorg. Med. Chem. Lett. 27(23)
           (2017) 5179–5184]
    • Abstract: Publication date: Available online 31 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Bruce J. Melancon, Atin Lamsal, Vincent B. Luscombe, Alice L. Rodriguez, Frank W. Byers, Sichen Chang, Hyekyung P. Cho, Darren W. Engers, Carrie K. Jones, Colleen M. Niswender, Michael W. Wood, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges, Craig W. Lindsley
       
  • Discovery of super soft-drug modulators of sphingosine-1-phosphate
           receptor 1
    • Abstract: Publication date: Available online 30 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Mark Bell, David Foley, Claire Naylor, Colin Robinson, Jennifer Riley, Ola Epemolu, Paul Scullion, Yoko Shishikura, Elad Katz, W.H. Irwin McLean, Paul Wyatt, Kevin D Read, Andrew Woodland The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.Graphical abstractGraphical abstract for this article
       
  • Identification of a novel series of potent and selective CCR6 inhibitors
           as biological probes
    • Abstract: Publication date: Available online 30 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Taisuke Tawaraishi, Nobuki Sakauchi, Kousuke Hidaka, Kyoko Yoshikawa, Toshitake Okui, Haruhiko Kuno, Ikumi Chisaki, Kazuyoshi Aso CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies. Initial SAR study of a hit compound provided potent N-benzenesulfonylpiperidine derivatives that suppressed CCL20-induced Gi signals. By subsequent scaffold morphing of the central ring and further optimization, we identified a novel series of 1,4-trans-1-benzenesulfonyl-4-aminocyclohexanes as potent and selective CCR6 inhibitors with good pharmacokinetic properties. Our compounds showed good correlation between Gi signal inhibitory activity and cell migration inhibitory activity in human CCR6-transfected CHO cells. In addition, representative compound 35 potently inhibited CCR6-dependent cell migration and the increase in ERK phosphorylation in human primary cells. Therefore, the compound could be used effectively as a biological probe against human CCR6.Graphical abstractGraphical abstract for this article
       
  • Synthesis, characterization and nociceptive screening of new
           VV-hemorphin-5 analogues
    • Abstract: Publication date: Available online 30 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Petar Todorov, Petia Peneva, Daniela Pechlivanova, Stela Georgieva, Elena Dzhambazova In the present study, some new analogues of VV-hemorphin-5, modified at position 1 and 7 by the non-proteinogenic and/or natural amino acids followed the structures Xxx-Val-Val-Tyr-Pro-Trp-Thr-Gln-NH2 and Val-Val-Tyr-Pro-Trp-Thr-Yyy-NH2, where Xxx is Ile or Aib and Yyy is Lys/Orn/Dap/Dab were synthesized to investigate their potential antinociceptive activities. We report also the redox potentials and the acid/base properties as pKa values of these peptide analogues which were compared toward electrochemical behaviour of tryptophan containing peptides. All analogues showed a short lasting initial antinociceptive effect, however H2 hemorphin analogue is characterized with prolong and strong antinociceptive effect, while the other peptide analogues exerted more variable effects on the visceral nociception depending on the dose or time after the intracerebral injection.Graphical abstractGraphical abstract for this article
       
  • Conversion of Carbazole Carboxamide Based Reversible Inhibitors of
           Bruton’s Tyrosine Kinase (BTK) into Potent, Selective Irreversible
           Inhibitors in the Carbazole, Tetrahydrocarbazole, and a New
           2,3-Dimethylindole Series
    • Abstract: Publication date: Available online 30 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Qingjie Liu, Douglas G. Batt, Charu Chaudhry, Jonathan S. Lippy, Mark A. Pattoli, Neha Surti, Songmei Xu, Percy H. Carter, James R. Burke, Joseph A. Tino Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.Graphical abstractGraphical abstract for this article
       
  • Discovery of Small Molecule Inhibitors of Adenovirus by Disrupting
           E3-19K/HLA-A2 Interactions
    • Abstract: Publication date: Available online 29 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jinhong Ren, Nikita R Dsouza, Hui Deng, Hyun Lee, Marlene Bouvier, Michael E. Johnson The binding of the adenovirus (Ad) protein E3-19K with the human leukocyte antigen (HLA) plays an important role in Ad infections, which is the causative agent of a series of gastrointestinal, respiratory and ocular diseases. The objective of this research is to evaluate the essential interactions between E3-19K and HLA-A2 using the X-ray crystal structure of the E3-19K/HLA-A2 complex, and to identify small molecules that could potentially disrupt their binding. Computational methods, including molecular dynamic simulations, MM/GBSA calculations, and computational solvent mapping, were implemented to determine potential binding site(s) for small molecules. The previous experimentally determined hot spot residues, Q54 and E177 in HLA-A2, were also predicted to be the dominant residues for binding to E3-19K by our theoretical calculations. Several other residues were also found to play pivotal roles for the binding of E3-19K with HLA-A2. Residues adjacent to E177, including Q54 and several other residues theoretically predicted to be crucial in HLA-A2 were selected as a potential binding pocket to perform virtual screening with 1,200 compounds from the Prestwick library. Seven hits were validated by surface plasmon resonance (SPR) as binders to HLA-A2 as a first step in identifying molecules that can perturb its association with the Ad E3-19K protein.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Preclinical Evaluation of
           5-Methyl-N4-aryl-furo[2,3-d]pyrimidines as Single Agents with Combination
           Chemotherapy Potential
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Ravi Kumar Vyas Devambatla, Shruti Choudhary, Michael Ihnat, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.Graphical abstractGraphical abstract for this article
       
  • Synthesis of enamino-2-oxindoles via conjugate addition between α-azido
           ketones and 3-alkenyl oxindoles: Cytotoxicity evaluation and apoptosis
           inducing studies
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Niggula Praveen Kumar, Yogesh Vanjari, Sowjanya Thatikonda, Venkatesh Pooladanda, Pankaj Sharma, Balasubramanisan Sridhar, Chandraiah Godugu, Ahmed Kamal, Nagula Shankaraiah A facile method for the construction of double bond between 3-ylidene oxindoles and α-azido ketones has been successfully accomplished with a mild base. This method features azido reduction with concomitant double bond formation to provide the new class of bioactive enamino-2-oxindoles. These new compounds were screened for their in vitro cytotoxic potential on selected human cancer cell lines such as colon, lung, breast, and cervical cancer cells. Among them, representative compounds 3a, 3h, 3k, 3p, 3w and 3x showed notable cytotoxicity profile with IC50 values ranging from 1.40±0.10 to 28.7±0.36 µM. Compound 3k displayed most potent cytotoxicity against lung cancer (NCI-H460) cells with an IC50 value of 1.40±0.10 µM. 3k also arrested the G2/M phase of the cell cycle and induced distinctive apoptotic features on lung cancer cells. The apoptosis induction is supported by various cellular assays such as AO/EB, DAPI, and DCFDA staining studies including clonogenic assay. Extent of apoptosis was also analyzed by Annexin binding and JC-1 staining. Moreover, this method is amenable for the generation of a library of new class of stable bioactive enamino-2-oxindoles.Graphical abstractGraphical abstract for this article
       
  • Antimicrobial synergy between mRNA targeted peptide nucleic acid and
           antibiotics on E. coli bacteria
    • Abstract: Publication date: Available online 27 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Jaime I. Castillo, Marcin Równicki, Monika Wojciechowska, Joanna Trylska A combination of antibacterial agents should make the emergence of resistance in bacteria less probable. Thus we have analyzed the synergistic effects between antibacterial antisense peptide nucleic acids (PNA) and conventional antibiotics against Escherichia coli AS19 (lipopolysaccharide defective) strain and a derivative of a pathogenic strain E. coli O157:H7. PNAs were designed to target mRNA transcripts encoding the essential acyl carrier protein (gene acpP) and conjugated to the cell-penetrating peptide (KFF)3K for cellular uptake. Antibiotics included aminoglycosides, aminopenicillins, polymyxins, rifamycins, sulfonamides and trimethoprim. Synergies were evaluated using the checkerboard technique. Fractional Inhibitory Concentration indices (FICi) were calculated for all combinations based on the minimal inhibitory concentration of each individual agent. The results demonstrate two novel synergistic combinations of antimicrobial agents, namely, (KFF)3K-PNA anti-acpP with polymyxin B and (KFF)3K-PNA anti-acpP with trimethoprim (both with FICi=0.38). Polymyxin B’s synergy postulates cell wall targeted antibiotics as attractive agents to improve the uptake of PNA while trimethoprim’s interaction with PNA my reveal a new inhibitory mechanism.Graphical abstractGraphical abstract for this article
       
  • Synthesis and anticancer activity studies of indolylisoxazoline analogues
    • Abstract: Publication date: Available online 26 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): M.V.S.K. Chaitanya, P.O. Venkataramana Reddy, Nikhil Kumar, Anil Kumar, Kavita Shah, Dalip Kumar A new library of thirteen indolylisoxazolines 6a-m has been synthesized by the treatment of indolylchalcones with hydroxylamine hydrochloride. Evaluation of anticancer activity of indolylisoxazolines 6a-m led to the identification of potent compounds 6c-d, 6i and 6l, with IC50 ranging 2.5-5.0 µM against the tested cancer cell lines. Using a number of complementary techniques such as acridine orange/ethidium bromide staining, PARP1 cleavage and DNA strand breaks assay, we show that the compounds 6c and 6i induce apoptosis in highly aggressive C4-2 cells. Our data further revealed that 6c and 6i inhibited C4-2 cells proliferation without inducing ROS. Finally, we show that compounds 6c and 6i also potently inhibit cell migration, indicating these compounds have the potential to serve as effective anti-cancer agents.Graphical abstractGraphical abstract for this article
       
  • Activating frataxin expression by single-stranded siRNAs targeting the GAA
           repeat expansion
    • Abstract: Publication date: Available online 21 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Xiulong Shen, Audrius Kilikevicius, Daniel O'Reilly, Thazha P. Prakash, Masad J. Damha, Frank Rigo, David R. Corey Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). The genetic cause of the disease is an expanded GAA repeat within the FXN gene. Agents that increase expression of FXN protein are a potential approach to therapy. We previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here we test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low Tm values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.Graphical abstractGraphical abstract for this article
       
  • Cyclic analogue of S-benzylisothiourea that suppresses kynurenine
           production without inhibiting indoleamine 2,3-dioxygenase activity
    • Abstract: Publication date: Available online 20 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Miwa Fukuda, Tomomi Sasaki, Tomoko Hashimoto, Hiroyuki Miyachi, Minoru Waki, Akira Asai, Osamu Takikawa, Osamu Ohno, Kenji Matsuno Kynurenine is biosynthesised from tryptophan catalysed by indoleamine 2,3-dioxygenase (IDO). The abrogation of kynurenine production is considered a promising therapeutic target for immunological cancer treatment. In the course of our IDO inhibitor programme, formal cyclisation of the isothiourea moiety of the IDO inhibitor 1 afforded the 5-Cl-benzimidazole derivative 2b-6, which inhibited both recombinant human IDO (rhIDO) activity and cellular kynurenine production. Further derivatisation of 2b-6 provided the potent inhibitor of cellular kynurenine production 2i (IC50 = 0.34 µM), which unexpectedly exerted little effect on the enzymatic activity of rhIDO. Elucidation of the mechanism of action revealed that compound 2i suppresses IDO expression at the protein level by inhibiting STAT1 expression in IFN-γ-treated A431 cells. The kynurenine-production inhibitor 2i is expected to be a promising starting point for a novel approach to immunological cancer treatment.Graphical abstractGraphical abstract for this article
       
  • An efficient synthetic route for preparation of antimycobacterial
           wollamides and evaluation of their in vitro and in vivo efficacy
    • Abstract: Publication date: Available online 19 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Henok Asfaw, Thomas Wetzlar, Maria Santos Martinez-Martinez, Peter Imming A convenient solid phase peptide synthetic (SPPS) route is reported for the preparation of antimycobacterial wollamides. The method is based on on-resin head-to-tail cyclization and is fast, efficient and amenable to automation. The in vitro antimycobacterial activities of the newly synthesized wollamides were evaluated against M. tuberculosis H37Rv (Mtb H37Rv). To assess their drug-likeness, in vitro pharmacokinetic (ADME) profiling was also performed. For wollamides with potent extracellular potency, intracellular activities and in vivo efficacy were determined. The results disclose the potent antimycobacterial (MICMtb H37Rv = 1.1 µM) and suitable drug-like properties of wollamide A (4b). Out of the synthesized wollamides, four compounds (4b–e) exhibited potent intracellular activities against Mtb H37Rv infected human macrophages (IC50 = 0.2–1.3 µM). Results of in vivo blood exposure and efficacy assays for 4d and 4e are discussed.Graphical abstractGraphical abstract for this article
       
  • Natural products as sources of new fungicides (V): Design and synthesis of
           acetophenone derivatives against phytopathogenic fungi in vitro and in
           vivo
    • Abstract: Publication date: Available online 19 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Wen-Jia Dan, Thi-Mai-Luong Tuong, Da-Cheng Wang, Ding Li, An-Ling Zhang, Jin-Ming Gao A series of acetophenone derivatives (10a–10i, 11, 12a–12g, 13a–13g, 14a–14d and 15a–15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure–activity relationship was summarized. Compounds 10a–10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC50 values of 6.0 to 22.6 µg/mL, especially Cytospora sp. (IC50 = 6.0 µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation.Graphical abstractGraphical abstract for this article
       
  • Novel cinnamaldehyde-based aspirin derivatives for the treatment of
           colorectal cancer
    • Abstract: Publication date: Available online 19 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Shan Lu, Obinna N. Obianom, Yong Ai Colorectal cancer (CRC) is a leading cause of mortality worldwide. Current treatments of CRC involve anti-cancer agents with relatively good efficacy but unselectively target both cancer and non-cancer cells. Thus, there is a need to discover and develop novel CRC therapeutics that have potent anti-cancer effects, but show reduced off-target cell effects. Here, a novel series of cinnamaldehyde-based aspirin derivatives were designed and synthesized. Biological evaluation indicated that the most active compound 1f exhibited more than 10-fold increase in the anti-proliferation efficacy in HCT-8 cells compared to the parent compounds. Its effects were similarly reproduced in another CRC cell line, DLD-1, but with 7- to 11-fold less inhibitory activity in non-tumorigenic colon cells. Flow cytometry analysis showed that 1f induced cell cycle arrest and apoptosis, which was further validated with immunoblot analysis of the relative protein levels of cleaved caspase 3 and PARP as well as the ROS production in CRC cells. More so, 1f significantly inhibited the growth of implanted CRC in vivo in mouse xenograft model. Taken together, our results show that cinnamaldehyde-based aspirin derivatives such as 1f show promise as novel anti-CRC agent for further pharmaceutical development.Graphical abstractGraphical abstract for this article
       
  • Generation of methylated violapyrones with improved anti-influenza A virus
           activity by heterologous expression of a type III PKS gene in a marine
           Streptomyces strain
    • Abstract: Publication date: Available online 18 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Lukuan Hou, Shuyao Wang, Huiming Huang, Huayue Li, Wei Wang, Wenli Li Heterologous expression of the type III polyketide synthase (PKS) gene vioA in marine-derived Streptomyces youssoufiensis OUC6819 led to production of six violapyrones (VLPs), including four novel compounds VLPs Q–T (1–4) and two known compounds VLPs B and I (5 and 6). The structures of 1–4 were elucidated by a combination of spectroscopic analyses, including HR-ESIMS and 1D and 2D NMR data, demonstrating that 1–4 are novel VLPs which are methylated at 4-OH with their corresponding non-methylated counterparts to be VLP A, 5 and 6 and VLP C, respectively. Anti-influenza A [H1N1 (A/Virginia/ATCC1/2009) and H3N2 (A/Aichi/2/1968)] virus activity of compounds 1–6 as well as VLPs A and C were then evaluated using ribavirin as a positive control (IC50 = 66.7 and 99.6 μM). The results revealed that these VLPs showed considerable anti-H1N1 and anti-H3N2 activities with IC50 values of 30.6–132.4 μM and 45.3–150.0 μM, respectively. Notably, all the methylated VLPs displayed better anti-virus activity than their non-methylated counterparts, among which compound 3 (VLP S) exhibited the best activities. Interestingly, methylation at 4-OH has negative effect on the anti-MRSA (methicillin-resistant Staphylococcus aureus) activity instead, with methylated VLPs displaying decreased (2) or abolished (3 and 4) activities in comparison with each of their non-methylated counterparts.Graphical abstractGraphical abstract for this article
       
  • Secondary Carbamate Linker Can Facilitate the Sustained Release of
           Dopamine from Brain-Targeted Prodrug
    • Abstract: Publication date: Available online 18 July 2018Source: Bioorganic & Medicinal Chemistry LettersAuthor(s): Nikki A. Thiele, Jussi Kärkkäinen, Kenneth B. Sloan, Jarkko Rautio, Kristiina M. Huttunen To achieve the sustained release of dopamine in the brain for the symptomatic treatment of Parkinson’s disease, dopamine was conjugated to L-tyrosine, an L-type amino acid transporter 1 (LAT1)-targeting vector, using a secondary carbamate linker. The resulting prodrug, dopa-CBT, inhibited the uptake of the LAT1 substrate [14C]-L-leucine in LAT1-expressing MCF-7 cells with an IC50 value of 28 µM, which was 3.5-times lower than that of the gold standard for dopamine replacement therapy, L-dopa (IC50 ca. 100 µM). Despite its high affinity for LAT1, dopa-CBT was transported via LAT1 into MCF-7 cells 850-times more slowly (Vmax < 3 pmol/min/mg) than L-dopa (Vmax 2.6 nmol/min/mg), most likely due to its large size compared to L-dopa. However, dopa-CBT was significantly more stable in 10% rat liver homogenate than L-dopa, releasing dopamine and L-tyrosine, an endogenous dopamine precursor, slowly, which indicates that it may serve as a dual carrier of dopamine across the blood-brain barrier selectively expressing LAT1.Graphical abstractGraphical abstract for this article
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.196.98.96
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-