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Bioorganic & Medicinal Chemistry
Journal Prestige (SJR): 0.871
Citation Impact (citeScore): 3
Number of Followers: 141  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0968-0896
Published by Elsevier Homepage  [3162 journals]
  • From controlling chemical bonding to deciphering and manipulating
           biological processes
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Raphaël Rodriguez
       
  • New pyrazolopyrimidine derivatives as Leishmania amazonensis
           arginase inhibitors
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Livia M. Feitosa, Edson R. da Silva, Lucas V.B. Hoelz, Danielle L. Souza, Julio A.A.S.S. Come, Camila Cardoso-Santos, Marcos M. Batista, Maria de Nazare C. Soeiro, Nubia Boechat, Luiz C.S. Pinheiro Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 µM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R = H) and 6 (R = CF3), showed arginase inhibition>70% and IC50 values of 12 µM and 47 µM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing Kis values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 µM and 29 ± 5 µM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 µM. The maximum growth inhibition reached was between 20-30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds.Graphical abstractGraphical abstract for this article
       
  • Investigation of Flexibility of Neuraminidase 150-loop using Tamiflu
           Derivatives in Influenza A Viruses H1N1
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Václav Zima, Carlos Berenguer Albiñana, Kateřina Rojíková, Jana Pokorná, Petr Pachl, Pavlína Řezáčová, Jason Hudlicky, Václav Navrátil, Pavel Majer, Jan Konvalinka, Milan Kožíšek, Aleš Machara This study focuses on design, synthesis and in vitro evaluation of inhibitory potency of two series of sialylmimetic that target an exosite (“150-cavity”) adjacent to the active site of influenza neuraminidases from A/California/07/2009 (H1N1) pandemic strain and A/chicken/Nakorn-Patom/Thailand/CU-K2-2004 (H5N1). The structure-activity analysis as well as 3-D structure of the complex of parental compound with the pandemic neuraminidase p09N1 revealed high flexibility of the 150-cavity towards various modification of the neuraminidase inhibitors. Furthermore, our comparison of two methods for inhibition constant determination performed at slightly different pH values suggest that the experimental conditions of the measurement could dramatically influence the outcome of the analysis in the compound-dependent manner. Therefore, previously reported Ki values determined at non-physiological pH should be carefully scrutinized.Graphical abstractGraphical abstract for this article
       
  • 2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator
           pharmacophore
    • Abstract: Publication date: Available online 17 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sungjin Ahn, Jungmin Kim, Seungchan An, Jeong Joo Pyo, Daram Jung, Joochang Lee, Seok Young Hwang, Junpyo Gong, Iljin Shin, Hong Pyo Kim, Hyoungsu Kim, Minsoo Noh Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of novel
           4-oxobenzo[d]1,2,3-triazin-benzylpyridinum derivatives as potent
           anti-Alzheimer agents
    • Abstract: Publication date: Available online 16 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Fahimeh Hosseini, Ali Ramazani, Maryam Mohammadi-Khanaposhtani, Maliheh Barazandeh Tehrani, Hamid Nadri, Bagher Larijani, Mohammad Mahdavi Novel 4-oxobenzo[d]1,2,3-triazin derivatives bearing pyridinium moiety 6a-q were synthesized and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Most of the synthesized compounds showed good inhibitory activity against AChE. Among the synthesized compounds, the compound 6j exhibited the highest AChE inhibitory activity. It should be noted that these compounds displayed low anti-BuChE activity with the exception of the compound 6i, as it exhibited BuChE inhibitory activity more than donepezil. The kinetic study of the compound 6j revealed that this compound inhibited AChE in a mixed-type inhibition mode. This finding was also confirmed by the docking study. The latter study demonstrated that the compound 6j interacted with both the catalytic site and peripheral anionic site of the AChE active site. The compound 6j was also observed to have significant neuroprotective activity against H2O2-induced PC12 oxidative stress, but low activity against β-secretase.Graphical abstractGraphical abstract for this article
       
  • Synthesis of Distal and Proximal fleximer Base Analogues and Evaluation in
           the Nucleocapsid Protein of HIV-1
    • Abstract: Publication date: Available online 15 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Therese Ku, Natalie Lopresti, Matthew Shirley, Mattia Mori, Jan Marchant, Xiao Heng, Maurizio Botta, Michael Summers, Katherine Seley-Radtke Anti-HIV-1 drug design has been notably challenging due to the virus’ ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.Graphical abstractGraphical abstract for this article
       
  • Capsaicin-like analogue induced selective apoptosis in A2058 melanoma
           cells: Design, synthesis and molecular modeling
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gustavo José Vasco Pereira, Maurício Temotheo Tavares, Ricardo Alexandre Azevedo, Barbara Behr Martins, Micael Rodrigues Cunha, Rajesh Bhardwaj, Yara Cury, Vanessa Olzon Zambelli, Euzébio Guimarães Barbosa, Matthias A. Hediger, Roberto Parise-Filho The use of molecules inspired by natural scaffolds has proven to be a very promising and efficient method of drug discovery. In this work, capsaicin, a natural product from Capsicum peppers with antitumor properties, was used as a prototype to obtain urea and thiourea analogues. Among the most promising compounds, the thiourea compound 6g exhibited significant cytotoxic activity against human melanoma A2058 cells that was twice as high as that of capsaicin. Compound 6g induced significant and dose-dependent G0/G1 cell cycle arrest in A2058 cells triggering cell death by apoptosis. Our results suggest that 6g modulates the RAF/MEK/ERK pathway, inducing important morphological changes, such as formation of apoptotic bodies and increased levels of cleaved caspase-3. Compared to capsaicin, 6g had no significant TRPV1/6 agonist effect either irritant effects on mice. Molecular modeling studies corroborate the biological findings and suggest that 6g, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. Inverse virtual screening strategy found MEK1 as a possible biological target for 6g. Consistent with these findings, our observations suggested that 6g could be developed as a potential anticancer agent.Graphical abstractGraphical abstract for this article
       
  • Optimization of Novel Reversible Bruton’s Tyrosine Kinase Inhibitors
           Identified Using Tethering-Fragment-Based Screens
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Brian T. Hopkins, Eris Bame, Noah Bell, Tonika Bohnert, Jon K. Bowden-Verhoek, Minna Bui, Mark T. Cancilla, Patrick Conlon, Patrick Cullen, Daniel A. Erlanson, Junfa Fan, Tarra Fuchs-Knotts, Stig Hansen, Stacey Heumann, Tracy J. Jenkins, Douglas Marcotte, Bob McDowell, Elisabeth Mertsching, Ella Negrou, Kevin L. Otipoby Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton’s tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.Graphical abstractGraphical abstract for this article
       
  • Development of Novel Macrocyclic Small Molecules that Target CTG
           Trinucleotide Repeats
    • Abstract: Publication date: Available online 14 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Julio F. Serrano, JuYeon Lee, L. Daniel Curet, Lauren D. Hagler, Sarah E. Bonson, Emma J. Schuster, Steven C. Zimmerman We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to dCTG mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions and form a 1:1 complex. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.Graphical abstractGraphical abstract for this article
       
  • Highly tunable thiosulfonates as a novel class of cysteine protease
           inhibitors with anti-parasitic activity against Schistosoma mansoni
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): D.J. Ward, H. Van de Langemheen, E. Koehne, A. Kreidenweiss, R.M.J. Liskamp The development of a new class of cysteine protease inhibitors utilising the thiosulfonate moiety as an SH specific electrophile is described. This moiety has been introduced into suitable amino acid derived building blocks, which were incorporated into peptidic sequences leading to very potent i.e. sub micromolar inhibitors of the cysteine protease papain in the same range as the vinyl sulfone based inhibitor K11777. Therefore, their inhibitory effect on Schistosoma mansoni, a human blood parasite, that expresses several cysteine proteases, was evaluated. The homophenylalanine side chain containing compounds 27 - 30 and especially 36 showed promising activities compared with K11777 and warrant further investigations of these peptidic thiosulfonate inhibitors as new potential anti-parasitic compounds.Graphical abstractGraphical abstract for this article
       
  • Eicosanoid Mediation of Cannabinoid Actions
    • Abstract: Publication date: Available online 13 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sumner H. Burstein Interactions between cannabinoids and eicosanoids have been observed for the last several decades and account for a variety of cannabinoid actions. These were seen both in vitro and in vivo and may provide a molecular basis for these actions. Some of the topics included in this review are; effects on adenylate cyclase activity, alteration of behavioral responses, reduction of pain sensation, reduction and resolution of inflammation, hypotensive and vasorelaxant responses, anti-cancer and anti-metastatic activities, reduction of intraocular pressure and others. The most widely studied cannabinoids so far are tetrahydrocannabinol and cannabidiol. However, synthetic agents such as CP55,940, ajulemic acid, JWH-133 and WIN-55,212-2 were also investigated for interaction with eicosanoids. The endocannabinoids anandamide and 2-arachidonoylglycerol have been examined as well. Among the eicosanoids mediating cannabinoid actions are PGE2, 15-deoxy- Δ 12, 14-prostaglandin-J2 , lipoxin A4, lipoxin B4, and leukotriene B4. Enzyme activities involved include monoacylglycerylipase, adenylatecyclase, phospholipase A2, cyclooxygenases-1, 2 and 5, lipoxygenases-12 and 15. Receptors involved include CB1, CB2 and the EP3 and EP3 prostanoid receptors. While not all cannabinoid activities can be accounted for, many are best explained by eicosanoid participation. The recent surge in interest in “medical marijuana” makes understanding mechanisms of cannabinoid actions particularly important.Graphical abstractGraphical abstract for this article
       
  • Design, Synthesis and Evaluation of Antiproliferative Activity of
           Fluorinated Betulinic Acid
    • Abstract: Publication date: Available online 11 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Jizhen Li, Ling-Chu Chang, Kan-Yen Hsieh, Pei-Ling Hsu, Stephen J. Capuzzi, Ying-Chao Zhang, Kang-Po Li, Susan L. Morris-Natschke, Masuo Goto, Kuo-Hsiung Lee Betulinic acid (BA), a pentacyclic triterpenoid, exhibits broad spectrum antiproliferative activity, but generally with only modest potency. To improve BA’s pharmacological properties, fluorine was introduced as a single atom at C-2, creating two diastereomers, or in a trifluoromethyl group at C-3. We evaluated the impact of these groups on antiproliferative activity against five human tumor cell lines. A racemic 2-F-BA (compound 6) showed significantly improved antiproliferative activity, while each diastereomer exhibited similar effects. We also demonstrated that 2-F-BA is a topoisomerase (Topo) I and IIα dual inhibitor in cell-based and cell-free assays. A hypothetical mode of binding to the Topo I-DNA suggested a difference between the hydrogen bonding of BA and 2-F-BA to DNA, which may account for the difference in bioactivity against Topo I.Graphical abstractGraphical abstract for this article
       
  • Correlating the structure and reactivity of a contact allergen, DNCB, and
           its analogs to sensitization potential
    • Abstract: Publication date: Available online 11 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Flora Kimani, Seong-Min Kim, Rachel Steinhardt, Aaron P. Esser-Kahn We report a study that seeks to find a correlation between the overall sensitization potential quantified by the expression of IL-8 by stimulated monocytes and the chemical structure of a model contact allergen, 2,4-dinitrochlorobenzene (DNCB). We show that structure and reactivity of the chemical compounds play an important role in activation of the monocytes and subsequent inflammation in tissue. However, we observed a non-linear correlation between the rate of reaction and biological activity indicating a required balance of stability and reactivity.Graphical abstractGraphical abstract for this article
       
  • A structure-activity relationship of a thrombin-binding aptamer containing
           LNA in novel sites
    • Abstract: Publication date: Available online 11 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): GuoQing Ying, XingRu Lu, JianFeng Mei, YanLu Zhang, JianShu Chen, XuDong Wang In this report, structural characterization, aptamer stability and thrombin of a new modified thrombin-ligand complex binding aptamer (TBA) containing anti-guanine bases and a loop position locked nucleic acid (LNA) are presented. NMR, circular dichroic spectroscopy and molecular modeling were used to characterize the three-dimensional structure of two G-quadruplexes. LNA-modification of the anti-guanosines yields G-quadruplexes that show affinity and inhibitory activity toward thrombin, whereas LNA-modification of a thymine nucleotide in the TGT loop increases the thermal stability of TBA. As assessed by denatured PAGE electrophoresis, all modified aptamers display an increase in environmental stability.The prothrombin time assay and fibrinogen assay showed that the aptamers still had good inhibitory activity, and 15 of them had the longest PT time. Therefore, the LNA modification is well suited to improve the physicochemical and biological properties of the native thrombin-binding aptamer.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, in-silico studies and biological screening of
           Quinazolinone analogues as potential antibacterial agents against MRSA
    • Abstract: Publication date: Available online 10 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shahnawaz I. Qureshi, Hemchandra K. Chaudhari Type or The emergence of resistance to antibiotic has developed a complicated situation in the treatment of bacterial infections. Considering the antimicrobial resistance phenomenon as one of the greatest challenge of medicinal chemists for search of better anti-bacterial agents, which have potential narrow spectrum activity with low development of resistance potential and low toxicity to host. Cross-linking of peptidoglycan is a key step catalyze by Penicillin binding protein (PBP) to maintain integrity of cell wall in bacterial cell. However, these Penicillin binding protein (PBP) has developed resistance in methicillin-resistant Staphylococcus aureus (MRSA) due to acquisition of additional PBP2a. Various Quinazolinone analogues are reported in literature as potential anti-bacterial agents against MRSA. In present study new quinazolinone analogues has been designed, guided by molecular docking, In-silico and MM-GBSA study. Newly designed molecules have been synthesized by medicinal chemistry route and their characterization was done by using IR, NMR, & HR-MS techniques. Biological evaluation of synthesized compounds has been done on wild type Gram-negative (Escherichia coli), Gram-positive (Staphylococcus aureus) and resistant MRSA bacterial strains using Streptomycin, Kanamycin and Linezolid as standard drugs respectively. The in vitro evaluation results have shown that compound 5f is active with MIC value 15.625 μg/mL against S. aureus and with MIC value 31.25 μg/mL against MRSA.Graphical abstractGraphical abstract for this article
       
  • Discovery of a new autophagy inducer for A549 lung cancer cells
    • Abstract: Publication date: Available online 10 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Na Li, GuoJing Qu, JingNa Xue, Xiao Li, Xuan Zhao, YeHao Yan, DongFang Gao, Lu Zhang, Peng Wang, Ming Zhang, BaoXiang Zhao, JunYing Miao, ZhaoMin Lin Biological activities of a series of fluorescent compounds against human lung cancer cell line A549 were investigated. The results showed that (E)-1,3,3-trimethyl-2-(4-(piperidin-1-yl)styryl)-3H-indol-1-ium iodide (8) and (E)-2-(5,5-dimethyl-3-(4-(piperazin-1-yl)styryl)cyclohex-2-en-1-ylidene) malononitrile (11) could inhibit the growth of A549 cancer cells in a dose and time-dependent manner. Furthermore, compound 8 could trigger autophagy and apoptosis, but not obviously induce necrosis under the stimulatory condition. Therefore, 8 can be used as autophagy activator to investigate the regulatory mechanism of autophagy and may offer new candidate for the treatment of lung cancer.Graphical abstractGraphical abstract for this article
       
  • Structure-based drug design of novel carborane-containing nicotinamide
           phosphoribosyltransferase inhibitors
    • Abstract: Publication date: Available online 10 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yasunobu Asawa, Kiyotaka Katsuragi, Akira Sato, Atsushi Yoshimori, Sei-ichi Tanuma, Hiroyuki Nakamura A series of carborane-containing NAMPT inhibitors were designed and synthesized based on the structure of compounds 1 and the NAMPT inhibitory activity was evaluated using NAMPT Colorimetric Assay. Among the compounds synthesized, compounds 2b and 2c showed significant NAMPT inhibitory activity with IC50 values of 0.098 ± 0.008 and 0.057 ± 0.001 µM, respectively. Docking simulation of compound 2 toward NAMPT using the crystal structure of the FK866-NAMPT complex (PDB code: 2GVJ) with replacing the boron atom type by the C3 atom type of carboranes predicted that the NAMPT inhibitory activity of 2c was improved by the hydrogen bond formation between the carborane amide and H191 of NAMPT. Although dicarborane compounds 38, 50, 51, and 55 were synthesize aiming to two hydrophobic pockets present in the binding pocket of NAMPT, their inhibitory activity was moderate.Graphical abstractGraphical abstract for this article
       
  • A Ru(II) Polypyridyl Complex Bearing Aldehyde Functions as a Versatile
           Synthetic Precursor for Long-Wavelength Absorbing Photodynamic Therapy
           Photosensitizers
    • Abstract: Publication date: Available online 10 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Johannes Karges, Franz Heinemann, Federica Maschietto, Malay Patra, Olivier Blacque, Ilaria Ciofini, Bernhard Spingler, Gilles Gasser The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, the currently clinically approved photosensitizers (PSs) have several drawbacks, including photobleaching, slow clearance from the organism and poor water solubility. To overcome these shortcomings, much effort has been made in the development of new types of PSs, such as Ru(II) polypyridyl complexes. Nevertheless, most studied Ru(II) polypyridyl complexes have a low absorbance in the spectral therapeutic window. In this work, we show that, by carefully selecting substituents on the polypyridyl complex, it is possible to prepare a complex absorbing at much higher wavelength. Specifically, we report on the synthesis and in-depth experimental and theoretical characterisation of a Ru(II) polypyridyl complex (complex 3) combining a shift in absorbance towards the spectral therapeutic window with a high 1O2 production. To overcome the absence or poor selectivity of most approved PS into targeted cells/bacteria, they can be linked to targeting moieties. In this line, compound 3 was designed with reactive aldehyde groups, which can be used as a highly versatile synthetic precursor for further conjugation. As a proof of concept, 3 was reacted with benzylamine and the stability of the resulting conjugate 4 was investigated in DMSO, PBS and cell media. 4 showed an impressive ability to act as a PDT PS with no measurable dark cytotoxicity and photocytotoxicity in the low micromolar range against cancerous HeLa cells from 450 nm up to 540 nm.Graphical abstractGraphical abstract for this article
       
  • Enhancing the Ligand Efficiency of Anti-HIV Compounds Targeting
           Frameshift-Stimulating RNA
    • Abstract: Publication date: Available online 9 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Viktoriya S. Anokhina, John D. McAnany, Jessica H. Ciesla, Thomas A. Hilimire, Netty Santoso, Hongyu Miao, Benjamin L. Miller Ribosomal frameshifting, a process whereby a translating ribosome is diverted from one reading frame to another on a contiguous mRNA, is an important regulatory mechanism in biology and an opportunity for therapeutic intervention in several human diseases. In HIV, ribosomal frameshifting controls the ratio of Gag and Gag-Pol, two polyproteins critical to the HIV life cycle. We have previously reported compounds able to selectively bind an RNA stemloop within the Gag-Pol mRNA; these compounds alter the production of Gag-Pol in a manner consistent with increased frameshifting. Importantly, they also display antiretroviral activity in human T-cells. Here, we describe new compounds with significantly reduced molecular weight, but with substantially maintained affinity and anti-HIV activity. These results suggest that development of more “ligand efficient” enhancers of ribosomal frameshifting is an achievable goal.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel
           4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4
           inhibitors
    • Abstract: Publication date: Available online 7 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Xinzhou Bi, Jieming Li, Jiuhui Li, Wei Shi, Yuxuan Dai, Qifei Li, Wenjie Zhang, Wenlong Huang, Hai Qian, Cheng Jiang Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 μM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.Graphical abstractGraphical abstract for this article
       
  • Identification and immunological evaluation of novel TLR2 agonists through
           structure optimization of Pam3CSK4
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Xinming Du, Jiawen Qian, Yujie Wang, Mingming Zhang, Yiwei Chu, Yingxia Li Toll-like receptor 2 (TLR2) is a bridge between innate immunity and adaptive immunity. TLR2 agonists have been exploited as potential vaccine adjuvants and antitumor agents. However, no TLR2 agonists have been approved by FDA up to now. To discover drug-like TLR2 selective agonists, a novel series of Pam3CSK4 derivatives were designed based on the crystal structure of hTLR2-hTLR1-Pam3CSK4 complex, synthesized and evaluated for their immune-stimulatory activities. Among them, 35c was identified as a murine-specific TLR2 agonist, while 35f was a human-specific TLR2 agonist. Besides, 35d (human and murine TLR2 agonist) showed TLR2 agonistic activity comparable to Pam3CSK4, which included: elevated IL-6 expression level (EC50 = 83.08 ± 5.94 nM), up-regulated TNF-α and IL-6 mRNA expression and promoted maturation of DCs through activating the NF-κB signaling pathway. TLRs antibodies test showed that 35a and 35d were TLR2/1 agonists, while 35f was a TLR2/6 agonist.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and evaluation of sulfonylurea-containing
           4-phenoxyquinolines as highly selective c-Met kinase inhibitors
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Xiang Nan, Yi-Fan Jiang, Hui-Jing Li, Jun-Hu Wang, Yan-Chao Wu Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 µM, 0.064 µM, 0.16 µM and 0.49 µM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.Graphical abstractGraphical abstract for this article
       
  • Synthetic glycopeptides reveal specific binding pattern and conformational
           change at O-mannosylated position of α-dystroglycan by POMGnT1 catalyzed
           GlcNAc modification
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hiroshi Hinou, Seiya Kikuchi, Rika Ochi, Kota Igarashi, Wataru Takada, Shin-Ichiro Nishimura Structural and functional effects of core M1 type glycan modification catalyzed by protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) were investigated using a core M1 glycoform focused library of an α-dystroglycan fragment, 372TRGAIIQTPTLGPIQPTRV390. Evanescent-field fluorescence-assisted microarray system illuminated the specific binding pattern of plant lectins that can discriminate the glycan structure of core M1 glycan of the library. The comparative NMR analysis of synthetic glycopeptide having different length of the O-mannosylated glycans revealed a conformational change of the peptide backbone along with core M1 disaccharide formation. No long-range NOE signals of glycan-amino acid nor inter amino acid indicate the conformational change is induced by steric hindrance of core M1, the sole 1,2-O-modified form among protein binding sugar residue found in mammals.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of isochroman-4-one hybrids
           bearing piperazine moiety as antihypertensive agent candidates
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shaowen Xie, Xinnan Li, Hao Yu, Pengfei Zhang, Jia Wang, Chaolei Wang, Shengtao Xu, Zheng Wu, Jie Liu, Zheying Zhu, Jinyi Xu 7,8-Dihydroxy-3-methyl-isochromanone-4 (XJP), is a polyphenolic natural product with moderate antihypertensive activity. To obtain new agents with stronger potency and safer profile, we employed XJP and naftopidil as the lead compounds to design and synthesize a novel class of hybrids as antihypertensive agent candidates. In the present study, a series of hybrids (6a-r) of XJP bearing arylpiperazine moiety, which is identified as the pharmacophore of naftopidil, were designed and synthesized as novel α1-adrenergic receptor antagonists. The biological evaluation showed that target compounds 6c, 6e, 6f, 6g, 6h, 6m and 6q possessed potent in vitro vasodilation potency and α1-adrenergic receptor antagonistic activity. Furthermore, the most potent compound 6e significantly reduced the systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs),which was comparable to that of naftopidil, and it had no observable effects on the basal heart rate, suggesting that 6e deserves to be further investigated as a potential clinical candidate for the treatment of hypertension.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and preliminary bioactivity studies of indomethacin
           derivatives as Bcl-2/Mcl-1 dual inhibitors
    • Abstract: Publication date: Available online 6 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Chen Chen, Yiming Nie, Guangsen Xu, Xinying Yang, Hao Fang, Xuben Hou Bcl-2 family proteins, which divides into pro-apoptosis proteins and anti-apoptosis proteins, are involved in cell apoptosis progression. As numerous studies illustrated, targeting Bcl-2 family proteins is more and more attractive and practicable to cancer treatment. In this work, we designed and synthesized a series of indomethacin derivatives as new inhibitors for Bcl-2 family proteins. Our results of binding assay to Bcl-2 proteins, MTT assay and apoptotic assay indicated that some compounds had potent binding affinity to Bcl-2/Mcl-1 but not Bcl-XL. Furthermore, compound 8j showed improved anti-proliferative activity than known Bcl-2 inhibitor WL-276.Graphical abstractGraphical abstract for this article
       
  • Identification of BMI1 promoter inhibitors from Streptomyces sp.
           IFM-11958
    • Abstract: Publication date: Available online 4 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi B-cell-specific Moloney murine leukemia virus region 1 (BMI1) is a central component of polycomb repressive complex 1 (PRC1), which maintains epigenetic repression of genes expression via chromatin condensation. BMI1 overexpression downregulates the expression of tumor suppressor genes, such as p16Ink4a and PTEN. BMI1 expression is upregulated in cancer stem cells (CSCs). Therefore, inhibitors of BMI1 expression have potential as therapeutic agents for cancer.This study aimed to identify BMI1 promoter inhibitors from actinomycetes. Using a recently constructed BMI1 promoter assay, we isolated three known compounds, elaiophylin (1), 2-methylelaiophylin (2), and nocardamin (3), from Streptomyces sp. IFM-11958 that inhibited BMI1 promoter activity with IC50 values of 30 nM, 447 nM, 22 µM, respectively. Elaiophylin (1) was the most potent. Western blot and PCR analyses revealed that elaiophylin (1) inhibited BMI1 expression at the mRNA level in human prostate cancer cells (DU145). elaiophylin (1) also inhibited the sphere-forming activity of human hepatocellular carcinoma cells (Huh7), indicating that elaiophylin (1) suppresses the self-renewal capacity of CSCs. Elaiophylin (1) is the first BMI1 promoter inhibitor isolated from actinomycete metabolites.Graphical abstractGraphical abstract for this article
       
  • Application of the Concept of Oxime Library Screening by Mass Spectrometry
           (MS) Binding Assays to Pyrrolidine-3-carboxylic Acid Derivatives as
           Potential Inhibitors of γ-Aminobutyric Acid Transporter 1 (GAT1)
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Simone K. Huber, Georg Höfner, Klaus T. Wanner In the present study, the concept of oxime library screening by MS Binding Assays was successfully extended to N-substituted lipophilic pyrrolidine-3-carboxylic acid derivatives in the pursuit of varying the amino acid motif in order to identify new inhibitors for GAT1 and to broaden structure-activity-relationships for this target, the most abundant GABA transporter in the central nervous system. For the screening, 28 different oxime sub-libraries were employed that were generated by simple condensation reaction of an excess of pyrrolidine-3-carboxylic acid derivatives carrying a hydroxylamine functionality with various sub-libraries each assembled of eight aldehydes with broadly varying chemical structures and functionalities. The compounds responsible for the activity of an oxime sub-library were identified by deconvolution experiments performed by employing single oximes. Binding affinities of the oxime hits were confirmed in full-scale competitive MS Binding Assays. Thereby, oxime derivatives with a 1,1’-biphenyl moiety were found as the first inhibitors of mGAT1 comprising a pyrrolidine-3-carboxylic acid motif with affinities in the submicromolar range.Graphical abstractGraphical abstract for this article
       
  • Insights of synthetic analogues of anti-leprosy agents
    • Abstract: Publication date: Available online 2 May 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Smritilekha Bera, Dhananjoy Mondal Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leading cause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and antitumour and anti-angiogenesis evaluation of 22
           moscatilin derivatives
    • Abstract: Publication date: Available online 27 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Li Guan, Junting Zhou, Qinghua Lin, Huilin Zhu, Wenyuan Liu, Baolin Liu, Yanbo Zhang, Jie Zhang, Jing Gao, Feng Feng, Wei Qu Two series of moscatilin derivatives were designed, synthesized and evaluated as anti-tumor and anti-angiogenesis agents. Most of these compounds showed moderate-to-obvious cytotoxicity against five cancer cell lines (A549, HepG2, MDA-MB-231, MKN-45, HCT116). Among these cell lines, compounds had obvious effects on HCT116. Especially for 8Ae, the IC50 was low to 0.25 μM. 8Ae can inhibit the viability and induce the apoptosis of HCT116 cells but exhibit no cytotoxic activity in noncancerous NCM460 colon cells. 8Ae can also arrest the G2/M cell cycle in HCT116 cells by inhibiting the α-tubulin expression. Zebrafish bioassay-guided screen showed the 22 moscatilin derivatives had potent anti-angiogenic activities and compound 8Ae had better activities than positive compound. Molecular docking indicated 8Ae interacted with tubulin at the affinity of −7.2 Kcal/mol. In conclusion, compound 8Ae was a potential antitumor and anti-angiogenesis candidate for further development.Graphical abstractGraphical abstract for this article
       
  • Enantioselective Total Synthesis of Altersolanol A and N
    • Abstract: Publication date: Available online 27 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Bastian Mechsner, Dietrich Böse, Fabian Hogenkamp, Nadia Ledermann, Rudolf Hartmann, Kevin Bochinsky, Wolfgang Frey, Jörg Pietruszka The development of the first enantioselective total synthesis of Altersolanol N is reported. The decisive step of the synthesis is the enantioselective formation of the tetrahydroanthraquinone nucleus by a [4+2]-cycloaddition in high yield and with excellent diastereo- and enantioselectivity (>95:5 dr and 95:5 er). In addition, a demanding selective monoacetylation of the OH group at the C-2 position was achieved: an epoxide ring opening with the participation of a neighbouring acetyl group could be established. The route proved to be an efficient alternative to also access enantiomerically pure Altersolanol A.Graphical abstractGraphical abstract for this article
       
  • Synthesis, biological evaluation, and molecular docking study of sulfonate
           derivatives as nucleotide pyrophosphatase (NPPs) inhibitors
    • Abstract: Publication date: Available online 26 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Mohammad H. Semreen, Mohammed I. El-Gamal, Saif Ullah, Saquib Jalil, Sumera Zaib, Hanan S. Anbar, Joanna Lecka, Jean Sévigny, Jamshed Iqbal A new series of sulfonate derivatives 1a-zk were synthesized and evaluated as inhibitors of nucleotide pyrophosphatases. Most of the compounds exhibited good to moderate inhibition towards NPP1, NPP2, and NPP3 isozymes. Compound 1m was a potent and selective inhibitor of NPP1 with an IC50 value of 0.387 ± 0.007 µM. However, the most potent inhibitor of NPP3 was found as 1x with an IC50 value of 0.214 ± 0.012 µM. In addition, compound 1e was the most active inhibitor of NPP2 with an IC50 value of 0.659 ± 0.007 µM. Docking studies of the most potent compounds were carried out, and the computational results supported the in vitro results.Graphical abstractDocking pose of compound 1x into the crystal structure of NPP3Graphical abstract for this article
       
  • Synthesis and biological evaluation of
           Tc-99m-cyclopentadienyltricarbonyl-technetium-labeled A-85380: An imaging
           probe for single-photon emission computed tomography investigation of
           nicotinic acetylcholine receptors in the brain
    • Abstract: Publication date: Available online 25 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hiroyuki Kimura, Masashi Ueda, Hidekazu Kawashima, Kenji Arimitsu, Yusuke Yagi, Hideo Saji We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT–A–E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR–A–E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT–A–E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT–A–E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT–A–E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT–A–E to the brain, [99mTc]CPTT–A–E met the basic requirements for nAChR imaging.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s):
       
  • Unveiling the druggable RNA targets and small molecule therapeutics
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Joanna Sztuba-Solinska, Gabriela Chavez-Calvillo, Sabrina Elizabeth Cline The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets.Graphical abstractGraphical abstract for this article
       
  • Inhibition of pre-miRNA-136 processing by Dicer with small molecule BzDANP
           suggested the formation of ternary complex of pre-miR-136–BzDANP–Dicer
           
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Takahiro Otabe, Konami Nagano, Gota Kawai, Asako Murata, Kazuhiko Nakatani Small-molecule modulators, along with antisense oligonucleotide, would be powerful tools and potential drug candidates for modulating miRNA-related gene expressions. The mechanism of the inhibitory effect of the C-bulge binding small molecule BzDANP for the Dicer processing reaction of pre-miR-136 was discussed on the data obtained by SPR, NMR, and kinetic analysis for Dicer processing. SPR and NMR analysis showed the preference of BzDANP binding to the C-bulge. Michaelis-Menten analysis suggested the formation of a ternary complex pre-miR-136–BzDANP–Dicer during the Dicer-cleavage reaction of pre-miR-136 in the presence of BzDANP. The inhibitory effect of BzDANP is likely attributed to the slower reaction from the ternary complex than that from the binary pre-miR-136–Dicer complex.Graphical abstractGraphical abstract for this article
       
  • Discovery of thiazolidin-4-one urea analogues as novel multikinase
           inhibitors that potently inhibit FLT3 and VEGFR2
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Baohui Qi, Xingwei Xu, Ying Yang, Yuting Zhou, Tao Chen, Guowei Gong, Xupeng Yue, Xin Xu, Liping Hu, Huan He A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC50 values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC50 = 8.6 nM) and VEGFR2 (IC50 = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.Graphical abstractGraphical abstract for this article
       
  • Development of a platform for activatable fluorescent substrates of
           glucose transporters (GLUTs)
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Tomohiro Takasugi, Kenjiro Hanaoka, Ayako Sasaki, Takayuki Ikeno, Toru Komatsu, Tasuku Ueno, Katsuya Yamada, Yasuteru Urano We have developed a platform for activatable fluorescent substrates of glucose transporters (GLUTs). We firstly conjugated fluorescein to glucosamine via an amide or methylene linker at the C-2 position of d-glucosamine, but the resulting compounds, FLG1 and FLG2, showed no uptake into MIN6 cells. So, we changed the fluorophore moiety to a fluorescein analogue, 2-Me TokyoGreen, which is less negatively charged. TokyoGreen-conjugated glucosamines TGG1 and TGG2 were successfully taken up into cells via GLUT. We further derivatized TGG1 and TGG2, and among the synthesized compounds, 2-Me-4-OMe TGG showed weak fluorescence under the acidic conditions of the extracellular environment inside tumors and in gastric cancers, and strong fluorescence at the intracellular physiological pH, under the control of a photoinduced electron transfer (PeT) process. This fluorogenic platform should be useful for developing a range of activatable fluorescent substrates targeting GLUTs, as well as derivatives that would be fluorescently activated by various intracellular enzymes, such as esterases, β-galactosidase and bioreductases.Graphical abstractGraphical abstract for this article
       
  • Synthesis and evaluation of bi-functional 7-hydroxycoumarin platinum(IV)
           complexes as antitumor agents
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Qingpeng Wang, Yan Chen, Guoshuai Li, Zhifang Liu, Jing Ma, Min Liu, Dacheng Li, Jun Han, Bingquan Wang A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.Graphical abstractGraphical abstract for this article
       
  • Chemical synthesis, microbial transformation and biological evaluation of
           tetrahydroprotoberberines as dopamine D1/D2 receptor ligands
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Haixia Ge, Yan Zhang, Zhuo Yang, Kun Qiang, Chao Chen, Laiyu Sun, Ming Chen, Jian Zhang Dopamine D1/D2 receptors are important targets for drug discovery in the treatment of central nervous system diseases. To discover new and potential D1/D2 ligands, 17 derivatives of tetrahydroprotoberberine (THPB) with various substituents were prepared by chemical synthesis or microbial transformation using Streptomyces griseus ATCC 13273. Their functional activities on D1 and D2 receptors were determined by cAMP assay and calcium flux assay. Seven compounds showed high activity on D1/D2 receptor with low IC50 values less than 1 µM. Especially, top compound 5 showed strong antagonistic activity on both D1 and D2 receptor with an IC50 of 0.391 and 0.0757 µM, respectively. Five compounds displayed selective antagonistic activity on D1 and D2 receptor. The SAR studies revealed that (1) the hydroxyl group at C-9 position plays an important role in keeping a good activity and small or fewer substituents on ring D of THPBs may also stimulate their effects, (2) the absence of substituents at C-9 position tends to be more selective for D2 receptor, and (3) hydroxyl substitution at C-2 position and the substitution at C-9 position may facilitate the conversion of D1 receptor from antagonist to agonist. Molecular docking simulations found that Asp 103/Asp 114, Ser 107/Cys 118, and Trp 285/ Trp 386 of D1/ D2 receptors are the key residues, which have strong interactions with the active D1/D2 compounds and may influence their functional profiles.Graphical abstractGraphical abstract for this article
       
  • 6-Bromoindolglyoxylamido derivatives as antimicrobial agents and
           antibiotic enhancers
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Steven A. Li, Melissa M. Cadelis, Kenneth Sue, Marine Blanchet, Nicolas Vidal, Jean Michel Brunel, Marie-Lise Bourguet-Kondracki, Brent R. Copp The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa. A series of 6-bromo derivatives (5–15) were prepared and biologically evaluated, identifying analogues with enhanced antibacterial activity towards Escherichia coli and with moderate to excellent antifungal properties. Polyamine 3, which includes a spermine chain, was the most potent of the series – its mechanism of action was attributed to rapid membrane permeabilization and depolarization in both Gram-positive and Gram-negative bacteria.Graphical abstractGraphical abstract for this article
       
  • Kinase inhibitions in pyrido[4,3-h] and [3,4-g]quinazolines: Synthesis,
           SAR and molecular modeling studies
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Wael Zeinyeh, Yannick J. Esvan, Béatrice Josselin, Blandine Baratte, Stéphane Bach, Lionel Nauton, Vincent Théry, Sandrine Ruchaud, Fabrice Anizon, Francis Giraud, Pascale Moreau New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities.Graphical abstractGraphical abstract for this article
       
  • Synthesis and characterization of hydrogen peroxide activated estrogen
           receptor beta ligands
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Hyejin Park, Joseph D. McEachon, Julie A. Pollock The development and evaluation of selective estrogen receptor modulators (SERMs) is of interest because of the complex and significant role of estrogen receptors in normal tissues as well as disease states. In neurodegenerative disorders such as Alzheimer’s disease and multiple sclerosis, estrogen receptor beta (ERβ) seems to provide a protective anti-inflammatory response. Due to the increase in reactive oxygen species (ROS) in these diseases, we have masked ERβ ligands, including diarylpropionitrile (DPN), as boronate esters that release the active estrogen in the presence of H2O2. Here we demonstrate their synthesis, decreased binding affinities, kinetics of release, and selectivity toward ROS. The most promising ligand can be unmasked in the presence of pathological H2O2 to modulate ERβ transcription in cells.Graphical abstractGraphical abstract for this article
       
  • Characterising covalent warhead reactivity
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): James S. Martin, Claire J. MacKenzie, Daniel Fletcher, Ian H. Gilbert Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.Graphical abstractGraphical abstract for this article
       
  • Synthesis and structure-activity relationships for new 6-fluoroquinoline
           derivatives with antiplasmodial activity
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Patrick Hochegger, Johanna Faist, Werner Seebacher, Robert Saf, Pascal Mäser, Marcel Kaiser, Robert Weis The substitution of 6-fluoroquinolines was modified in ring positions 2 and 4. The new compounds were tested in vitro for their activities against a sensitive and a multidrug resistant strain of Plasmodium falciparum. Some physicochemical parametres were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability). The most promising compounds were tested for their in vivo activity against Plasmodium berghei in a mouse model. The 6-fluoro-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-N-[2-(pyrrolidin-1-yl)ethyl]quinoline-4-carboxamide possessed proper physicochemical properties and showed high antiplasmodial activity in vitro (IC50 ≤ 0.0029 µM) and in vivo (99.6% activity).Graphical abstractGraphical abstract for this article
       
  • Anticancer profile of newly synthesized BRAF inhibitors possess
           5-(pyrimidin-4-yl)imidazo[2,1-b]thiazole scaffold
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Mohammed S. Abdel-Maksoud, Usama M. Ammar, Chang-Hyun Oh In this work, a new series of imidazo[2,1-b]thiazole was designed and synthesized. The new compounds are having 3-fluorophenyl at position 6 of imidazo[2,1-b]thiazole and pyrimidine ring at position 5. The pyrimidine ring containing either amide or sulphonamide moiety attached to a linker (ethyl or propyl) at position 2 of the pyrimidine ring. The final compounds were selected by NCI for in vitro cytotoxicity screening. Most derivatives showed cytotoxic activity against colon cancer and melanoma cell lines. In addition, IC50s of the target compounds were determined over A375 and SK-MEL-28 cell lines using sorafenib as positive control. Compounds12b, 12c, 12e, 12f, 15a, 15d, 15f, 14g and 15h exhibited superior activity when compared to sorafenib. The most potent compounds were tested against wild type BRAF, v600e BRAF, and CRAF. Compound 15h exhibited a potential inhibitory effect againstV600EBRAF (IC50 = 9.3 nM).Graphical abstractGraphical abstract for this article
       
  • Discovery, synthesis, biological evaluation and molecular docking study of
           (R)-5-methylmellein and its analogs as selective monoamine oxidase A
           inhibitors
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Chao Huang, Juan Xiong, Hui-Da Guan, Chang-Hong Wang, Xinsheng Lei, Jin-Feng Hu (R)-5-Methylmellein (5-MM), the major ingredient in the fermented mycelia of the medicinal fungus Xylaria nigripes (called Wuling Shen in Chinese)¸ was found to be a selective inhibitor against monoamine oxidase A (MAO-A) and might play an important role in the clinical usage of this edible fungus as an anti-depressive traditional Chinese medicine (TCM). Based on the discovery and hypothesis, a variety of (R)-5-MM analogs were synthesized and evaluated in vitro against two monoamine oxidase isoforms (MAO-A and MAO-B). Most synthetic analogs showed selective inhibition of MAO-A with IC50 values ranging from 0.06 to 29 µM, and compound 13aR is the most potent analog with high selectivity (IC50, MAO-A: 0.06 µM; MAO-B:>50 µM). Interestingly, the enzyme kinetics study of 13aR indicated that this ligand seemed to bind in the MAO-A active site according to so-called “tight-binding inhibition” mode. The molecular docking study of 13aR was thereafter performed in order to rationalize the obtained biological results.Graphical abstractGraphical abstract for this article
       
  • Scaffold hopping of fused piperidine-type NK3 receptor antagonists to
           reduce environmental impact
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Koki Yamamoto, Shinsuke Inuki, Hiroaki Ohno, Shinya Oishi Neurokinin-3 receptor (NK3R) plays a pivotal role in the release of gonadotropin-releasing hormone in the hypothalamus–pituitary–gonadal (HPG) axis. To develop novel NK3R antagonists with less environmental toxicity, a series of heterocyclic scaffolds for the triazolopiperazine substructure in an NK3R antagonist fezolinetant were designed and synthesized. An isoxazolo[3,4–c]piperidine derivative exhibited moderate NK3R antagonistic activity and favorable properties that were decomposable under environmental conditions.Graphical abstractGraphical abstract for this article
       
  • Proline-based hydroxamates targeting the zinc-dependent deacetylase LpxC:
           Synthesis, antibacterial properties, and docking studies
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Dmitrii V. Kalinin, Oriana Agoglitta, Hélène Van de Vyver, Jelena Melesina, Stefan Wagner, Burkhard Riemann, Michael Schäfers, Wolfgang Sippl, Bettina Löffler, Ralph Holl The Zn2+-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d- and l-proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l-proline-based tertiary amine 41g ((S)-N-hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (Ki = 1.4 μM) over several human MMPs.Graphical abstractGraphical abstract for this article
       
  • Syntheses and evaluation of a homologous series of aza-vesamicol as
           improved radioiodine-labeled probes for sigma-1 receptor imaging
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Kazuma Ogawa, Ryohei Masuda, Kenji Mishiro, Mengfei Wang, Takashi Kozaka, Kazuhiro Shiba, Seigo Kinuya, Akira Odani Sigma-1 receptor imaging probes for determining the expression levels are desirable for diagnoses of various diseases and companion diagnoses of therapeutic agents targeting the sigma-1 receptor. In this study, we aimed to develop probes with higher affinity for the sigma-1 receptor. For this purpose, we synthesized and evaluated compounds, namely, vesamicol derivatives, in which alkyl chains of varying chain length were introduced between a piperazine ring and a benzene ring. The binding affinity of the vesamicol derivatives for the sigma-1 receptor tended to increase depending on the length of the alkyl chain between the benzene ring and the piperazine ring. The sigma-1 receptor of 2-(4-(3-phenylpropyl)piperazin-1-yl)cyclohexan-1-ol (5) (Ki = 5.8 nM) exhibited the highest binding affinity; therefore, we introduced radioiodine into the benzene ring in 5. The radioiodine labeled probe [125I]2-(4-(3-(4-iodophenyl)propyl)piperazin-1-yl)cyclohexan-1-ol ([125I]10) showed high accumulation in the sigma-1 receptor expressing DU-145 cells both in vitro and in vivo. Co-injection of [125I]10 with an excess level of a sigma receptor ligand, haloperidol, resulted in a significant decrease in the tumor accumulation in vitro and in vivo, indicating sigma receptor-mediated tumor uptake. These results provide useful information for developing sigma-1 receptor imaging probes.Graphical abstractGraphical abstract for this article
       
  • Identification and design of novel small molecule inhibitors against
           MERS-CoV papain-like protease via high-throughput screening and molecular
           modeling
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Hyun Lee, Jinhong Ren, Russell P. Pesavento, Isabel Ojeda, Amy J. Rice, Haining Lv, Youngjin Kwon, Michael E. Johnson The development of new therapeutic agents against the coronavirus causing Middle East Respiratory Syndrome (MERS) is a continuing imperative. The initial MERS-CoV epidemic was contained entirely through public health measures, but episodic cases continue, as there are currently no therapeutic agents effective in the treatment of MERS-CoV, although multiple strategies have been proposed. In this study, we screened 30,000 compounds from three different compound libraries against one of the essential proteases, the papain-like protease (PLpro), using a fluorescence-based enzymatic assay followed by surface plasmon resonance (SPR) direct binding analysis for hit confirmation. Mode of inhibition assays and competition SPR studies revealed two compounds to be competitive inhibitors. To improve upon the inhibitory activity of the best hit compounds, a small fragment library consisting of 352 fragments was screened in the presence of each hit compound, resulting in one fragment that enhanced the IC50 value of the best hit compound by 3-fold. Molecular docking and MM/PBSA binding energy calculations were used to predict potential binding sites, providing insight for design and synthesis of next-generation compounds.Graphical abstractGraphical abstract for this article
       
  • Structure and biological evaluation of new cyclic and acyclic laxaphycin-A
           type peptides
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Louis Bornancin, Eva Alonso, Rebeca Alvariño, Nicolas Inguimbert, Isabelle Bonnard, Luis M. Botana, Bernard Banaigs Five new laxaphycins were isolated and fully characterised from the bloom forming cyanobacteria Anabaena torulosa sampled from Moorea, French Polynesia: three acyclic laxaphycin A-type peptides, acyclolaxaphycin A (1), [des-Gly11]acyclolaxaphycin A (2) and [des-(Leu10-Gly11)]acyclolaxaphycin A (3), as well as two cyclic ones, [l-Val8]laxaphycin A (4) and [d-Val9]laxaphycin A (5). The absolute configuration of the amino acids, established using advanced Marfey’s analysis for compounds 2–5, highlights a conserved stereochemistry at the Cα carbons of the peptide ring that is characteristic of this family. To the best of our knowledge, this is the first report of acyclic analogues within the laxaphycin A-type peptides. Whether these linear laxaphycins with the aliphatic β-amino acid on the N-terminal are biosynthetic precursors or compounds obtained after enzymatic hydrolysis of the macrocycle is discussed. Biological evaluation of the new compounds together with the already known laxaphycin A shows that [l-Val8]laxaphycin A, [d-Val9]laxaphycin A and [des-Gly11]acyclolaxaphycin induce cellular toxicity whereas laxaphycin A and des-[(Leu10-Gly11)]acyclolaxaphycin A do not affect the cellular viability. An analysis of cellular death shows that the active peptides do not induce apoptosis or necrosis but instead, involve the autophagy pathway.Graphical abstractGraphical abstract for this article
       
  • Specific stabilization of DNA G-quadruplex structures with a chemically
           modified complementary probe
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Min Liu, Yaqian Liu, Fan Wu, Yuhao Du, Xiang Zhou The DNA G-quadruplex is an important higher-order structure formed from guanine-rich DNA sequences. There are many molecules which can stabilize this structure. However, the selectivity of these ligands to different G-quadruplexes was not satisfactory. Herein, we designed and synthesized a chemically modified G-quadruplex probe, Razo-DNA, for the unique stabilization of the G-quadruplex. Razo-DNA consists of two fragments: The first is an organic molecular moiety which can stabilize G-quadruplex structures, and the second is a DNA molecule that is complementary with a sequence adjacent to the guanine-rich sequence of targeted DNA. Further studies showed that Razo-DNA could precisely stabilize the targeted DNA G-quadruplex structures in vitro.Graphical abstractGraphical abstract for this article
       
  • Structure-activity relationship study of estrogen receptor down-regulators
           with a diphenylmethane skeleton
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Shun Nanjyo, Kenji Ohgane, Hiromasa Yoshioka, Makoto Makishima, Yuichi Hashimoto, Tomomi Noguchi-Yachide Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.Graphical abstractGraphical abstract for this article
       
  • Chemical modifications of imidazole-containing alkoxyamines increase
           C–ON bond homolysis rate: Effects on their cytotoxic properties in
           glioblastoma cells
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s): Toshihide Yamasaki, Duje Buric, Christine Chacon, Gérard Audran, Diane Braguer, Sylvain R.A. Marque, Manon Carré, Paul Brémond Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine (RS/SR)-4a, with both a high antitumour activity and favourable logD7.4 and pKa values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 15 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 10Author(s):
       
  • Tetramethylrhodamine is an Essential Scaffold of Azide Probe in Detecting
           Cellular Acrolein
    • Abstract: Publication date: Available online 20 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Ambara R. Pradipta, Motoko Fujii, Tomonori Tanei, Koji Morimoto, Kenzo Shimazu, Shinzaburo Noguchi, Katsunori Tanaka Tetramethylrhodamine (TAMRA)-phenyl azide is a chemical probe used to detect intracellular acrolein directly in live cells. Herein, we demonstrated that TAMRA is the optimum fluorophore for the probe. TAMRA-phenyl azide was used to reveal that high levels of acrolein are generated in a variety of breast cancer cells, regardless of the tumor subtype. These findings corroborate the analysis presented in our previous report, in which TAMRA-phenyl azide was used to label breast cancer tissues resected from breast cancer patients. Because high levels of acrolein were generated in all cancer cell types, we believe that acrolein detection may be useful as a general method for labeling cancerous tissues.Graphical abstractGraphical abstract for this article
       
  • Identification of potent farnesoid X receptor (FXR) antagonist showing
           favorable PK profile and distribution toward target tissues: Comprehensive
           understanding of structure-activity relationship of FXR antagonists
    • Abstract: Publication date: Available online 20 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Naoki Teno, Yukiko Yamashita, Arisa Masuda, Yusuke Iguchi, Keisuke Oda, Ko Fujimori, Takie Hiramoto, Tomoko Nishimaki-Mogami, Mizuho Une, Keigo Gohda Antagonizing transcriptional activity of farnesoid X receptor (FXR) in the intestine has been reported as an effective means for the treatment of nonalcoholic fatty liver disease, type 2 diabetes and obesity. We describe herein that the building blocks necessary to maintain the antagonism of our chemotype were investigated in order to modulate in vivo pharmacokinetic behavior and the tissue distribution without blunting the activity against FXR. A comprehensive understanding of the structure-activity relationship led to analogue 30, which is superior to 12 in terms of its pharmacokinetic profiles by oral administration and its tissue distribution toward target tissues (liver and ileum) in rats while preserving the in vitro activity of 12 against FXR. Thus, 30 should be a candidate compound to investigate the effects of inhibiting FXR activity while simultaneously improving the outcome of nonalcoholic fatty liver disease, type 2 diabetes and obesity.Graphical abstractGraphical abstract for this article
       
  • Corrigendum to “Synthesis and SAR of novel capsazepine analogs with
           significant anti-cancer effects in multiple cancer types” [Bioorg. Med.
           Chem. 27 (1) (2019) 208–215]
    • Abstract: Publication date: Available online 20 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Jorge De La Chapa, Matthew Valdez, Francisco Ruiz, Keith Gonzales, Wes Mitchell, Stanton F. McHardy, Matthew J. Hart, Srikanth R. Polusani, Cara B. Gonzales
       
  • Discovery of 4,6-bis(benzyloxy)-3-phenylbenzofuran as a novel Pin1
           inhibitor to suppress hepatocellular carcinoma via upregulating microRNA
           biogenesis
    • Abstract: Publication date: Available online 19 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Xin Fan, Huaiyu He, Jiao Li, Guoyong Luo, Yuanyuan Zheng, Jian-Kang Zhou, Juan He, Wenchen Pu, Yun Zhao Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) participates in diverse cancer-associated signaling pathways, playing an oncogenic role in multiple human cancers, including hepatocellular carcinoma (HCC). Our recent works clarify that Pin1 modulates miRNAs biogenesis by interacting with ERK-phosphorylated exportin-5 (XPO5) and changing XPO5 conformation, giving a potential target for HCC treatment. Herein, we discover 4,6-bis(benzyloxy)-3-phenylbenzofuran (TAB29) as a novel Pin1 inhibitor that targets Pin1 PPIase domain. TAB29 potently inhibits Pin1 activity with the IC50 value of 874 nM and displays an excellent selectivity toward Pin1 in vitro. Cell-based biological evaluation reveals that TAB29 significantly suppresses cell proliferation of HCC cells through restoring the nucleus-to-cytoplasm export of XPO5 and upregulating mature miRNAs expression. Collectively, this work provides a promising small molecule lead compound for Pin1 inhibition, highlighting the therapeutic potential of miRNA-based treatment for human cancers.Graphical abstractGraphical abstract for this article
       
  • Pyridone-containing Phenalenone-based Photosensitizer Working Both under
           Light and in the Dark for Photodynamic Therapy
    • Abstract: Publication date: Available online 17 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yifei Jing, Qi Xu, Meijun Chen, Xusheng Shao Photosensitizer attracts great attentions and has potential applications in cancer treatment. We developed here a novel pyridone-containing phenalenone-based (PPN-PYR) photosensitizer with excellent singlet oxygen generating ability. Upon light irradiation, PPN-PYR can produce singlet oxygen and transform to its endoperoxide form which in turn release singlet oxygen via thermal cycloreversion at dark. The ability of PPN-PYR to generate reactive oxygen species (ROS) in cell culture and induce corresponding apoptosis both at dark and under light was demonstrated. The efficient PDT performance of PPN-PYR was further verified on cancer cell in vitro. Our study indicate that PPN-PYR can alleviate tumor hypoxia problem and enhance the availability of intermittent photodynamic therapy.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of 4-
           aniline-thieno[2,3-d]pyrimidine derivatives as MNK1 inhibitors against
           renal cell carcinoma and nasopharyngeal carcinoma
    • Abstract: Publication date: Available online 17 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Min Zhang, Li Jiang, Jia Tao, Zhaoping Pan, Mingyao He, Dongyuan Su, Gu He, Qinglin Jiang MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1) play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and protein levels. Based on the crystallographic structure of MNK1 protein and binding modes analysis of known MNK inhibitors, we have designed and synthesized a series of 4-aniline-thieno[2,3-d]pyrimidine derivatives as potential MNK1 inhibitors. These synthetic compounds are tested in biochemical and cell proliferation assays, and six of them display potent inhibitory capacity against MNK1 kinase and cancer cell lines. Compound 12dj with strongest inhibitory capacity is transferred to molecular mechanism studies, and the results indicated that 12dj remarkably suppresses the phosphorylation of EIF4E, a substrate of MNK1. And the expression levels of MNK1, ERK1/2 and pERK1/2 are not affected by compound 12dj incubation in SUNE-1 and 786-O cells. In summary, our works suggested that these novel 4-aniline-thieno[2,3-d]pyrimidine based MNK1 inhibitors might be attractive lead compounds for targeted therapy of renal cell carcinoma and nasopharyngeal carcinoma.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis, and biological evaluation of some novel
           4-aminoquinazolines as Pan-PI3K inhibitors
    • Abstract: Publication date: Available online 17 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Huai-Wei Ding, Shu Wang, Xiao-Chun Qin, Jian Wang, Hong-Rui Song, Qing-Chun Zhao, Shao-Jiang Song A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents.Graphical abstractGraphical abstract for this article
       
  • Synthesis of andrographolide analogues and their neuroprotection and
           neurite outgrowth-promoting activities
    • Abstract: Publication date: Available online 16 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yuanzhen Xu, Hongbo Wei, Jianping Wang, Weiwei Wang, Jinming Gao Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and remains incurable. Currently, neuronal injury and synapse loss have been considered to be main features in the pathophysiology of AD. Thus, modulation of neuronal survival and neurite outgrowth may represent an efficient strategy for the treatment of AD. Based on the isolates from the traditional medicine Andrographis paniculata, a series of andrographolide analogues were prepared and evaluated for the neuroprotection and neurotrophic activity. Two compounds (3 and 12) could effectively inhibit LPS-induced NO production and iNOS expression as well as proinflammatory cytokines TNF-α and IL-6. Moreover, pretreatment with 3 and 12 could protect neurons against microglia-mediated neurotoxicity. Further, H2O2- and 6-OHDA induced neurotoxicity in PC12 cells were also attenuated by the novel 12. Our next study indicated that compounds 1, 4 and 10 promoted NGF-induced neurite outgrowth in PC12 cells, with 10 the most potent. To clarify the underlying mechanisms of active compounds (3, 10 and 12), system pharmacology was employed. The results revealed that muscarinic acetylcholine receptors (mAChRs) may be the main targets of 12 against AD, while thyroid hormone signaling pathway was involved in the mechanisms of 10. These study point to the therapeutic potential of andrographolide analogues against AD.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and biological evaluation of novel
           chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as
           potential PI3Kα inhibitors
    • Abstract: Publication date: Available online 15 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yong Yin, Jia-Qin Hu, Xu Wu, Shao Sha, She-Feng Wang, Fang Qiao, Zhong-Cheng Song, Hai-Liang Zhu A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα.Graphical abstractGraphical abstract for this article
       
  • Antioxidant, anti-tyrosinase and anti-melanogenic effects of
           (E)-2,3-diphenylacrylic acid derivatives
    • Abstract: Publication date: Available online 15 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Sultan Ullah, Yujin Park, Chaeun Park, Sanggwon Lee, Dongwan Kang, Jungho Yang, Jinia Akter, Pusoon Chun, Hyung Ryong Moon During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-β-phenyl-α,β-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a – 1n and one (Z)-2,3-DPA-derivative 1l' using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43±3.53%, IC50 = 20.04±1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56±2.93%, IC50 = 30.64±1.27 μM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (-7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (-5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 μM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 μM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.Graphical abstractGraphical abstract for this article
       
  • Targeted delivery of atorvastatin via asialoglycoprotein receptor (ASGPR)
    • Abstract: Publication date: Available online 11 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Youxi Zhang, Xinfu Zhang, Chunxi Zeng, Bin Li, Chengxiang Zhang, Wenqing Li, Xucheng Hou, Yizhou Dong Targeted drug delivery platforms can increase the concentration of drugs in specific cell populations, reduce adverse effects, and hence improve the therapeutic effect of drugs. Herein, we designed two conjugates by installing the targeting ligand GalNAc (N-acetylgalactosamine) onto atorvastatin (AT). Compared to the parent drug, these two conjugates, termed G2-AT and G2-K-AT, showed increased hepatic cellular uptake. Moreover, both conjugates were able to release atorvastatin, and consequently showed dramatic inhibition of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) reductase and increased LDL receptors on cell surface.Graphical abstractGraphical abstract for this article
       
  • Benzofuran-isatin hybrids tethered via different length alkyl linkers and
           their in vitro anti-mycobacterial activities
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Feng Gao, Zijian Chen, Long Ma, Lin Qiu, Jianguo Lin, Guangming Lu A series of novel benzofuran-isatin hybrids 6a-m tethered through different length alkyl linkers propylene, butylene, pentylene and hexylene were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against both drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (MTB) and cytotoxicity towards VERO cells. All hybrids with acceptable cytotoxicity in VERO cells (CC50: 64->1,024 μg/mL) also exhibited considerable anti-mycobacterial activities against both drug-susceptible and MDR-MTB strains with MIC in a range of 0.125 to 4 μg/mL. The SAR indicated that the length of the linker played a pivotal role on the activity, and the longer linker could enhance the activity. The most active hybrid 6d (MIC: 0.125 and 0.125 μg/mL) was comparable to or better than rifampicin (MIC: 0.5 μg/mL) and isoniazid (MIC: 0.06 μg/mL) against MTB H37Rv, and was ≥256 folds more potent than rifampicin (MIC: 64 μg/mL) and isoniazid (MIC:>128 μg/mL) against MDR-MTB strain, but was less active than TAM16 (MIC:
       
  • Novel 7-Formyl-naphthyridyl-ureas Derivatives as Potential Selective FGFR4
           Inhibitors: Design, Synthesis, and Biological Activity Studies
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Chang'an Sun, Lei Fang, Xiaobing Zhang, Peng Gao, Shaohua Gou Total twenty-five 7-formyl-naphthyridyl-urea derivatives were designed, synthesized and evaluated for their inhibition of FGFR4 kinase and antitumor activity. The pharmacological data indicated that most of the tested compounds showed high selectivity towards FGFR4 kinase and could significantly inhibit FGFR4 and the tumor cells lines with the high expression of FGFR4. In particular, compounds 6f, 6g, 6h, 6l, 6m and 6s showed a good performance in pharmacokinetic tests. When tested in mice, the representative compound 6f was found to have good pharmacokinetic parameters, low toxicity, and better tumor inhibiting activity in vivo.Graphical abstractGraphical abstract for this article
       
  • Orientation preferences of hairpin pyrrole–imidazole polyamides
           toward mCGG site
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Shinsuke Sato, Sefan Asamitsu, Toshikazu Bando, Hiroshi Sugiyama Hairpin pyrrole–imidazole (Py-Im) polyamides are promising medium-sized molecules that bind sequence-specifically to the minor groove of B-form DNA. Here, we synthesized a series of hairpin Py-Im polyamides and explored their binding affinities and orientation preferences to methylated DNA with the mCGG target sequence. Thermal denaturation assays revealed that the five hairpin Py-Im polyamides, which were anticipated to recognize mCGG in a forward orientation, bind to nontarget DNA, GGmC, in a reverse orientation. Therefore, we designed five Py-Im polyamides that could recognize mCGG in a reverse orientation. We found that the two Py-Im polyamides containing Im/β pairs preferentially bound to mCGG in a reverse orientation. The reverse binding Py-Im polyamide successfully inhibited TET1 binding on the methylated DNA. Taken together, this study illustrated the importance of designing reverse binding Py-Im polyamides for the target sequence, mCGG, which paved the way for Py-Im polyamides that can be used with otherwise difficult to access DNA with CG sequences.Graphical abstractGraphical abstract for this article
       
  • \Veratric acid derivatives containing benzylidene-hydrazine moieties as
           promising tyrosinase inhibitors and free radical scavengers
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Zahra Dehghani, Mahsima Khoshneviszadeh, Mehdi Khoshneviszadeh, Sara Ranjbar Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. A series of veratric acid derivatives containing benzylidene-hydrazine moieties with different substitutions were synthesized and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The results indicated that N'-(4-chlorobenzylidene)-3,4-dimethoxybenzohydrazide (D5) and N'-(2,3-dihydroxybenzylidene)-3,4-dimethoxybenzohydrazide (D12) showed the highest tyrosinase inhibitory activity with IC50 values of 19.72±1.84 and 20.63±0.79 μM, respectively, that were comparable with the IC50 value of kojic acid (19.08±1.21 μM). D12 was also a potent radical scavenger with EC50 value of 0.0097±0.0011 mM. The free radical scavenging activity of D12 was comparable with the standard quercetin. The inhibition kinetic analyzed by Lineweaver–Burk plots revealed that compound D5 was a competitive tyrosinase inhibitor. Molecular docking study was carried out for the derivatives demonstrating tyrosinase inhibitory activity. D5 and D12 possessed the most negative estimated free energies of binding in mushroom tyrosinase active site. Therefore, D5 and D12 could be introduced as potent tyrosinase inhibitors that might be promising leads in medicine, cosmetics and food industry.Graphical abstractGraphical abstract for this article
       
  • Development of 99mTc-labeled trivalent isonitrile radiotracer
           for folate receptor imaging
    • Abstract: Publication date: Available online 10 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Nadeem Ahmed Lodhi, Ji Yong Park, Mi Kyung Hong, Young Joo Kim, Yun-Sang Lee, Gi Jeong Cheon, Jae Min Jeong Folate receptors (FR) are frequently overexpressed in a wide variety of human cancers. The aim of this study was to develop a trivalent 99mTc(CO)3-labeled folate radiotracer containing isonitrile (CN-R) as the coordinating ligand for FR target imaging. [99mTc]Tc-10 was HPLC purified (>98% chemical purity) and evaluated in vitro and in vivo as a potential agent for targeting FR-positive KB cells. [99mTc]Tc-10 is a hydrophilic compound with partition coefficient of −2.90 ± 0.13 that showed high binding affinity (0.04 ± 0.002 nM) in vitro. High accumulation and retention of [99mTc]Tc-10 (5.32 ± 2.99% ID/g) was observed in mice with KB tumors at 4 h after injection through the tail vein, which was significantly inhibited by co-injection of free folic acid (FA). SPECT (single photon emission tomography)/CT results were in accordance with biodistribution data at all time points.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of novel imidazole nucleosides as
           potential anti-dengue virus agents
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Yuki Okano, Noriko Saito-Tarashima, Madoka Kurosawa, Ai Iwabu, Masashi Ota, Tadashi Watanabe, Fumihiro Kato, Takayuki Hishiki, Masahiro Fujimuro, Noriaki Minakawa In this work, we developed imidazole nucleoside derivatives with anti-dengue virus (DENV) activity was examined. First, compounds in a nucleosides library were screened to find lead compounds which inhibit replication of DENV. As a result, 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) and its 4-carbonitrile derivative EICNR (2) were selected as promising antiviral compounds. However, both of them also exhibited cytotoxicity. In order to develop an effective and less toxic compound, 4’-thio and 4’-seleno derivatives of EICAR and EICNR 3–6 were prepared. The resulting 4’-thioEICAR and 4’-thioEICNR showed inhibitory effect on DENV replication without cytotoxicity as potent as ribavirin, a positive control.Graphical abstractGraphical abstract for this article
       
  • New analogs of SYA013 as sigma-2 ligands with anticancer activity
    • Abstract: Publication date: Available online 8 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Gladys Asong, Xue Y Zhu, Barbara Bricker, Terrick Andey, Felix Amissah, Nazarius Lamango, Seth Y Ablordeppey Our previous study has revealed 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one·2HCl (SYA013) 1 as a sigma ligand with moderate selectivity for the sigma-2 receptor. Given the overexpression of sigma receptors in solid tumors and reports of sigma ligands with anticancer activities, we selected 1 for evaluation in several solid tumor cell lines. In addition, we have synthesized new analogs of 1 and now report that several of them bind preferentially at the sigma-2 receptor and have shown inhibition of several cancer cell lines including MDA-MB-231, MDA-MB-486, A549, PC-3, MIA PaCa-2 and Panc-1 cells. In particular, compounds 1 and 12 have demonstrated sub-micromolar activity against the Panc-1 cell line. It has also been observed that several of these compounds demonstrate selective toxicity toward cancer cells, when compared to normal cells.Graphical abstractGraphical abstract for this article
       
  • Is it possible to track intracellular chitosan nanoparticles using
           magnetic nanoparticles as contrast agent'
    • Abstract: Publication date: Available online 6 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Anielle Carvalho Bandeira, Amanda de Oliveira Matos, Bruna Soll Evangelista, Sueli Maria da Silva, Patricia Resende Alo Nagib, Adriana de Moraes Crespo, Andre Corre a Amaral Drug delivery systems prepared with nanostructures are able to overcome biological barriers. However, one of the main challenges in the use of these nanosystems is their internalization by macrophages. This study aims to prepare and characterize chitosan nanoparticles incorporating maghemite nanoparticles and investigate their intracellular tracking in RAW 264.7 macrophages in vitro. Then, maghemite nanoparticles were encapsulated within chitosan nanoparticles by ionotropic gelification method. The images from transmission electron microscopy were used to investigate the intracellular penetration of conjugated nanoparticles by macrophages using different times. Our data suggests that magnetic nanoparticles are suitable to act as a contrast agent to investigate the cellular internalization of chitosan nanoparticles.Graphical abstractGraphical abstract for this article
       
  • Ginnalin B induces differentiation markers and modulates the proliferation
           / differentiation balance via the upregulation of NOTCH1 in human
           epidermal keratinocytes
    • Abstract: Publication date: Available online 6 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Atsushi Kato, Junna Koyama, Kenta Shinzawa, Shuki Imaeda, Isao Adachi, Robert J. Nash, George W.J. Fleet, Megumi Shintani, Chihiro Takeuchi, Fumihiro Ishikawa The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro-D-glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on the beneficial effects of ginnalin B, (6-O-galloyl-1,5-AG, 5), leading to acceleration of skin metabolism and reduction of the turnover time. Ginnalin B dose-dependently increased the relative amount of keratin 10, keratin 1, and filaggrin gene, with maximal increase of 1.7-, 2.9, and 5.2-fold at 100 μM, respectively. The validation study showed that it had superior capacity to induce multiple stages of keratinocyte differentiation and significantly elevated the immunostaining site of keratin 10 and filaggrin in a 3-dimensional cultured human skin model, by 1.2 and 2.8-fold, respectively. Furthermore, ginnalin B caused the arrest of proliferation at the G0/G1 phase but it did not induce apoptotic cell death in normal human keratinocytes. Molecular studies revealed that ginnalin B up-regulated the levels of NOTCH1 and a concomitant increase p21 expression. Ginnalin B, therefore, represents a new class of promising functional and medical cosmetic compound and it could contribute to the maintenance of homeostasis of the epidermis.Graphical abstractGraphical abstract for this article
       
  • Evidence for Ligandable Sites in Structured RNA Throughout the Protein
           Data Bank
    • Abstract: Publication date: Available online 6 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): William Hewitt, David R. Calabrese, John S. Schneekloth RNA has attracted considerable attention as a target for small molecules. However, methods to identify, study, and characterize suitable RNA targets have lagged behind strategies for protein targets. One approach that has received considerable attention for protein targets has been to utilize computational analysis to investigate ligandable “pockets” on proteins that are amenable to small molecule binding. These studies have shown that selected physical properties of pockets are important parameters that govern the ability of a structure to bind to small molecules. This work describes a similar analysis to study pockets on all RNAs in the Protein Data Bank (PDB). Using parameters such as buriedness, hydrophobicity, volume, and other properties, the set of all RNAs is analyzed and compared to all proteins. Considerable overlap is observed between the properties of pockets on RNAs and proteins. Thus, many RNAs are capable of populating conformations with pockets that are likely suitable for small molecule binding. Further, principal moment of inertia (PMI) calculations reveal that liganded RNAs exist in diverse structural space, much of which overlaps with protein structural space. Taken together, these results suggest that complex folded RNAs adopt unique structures with pockets that may represent viable opportunities for small molecule targeting.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s):
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s):
       
  • Discovery of a novel class of potent and selective
           tetrahydroindazole-based sigma-1 receptor ligands
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Iredia D. Iyamu, Wei Lv, Neha Malik, Rama K. Mishra, Gary E. Schiltz The sigma-1 and sigma-2 receptors have been shown to play important roles in CNS diseases, cancer, and other disorders. These findings suggest that targeting these proteins with small-molecule modulators may be of important therapeutic value. Here we report the development of a new class of tetrahydroindazoles that are highly potent and selective ligands for sigma-1. Molecular modeling was used to rationalize the observed structure-activity relationships and identify key interactions responsible for increased potency of the optimized compounds. Assays for solubility and microsomal stability showed this series possesses favorable characteristics and is amenable to further therapeutic development. The compounds described herein will be useful in the development of new chemical probes for sigma-1 and to aid in future work therapeutically targeting this protein.Graphical abstractGraphical abstract for this article
       
  • Design, synthesis and bioevaluation of
           3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide derivatives as novel
           xanthine oxidase inhibitors
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Lichao Zhang, Sibo Wang, Mingzheng Yang, Ailong Shi, He Wang, Qi Guan, Kai Bao, Weige Zhang In view of expanding the structure activity relationship of xanthine oxidase inhibitors, a series of 3-oxo-6-aryl-2,3-dihydropyridazine-4-carbohydrazide/carboxylic acid derivatives were designed by molecular docking and synthesized. All the target compounds were evaluated for their in vitro XO inhibition by using febuxostat and allopurinol as the standard controls. Most of the hydrazide derivatives exhibited potency levels in the micromolar range. From the view of docking study, hydrazide derivatives bind to the active site of XO through a novel interaction mode, which is different from that of febuxostat bearing a carboxyl group. The most promising compound 8b was further subjected to kinetic analysis to deduce their modes of inhibition.Graphical abstractGraphical abstract for this article
       
  • Synthesis and biological evaluation of 3-substituted 2-oxindole
           derivatives as new glycogen synthase kinase 3β inhibitors
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Natalia A. Lozinskaya, Denis A. Babkov, Ekaterina V. Zaryanova, Elena N. Bezsonova, Alexander M. Efremov, Michael D. Tsymlyakov, Lada V. Anikina, Olga Yu. Zakharyascheva, Alexander V. Borisov, Valentina N. Perfilova, Ivan N. Tyurenkov, Marina V. Proskurnina, Alexander A. Spasov Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer’s disease, cancer, and diabetes mellitus. Inhibition of GSK-3β activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3β inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3β with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.Graphical abstractGraphical abstract for this article
       
  • Inhibition of diverse opportunistic viruses by structurally optimized
           retrograde trafficking inhibitors
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Dhimant Desai, Matthew Lauver, Alexandria Ostman, Linda Cruz, Kevin Ferguson, Ge Jin, Brianne Roper, Daniel Brosius, Aron Lukacher, Shantu Amin, Nick Buchkovich Opportunistic viruses are a major problem for immunosuppressed individuals, particularly following organ or stem cell transplantation. Current treatments are non-existent or suffer from problems such as high toxicity or development of resistant strains. We previously published that a trafficking inhibitor that targets a host protein greatly reduces the replication of human cytomegalovirus. This inhibitor was also shown to be moderately effective against polyomaviruses, another family of opportunistic viruses. We have developed a panel of analogues for this inhibitor and have shown that these analogues maintain their high efficacy against HCMV, while substantially lowering the concentration required to inhibit polyomavirus replication. By targeting a host protein these compounds are able to inhibit the replication of two very different viruses. These observations open up the possibility of pan-viral inhibitors for immunosuppressed individuals that are effective against multiple, diverse opportunistic viruses.Graphical abstractGraphical abstract for this article
       
  • Structural modification of indomethacin toward selective inhibition of
           COX-2 with a significant increase in van der Waals contributions
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Akari Ikeda, Eishi Funakoshi, Mitsugu Araki, Biao Ma, Yukiko Karuo, Atsushi Tarui, Kazuyuki Sato, Yasushi Okuno, Kentaro Kawai, Masaaki Omote We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were −13.80 kcal/mol for COX-1 and −18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.Graphical abstractGraphical abstract for this article
       
  • Tryptamine derivatives disarm colistin resistance in polymyxin-resistant
           gram-negative bacteria
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): William T. Barker, Courtney E. Chandler, Roberta J. Melander, Robert K. Ernst, Christian Melander The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.Graphical abstractGraphical abstract for this article
       
  • New SIRT2 inhibitors: Histidine-based bleomycin spin-off
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s): Taha F.S. Ali, Halil I. Ciftci, Mohamed O. Radwan, Ryoko Koga, Takeo Ohsugi, Yoshio Okiyama, Teruki Honma, Akiko Nakata, Akihiro Ito, Minoru Yoshida, Mikako Fujita, Masami Otsuka Bleomycin is considered to exert its antitumor activity via DNA cleavage mediated by activated oxygen generated from the iron complex in its chelator moiety. Spin-offs from this moiety, HPH-1Trt and HPH-2Trt, with anti-cancer activities were recently synthesized. In this paper, we developed inhibitors of nicotinamide adenine dinucleotide-dependent deacetylase isoform 2 of Sirtuin protein (SIRT2), based on HPH-1Trt/HPH-2Trt, and aimed to generate new anti-cancer drugs. HPH-1Trt and HPH-2Trt had in vitro anti-SIRT2 inhibitory activity with 50% inhibitory concentration (IC50) values of 5.5 and 8.8 μM, respectively. A structural portion of HPH-1Trt/HPH-2Trt, a tritylhistidine derivative TH-1, had stronger activity (IC50 = 1.7 μM), and thus, fourteen derivatives of TH-1 were synthesized. Among them, TH-3 had the strongest activity (IC50 = 1.3 μM). Selective binding of TH-3 in the pocket of SIRT2 protein was confirmed with a molecular docking study. Furthermore, TH-3 strongly lowered viability of the breast cancer cell line MCF7 with an IC50 of 0.71 μM. A structure-activity relationship study using cell lines suggested that the mechanism of TH-3 to suppress MCF7 cells involves not only SIRT2 inhibition, but also another function. This compound may be a new candidate anti-cancer drug.Graphical abstractGraphical abstract for this article
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 May 2019Source: Bioorganic & Medicinal Chemistry, Volume 27, Issue 9Author(s):
       
  • The unexplored potential of quinone methides in chemical biology
    • Abstract: Publication date: Available online 2 April 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Aisling Minard, Denise Liano, Xiaofan Wang, Marco Di Antonio Quinone methides are transient reactive species that can be efficiently generated from stable precursors under a variety of biocompatible conditions. Due to their electrophilic nature, quinone methides (QMs) have been widely explored as cross-linking agents of DNA and proteins under physiological conditions. However, QMs have also a diene character and can irreversibly react via Diels-Alder reaction with electron-rich dienophiles. This particular reactivity has been recently exploited to label biomolecules with fluorophores in living cells.QMs are characterised by two unique properties that make them ideal candidates for chemical biology applications: i) they can be efficiently generated in situ from very stable precursors by means of bio-orthogonal protocols ii) they are reversible cross-linking agents, making them suitable for “catch and release” target-enrichment experiments. Nevertheless, there are only few examples reported to date that truly take advantage of QMs unique chemistry in the context of chemical-biology assay development. In this review, we will examine the most relevant examples that illustrate the benefit of using QMs for chemical biology purposes and we will anticipate novel approaches to further their applications in biologically relevant contexts.Graphical abstractGraphical abstract for this article
       
  • Dispiropyrrolidinyl-piperidone embedded indeno[1,2-b]quinoxaline
           heterocyclic hybrids: Synthesis, cholinesterase inhibitory activity and
           their molecular docking simulation
    • Abstract: Publication date: Available online 30 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Natarajan Arumugam, Abdulrahman I. Almansour, Raju Suresh Kumar, D. Kotresha, R. Saiswaroop, S. Venketesh A small library of new class of dispiropyrrolidinyl-piperidone tethered indono[1,2-b]quinoxaline heterocyclic hybrids 7a-j were synthesized employing multicomponent 1,3-dipolar cycloaddition strategy in [bmim]Br. The azomenthine ylide employed is first of its kind and generated in situ from indenoquinoxalinone and L-tryptophan, a combination that has not been employed previously for the in situ generation of azomethine ylides. The synthesized heterocyclic hybrids 7a-j were evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, therein compounds 7h and 7j displayed more potent AChE and BChE enzyme inhibition than the standard drug with IC50 values of 3.22, 2.01, 12.40 and 10.45 mM, respectively. Molecular docking studies have also been investigated for most active compounds that disclosed interesting binding templates to the active site channel of cholinesterase enzyme.____________________________________________________________________Graphical abstractGraphical abstract for this article
       
  • Syntheses and bioactivities of Songorine derivatives as novel G
           protein-coupled receptor antagonists
    • Abstract: Publication date: Available online 23 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Jiangming Wang, Changhao Bian, Yinan Wang, Quan Shen, Bin Bao, Junting Fan, Aixue Zuo, Wenhui Wu, Ruihua Guo Songorine isolated from Aconitum brachypodum Diels possesses prominent activity of inhibiting G protein-coupled receptors (GPCRs) in the early screening process. In this paper, a series of Songoine derivatives were synthesized and their inhibitory activities on GPCRs were also evaluated by using the Double Antibody Sandwich ELISA (DAS-ELISA) in vitro. Among them, three derivatives (3a, 4, 7) exhibited significant inhibitory activity against GPCRs with IC50 values of 0.08-0.29 nM. Moreover, the structure-activity relationships (SARs) of songorine derivatives were discussed in detail. They have great potentials as novel GPCRs antagonists in the future.Graphical abstractGraphical abstract for this article
       
  • Identification of highly potent and selective MMP2 inhibitors addressing
           the S1’ subsite with D-proline-based compounds
    • Abstract: Publication date: Available online 22 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Elena Lenci, Riccardo Innocenti, Tommaso Di Francescantonio, Gloria Menchi, Francesca Bianchini, Alessandro Contini, Andrea Trabocchi MMP2 and MMP9, also called gelatinases, play a primary role in the angiogenic switch, as a fundamental step of tumor progression, and show high degree of structural similarity. Clinically successful gelatinase inhibitors need to be highly selective as opposite effects have been found for the two enzymes, and the S1’ subsite is the major driver to attain selective and potent inhibitors. The synthesis of D-proline-derived hydroxamic acids containing diverse appendages at the amino group, varying in length and decoration allowed to give insight on the MMP2/MMP9 selectivity around the S1’ subsite, resulting in the identification of sub-nanomolar compounds with high selectivity up to 730. Molecular docking studies revealed the existence of an additional hydrophobic channel at the bottom of S1’ subsite for MMP2 enzyme useful to drive selectivity towards such gelatinase.Graphical abstractGraphical abstract for this article
       
  • Effect of curcumin-nanoemulsion associated with photodynamic therapy in
           breast adenocarcinoma cell line
    • Abstract: Publication date: Available online 22 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Francielly Cristina Machado, Renata Prandini Adum de Matos, Fernando Lucas Primo, Antonio Claudio Tedesco, Paula Rahal, Marilia de Freitas Calmon Curcumin, a natural compound has several antineoplastic activities and is a promising natural photosensitizer used in photodynamic therapy. However, its low solubility in physiological medium limit the clinical use of curcumin. This study aimed to analyze the action of curcumin-nanoemulsion, a new and well-designed Drug Delivery System (DDS+) molecule, used as a photosensitizing agent in photodynamic therapy in an in vitro breast cancer model, MCF-7 cells. The empty nanoemulsion fulfils all necessary requirements to be an excellent DDS. Furthermore, the use of curcumin-nanoemulsion in photodynamic therapy resulted in a high phototoxic effect after activation at 440 nm, decreasing to less than 10% viable tumor cells after two irradiations and increasing the reactive oxygen species (ROS) production. The use of curcumin-nanoemulsion associated with photodynamic therapy resulted in an increase in the levels of caspase 3/7 activity for the studied MCF-7 cell model, indicating that this therapy triggers a cascade of events that lead to cell death, such as cellular apoptosis. In conclusion, curcumin-nanoemulsion proved to be efficient as a photosensitizing agent, had phototoxic effects, significantly decreased the proliferation of MCF-7 cells and stimulating the ROS production in combination with photodynamic therapy, so, this formulation has a great potential for use in treatment of breast cancer.Graphical abstractGraphical abstract for this article
       
  • Binding pocket-based design, synthesis and biological evaluation of novel
           selective BRD4-BD1 inhibitors
    • Abstract: Publication date: Available online 22 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Junlong Ma, Heng Chen, Jie Yang, Zutao Yu, Pan Huang, Haofeng Yang, Bifeng Zheng, Rangru Liu, Qianbin Li, Gaoyun Hu, Zhuo Chen Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 μM for BD1 but more than 100 μM for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.Graphical abstractGraphical abstract for this article
       
  • New heteroaryl carbamates: synthesis and biological screening in vitro and
           in mammalian cells of wild-type and mutant HIV-protease inhibitors
    • Abstract: Publication date: Available online 21 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Francesco Tramutola, Maria Francesca Armentano, Federico Berti, Lucia Chiummiento, Paolo Lupattelli, Rosarita D'Orsi, Rocchina Miglionico, Luigi Milella, Faustino Bisaccia, Maria Funicello New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results.The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors.Graphical abstractGraphical abstract for this article
       
  • Neurodegeneration meets immunology - a chemical biology perspective
    • Abstract: Publication date: Available online 20 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): C. Araman, B.A.t HartGraphical abstractGraphical abstract for this article
       
  • Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a
           deuterium-substituted plinabulin derivative as a tubulin polymerization
           inhibitor
    • Abstract: Publication date: Available online 20 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Mingxu Ma, Zhongpeng Ding, Shixiao Wang, Lingling Ma, Yuxi Wang, Lili Zhong, Zhongping Li, Jinliang Yang, Wenbao Li MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.Graphical abstractGraphical abstract for this article
       
  • Development of a dual-wavelength fluorescent nanoprobe for in vivo and in
           vitro cell tracking consecutively
    • Abstract: Publication date: Available online 19 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Hong Vu, Jun Zhou, Yihui Huang, Amirhossein Hakamivala, Min Kyung Khang, Liping Tang Many imaging probes have been developed for a wide variety of imaging modalities. However, no optical imaging probe could be utilized for both microscopic and whole animal imaging. To fill the gap, the dual-wavelength fluorescent imaging nanoprobe was developed to simultaneously carry both visible-range fluorescent dye and near-infrared (NIR) dye. Emission scan confirms that the nanoprobe exhibits two separate peaks with strong fluorescent intensity in both visible and NIR ranges. Furthermore, the dual-wavelength fluorescent nanoprobe has high photostability and colloidal stability, as well as long shelf-life. In vitro cell culture experiments show that the nanoprobe has the ability to label different types of cells (namely, esophageal, prostate, fibroblast and macrophage cell) for fluorescent microscope imaging. More importantly, cell tracking experiments confirm that cell migration and distribution in various organs can be tracked in real time using in vivo whole-body NIR imaging and in vitro microscopic imaging, respectively.Graphical abstractGraphical abstract for this article
       
  • Second-generation aryl isonitrile compounds targeting multidrug-resistant
           Staphylococcus aureus
    • Abstract: Publication date: Available online 19 March 2019Source: Bioorganic & Medicinal ChemistryAuthor(s): Kwaku Kyei-Baffour, Haroon Mohammad, Mohamed N. Seleem, Mingji Dai Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 – 4 µM) and were safe to human keratinocytes. Compound 19, with an additional isonitrile group exhibited improved activity against MRSA compared to the first-generation lead compound. This compound emerged as a candidate worthy of further investigation and further reinforced the importance of the isonitrile functionality in the compounds’ anti-MRSA activity. In a murine skin wound model, 19 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. In summary, 19 was identified as a new lead aryl isonitrile compound effective against MRSA.Graphical abstractGraphical abstract for this article
       
 
 
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