Journal Cover Bioorganic & Medicinal Chemistry
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3120 journals]
  • Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic
           tetrasaccharide as a high-affinity FGF-2 and midkine ligand
    • Abstract: Publication date: Available online 3 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Susana Maza, Noel Gandia-Aguado, José L. de Paz, Pedro M. Nieto
      Here, we present the preparation of a sulfated, fully protected tetrasaccharide derivative following the glycosaminoglycan (GAG)-related sequence GlcNAc-β(1 → 4)-Glc-β(1 → 3). The tetramer was efficiently assembled via an iterative glycosylation strategy using monosaccharide building blocks. A fluorous tag was attached at position 6 of the reducing end unit enabling the purification of reaction intermediates by simple fluorous solid phase extraction. Fluorescence polarization competition experiments revealed that the synthesized tetrasaccharide strongly interacts with two heparin-binding growth factors, midkine and FGF-2 (IC50 of 270 nM and 2.4 µM, respectively). Our data indicate that this type of oligosaccharide derivatives, displaying sulfates, hydrophobic protecting groups and a fluorinated tail can be considered as interesting GAG mimetics for the regulation of relevant carbohydrate-protein interactions.
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      PubDate: 2018-02-05T07:38:30Z
       
  • CycLS: Accurate, whole-librarysequencing of cyclic peptides using tandem
           mass spectrometry
    • Abstract: Publication date: Available online 3 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chad Townsend, Akihiro Furukawa, Joshua Schwochert, Cameron Pye, Quinn Edmondson, R. Scott Lokey
      Cyclic peptides are of great interest as therapeutic compounds due to their potential for specificity and intracellular activity, but specific compounds can be difficult to identify from large libraries without resorting to molecular encoding techniques. Large libraries of cyclic peptides are often DNA-encoded or linearized before sequencing, but both of those deconvolution strategies constrain the chemistry, assays, and quantification methods which can be used. We developed an automated sequencing program, CycLS, to identify cyclic peptides contained within large synthetic libraries. CycLS facilitates quick and easy identification of all library-members via tandem mass spectrometry data without requiring any specific chemical moieties or modifications within the library. Validation of CycLS against a library of 400 cyclic hexa-peptide peptoid hybrids (peptomers) of unique mass yielded a result of 95% accuracy when compared against a simulated library size of 234,256 compounds. CycLS was also evaluated by resynthesizing pure compounds from a separate 1800-member library of cyclic hexapeptides and hexapeptomers with high mass redundancy. Of 22 peptides resynthesized, 17 recapitulated the retention times assigned to them from the whole-library bulk assay results. Implementing a database-matching approach, CycLS is fast and provides a robust method for sequencing cyclic peptides that is particularly applicable to the deconvolution of synthetic libraries.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Development of selective inhibitors for the treatment of rheumatoid
           arthritis:
           (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile
           as a JAK1-selective inhibitor
    • Abstract: Publication date: Available online 3 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B. Moon Kim
      A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC50 11, 2.4x102, 2.8x103, and 1.1x102 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Synthesis of chondroitin sulfate CC and DD tetrasaccharides and
           interactions with 2H6 and LY111
    • Abstract: Publication date: Available online 3 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kenya Matsushita, Tomomi Nakata, Naoko Takeda-Okuda, Satomi Nadanaka, Hiroshi Kitagawa, Jun-ichi Tamura
      We synthesized the biotinylated chondroitin sulfate tetrasaccharides CS-CC [-3)βGalNAc6S(1–4)βGlcA(1-]2 and CS-DD [-3)βGalNAc6S(1–4)βGlcA2S(1-]2 which possess sulfate groups at O-6 of GalNAc and an additional sulfate group at O-2 of GlcA, respectively. We also analyzed interactions among CS-CC and CS-DD and the antibodies 2H6 and LY111, both of which are known to bind with CS-A, while CS-DD was shown for the first time to bind with both antibodies.
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      PubDate: 2018-02-05T07:38:30Z
       
  • In silico studies, synthesis and pharmacological evaluation to explore
           multi-targeted approach for imidazole analogues as potential
           cholinesterase inhibitors with neuroprotective role for Alzheimer’s
           disease.
    • Abstract: Publication date: Available online 2 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Archana S. Gurjar, Mrunali N. Darekar, Keng Yoon Yeong, Luyi Ooi
      Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Mechanistic analyses of the suppression of amyloid β42 aggregation by
           apomorphine
    • Abstract: Publication date: Available online 2 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mizuho Hanaki, Kazuma Murakami, Sumie Katayama, Ken-ichi Akagi, Kazuhiro Irie
      (R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer’s disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity. 1H-15N SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13,14, Gln15, and Lys16 of the Aβ42 monomer. These regions form intermolecular β-sheets in Aβ42 aggregates. Since 3 did not perturb the chemical shift of monomeric Aβ42, we performed aggregation experiments using 1,1,1,3,3,3-hexafluoro-2-propanol–treated Aβ42 to investigate whether 3 associates with Aβ42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate Aβ42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the β-sheet of Aβ42 nuclei, thereby suppressing further aggregation.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Design, synthesis and evaluation of 4′-OH-flurbiprofen-chalcone hybrids
           as potential multifunctional agents for Alzheimer’s disease treatment
    • Abstract: Publication date: Available online 2 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhongcheng Cao, Jie Yang, Rui Xu, Qin Song, Xiaoyu Zhang, Hongyan Liu, Xiaoming Qiang, Yan Li, Zhenghuai Tan, Yong Deng
      A series of 4′-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ 1–42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ 1–42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Synthesis and biological evaluation of 6-substituted-5-fluorouridine
           ProTides
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Magdalena Slusarczyk, Salvatore Ferla, Andrea Brancale, Christopher McGuigan
      A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P–N bond cleavage and free nucleoside 5′-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Antiobesity and emetic effects of a short-length peptide YY analog and its
           PEGylated and alkylated derivatives
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Ayumu Niida, Yoko Kanematsu-Yamaki, Tomoko Asakawa, Yoshimasa Ishimura, Hisashi Fujita, Kouta Matsumiya, Naoki Nishizawa, Yusuke Adachi, Taisuke Mochida, Kazue Tsuchimori, Mariko Yoneyama-Hirozane, Junichi Sakamoto, Hideki Hirabayashi, Hideo Fukui, Shiro Takekawa, Taiji Asami
      Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Novel fluconazole derivatives with promising antifungal activity
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Kaitlind C. Howard, Sylvie Garneau-Tsodikova
      The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for
           treatment of breast cancer
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Andrii Monastyrskyi, Napon Nilchan, Victor Quereda, Yoshihiko Noguchi, Claudia Ruiz, Wayne Grant, Michael Cameron, Derek Duckett, William Roush
      Casein kinase 1δ/ε have been identified as promising therapeutic target for oncology application, including breast and brain cancer. Here, we described our continued efforts in optimization of a lead series of purine scaffold inhibitors that led to identification of two new CK1δ/ε inhibitors 17 and 28 displaying low nanomolar values in antiproliferative assays against the human MDA-MB-231 triple negative breast cancer cell line and have physical, in vitro and in vivo pharmacokinetic properties suitable for use in proof of principle animal xenograft studies against human cancers.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA
           channel blockers
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Takuya Kumamoto, Marie Nakajima, Reina Uga, Naoko Ihayazaka, Haruna Kashihara, Kazuaki Katakawa, Tsutomu Ishikawa, Ryotaro Saiki, Kazuhiro Nishimura, Kazuei Igarashi
      N-Methyl-d-aspartate (NMDA) receptors have been implicated in learning and memory, and may also play a central role in various conditions leading to neuronal degradation. NMDA receptor antagonists could therefore be of therapeutic benefit for a number of neurological disorders. We have designed hybrid compounds of polyamines and memantine, both of which function as NMDA channel blockers. The triamine derivative with a guanidine moiety showed more potent antagonistic activity than memantine.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Identification of novel quinazolinedione derivatives as RORγt inverse
           agonist
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Yoshiyuki Fukase, Ayumu Sato, Yoshihide Tomata, Atsuko Ochida, Mitsunori Kono, Kazuko Yonemori, Keiko Koga, Toshitake Okui, Masashi Yamasaki, Yasushi Fujitani, Hideyuki Nakagawa, Ryoukichi Koyama, Masaharu Nakayama, Robert Skene, Bi-Ching Sang, Isaac Hoffman, Junya Shirai, Satoshi Yamamoto
      Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure–activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors
           bearing an indazole scaffold
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Jian Liu, Chengbo Qian, Yehua Zhu, Jianguo Cai, Yufang He, Jie Li, Tianlin Wang, Haohao Zhu, Zhi Li, Wei Li, Lihong Hu
      Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven’t been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective
           inhibitors
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki
      Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Fusarithioamide B, a new benzamide derivative from the endophytic fungus
           Fusarium chlamydosporium with potent cytotoxic and antimicrobial
           activities
    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3
      Author(s): Sabrin R.M. Ibrahim, Gamal A. Mohamed, Rwaida A. Al Haidari, Mohamed F. Zayed, Amal A. El-Kholy, Ehab S. Elkhayat, Samir A. Ross
      Fusarithioamide B (6), a new aminobenzamide derivative with unprecedented carbon skeleton and five known metabolites: stigmast-4-ene-3-one (1), stigmasta-4,6,8(14),22-tetraen-3-one (2), p-hydroxyacetophenone (3), tyrosol (4), and fusarithioamide A (5) were separated from Fusarium chlamydosporium EtOAc extract isolated from Anvillea garcinii (Burm.f.) DC. leaves (Asteraceae). The structure elucidation and completeassignment of the isolated metabolites were performed mainly by the aid of various NMR and MS data. Fusarithioamide B (6) has been assessed for antibacterial and antifungal activities towards various microbial strains by disc diffusion assay. It exhibited selective antifungal activity towards C. albicans (MIC 1.9 µg/ml and IZD 14.5 mm), comparing to clotrimazole (MIC 2.8 µg/ml and IZD 17.9 mm). Also, it possessed high antibacterial potential towards E. coli, B. cereus, and S. aureus compared to ciprofloxacin. Furthermore, 6 was tested for the in vitro cytotoxic effect against KB, HCT-116, BT-549, MCF-7, SKOV-3, and SK-MEL cell lines. It had selective and potent effect towards BT-549, MCF-7, SKOV-3, and HCT-116 cell lines with IC50s 0.09, 0.21, 1.23, and 0.59 μM, respectively compared to doxorubicin (IC50s 0.046, 0.05, 0.321, and 0.24 μM, respectively). Fusarithioamide B may provide a lead molecule for future developing of antitumor and antimicrobial agents.
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    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3


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    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3


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    • Abstract: Publication date: 1 February 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 3


      PubDate: 2018-02-05T07:38:30Z
       
  • Synthesis and antibacterial studies of teixobactin analogues with
           non-isostere substitution of enduracididine
    • Abstract: Publication date: Available online 1 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kang Jin, Kathy Hiu Laam Po, Wang Yeuk Kong, Chung Hei Lo, Chun Wah Lo, Ho Yin Lam, Amaya Sirinimal, Jonathan Avraham Reuven, Sheng Chen, Xuechen Li
      Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0.25 to 1.0 µM. Structure-activity relationship is also established for further development of more promising teixobactin analogues.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Sequence-specific DNA Binding Pyrrole–Imidazole Polyamides and Their
           Applications
    • Abstract: Publication date: Available online 1 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama
      Pyrrole–imidazole polyamides (Py–Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py–Im polyamides.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Evaluation of Astatine-211-Labeled Octreotide as a Potential
           Radiotherapeutic Agent for NSCLC Treatment
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bingkun Zhao, Shanshan Qin, Li Chai, Gaixia Lu, Yuanyou Yang, Huawei Cai, Xueyu Yuan, Suyun Fan, Qingqing Huang, Fei Yu
      Octreotide is a somatostatin (SST) analogue currently used in the treatment of neuroendocrine tumors (NETs) with high binding affinity for the somatostatin receptor-2 (SSTR2) that is also overexpressed in non-small cell lung cancer cell (NSCLC). Alpha-particle-emitting astatine-211 (211At) is a promising radionuclide with appropriate physical and chemical properties for use in targeted anticancer therapies. To obtain an additional pharmacological agent for the treatment of NSCLC, we present the first investigation of the possible use of 211At-labeled octreotide as a potential alpha-radionuclide therapeutic agent for NSCLC treatment. 211At-SPC-octreotide exhibited observable higher uptake in lung, spleen, stomach and intestines than in other tissues. Through histological examination, 211At-SPC-octreotide demonstrated much more lethal effect than control groups (PBS, octreotide and free 211At). These promising preclinical results suggested that 211At labeled octreotide deserved to be further developed as a new anticancer agent for NSCLC.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Enhancing the anti-biofilm activity of 5-aryl-2-aminoimidazoles through
           nature inspired dimerisation
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tran Thi Thu Trang, Lise Dieltjens, Geert Hooyberghs, Kai Waldrant, Denis S. Ermolat'ev, Erik V. Van der Eycken, Hans P.L. Steenackers
      The increased tolerance of biofilms against disinfectants and antibiotics has stimulated research into new methods of biofilm prevention and eradication. In our previous work, we have identified the 5-aryl-2-aminomidazole core as a scaffold that demonstrates preventive activity against biofilm formation of a broad range of bacterial and fungal species. Inspired by the dimeric nature of natural 2-aminoimidazoles of the oroidin family, we investigated the potential of dimers of our decorated 5-aryl-2-aminomidazoles as biofilm inhibitors. A synthetic approach towards 2-aminoimidazole dimers linked by an alkyl chain was developed and a total of 48 dimers were synthesized. The linkers were introduced at two different positions, the N1-position or the N2-position, and the linker length and the substitution of the 5-phenyl ring (H, F, Cl, Br) were varied. Although, no clear correlation between linker length and biofilm inhibition was observed, a strong increase in anti-biofilm activity for almost all N1,N1’-linked dimers was obtained, compared to the respective monomers against Salmonella Typhimurium, Escherichia coli and Staphylococcus aureus. The N2,N2’-linked dimers, having a H- or F-substitution, were also found to show a strong increase in anti-biofilm activity compared to the respective monomers against these three bacterial species and against Pseudomonas aeruginosa. In addition, the obtained growth measurements suggest a broad concentration range with specific biofilm inhibition and no effect on the planktonic growth against Salmonella Typhimurium and Pseudomonas aeruginosa.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Heterobicyclic inhibitors of transforming growth factor beta receptor I
           (TGFβRI)
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Lalgudi S. Harikrishnan, Jayakumar Warrier, Andrew J. Tebben, Gopikishan Tonukunuru, Sudhakara R. Madduri, Vishweshwaraiah Baligar, Raju Mannoori, Balaji Seshadri, Hasibur Rahaman, P.N. Arunachalam, Amol Dikundwar, Brian E. Fink, Joseph Fargnoli, Mark Fereshteh, Yi Fan, Jonathan Lippy, Ching-Ping Ho, Barri Wautlet, Steven Sheriff, Max Ruzanov, Robert M. Borzilleri
      The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFβ-stimulated phospho-SMAD was observed in primary human T cells.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Synthetic Peptide API Manufacturing A Mini Review of Current Perspectives
           for Peptide Manufacturing
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jon H. Rasmussen
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      PubDate: 2018-02-05T07:38:30Z
       
  • Synthesis and activity evaluation of a series of cholanamides as
           modulators of the liver X receptors
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mario D. Martínez, Alberto A. Ghini, M. Virginia Dansey, Adriana S. Veleiro, Adali Pecci, Lautaro D. Alvarez, Gerardo Burton
      The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3 β -hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid. The LXRα and LXRβ activity of these analogues was evaluated by using a luciferase reporter assay in BHK21 cells. Compounds were tested in both the agonist and antagonist modes. Results indicated that the agonist/antagonist profile is dependent on the steroid configuration at the A/B ring junction. Notably, in contrast to DMHCA, the amide derived from lithocholic acid (2) with an A/B cis configuration and its 6,19-epoxy analogue 4 behaved as LXRα selective agonists, while the 2,19-epoxy analogues with an A/B trans configuration were antagonists of both isoforms. The binding mode of the analogues to both LXR isoforms was assessed by using 50 ns molecular dynamics (MD) simulations. Results revealed conformational differences between LXRα- and LXR β -ligand complexes, mainly in the hydrogen bonding network that involves the C-3 hydroxyl. Overall, these results indicate that the synthetized DMHCA analogues could be interesting candidates for a therapeutic modulation of the LXRs.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer’s
           agents: Structure-activity relationship study of Arg-mimetic region
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Van T.H. Ngo, Van-Hai Hoang, Phuong-Thao Tran, Jihyae Ann, Minghua Cui, Gyungseo Park, Sun Choi, Jiyoun Lee, Hee Kim, Hee-Jin Ha, Kwanghyun Choi, Young-Ho Kim, Jeewoo Lee
      Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer’s disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Peptide chemistry toolbox – Transforming natural peptides into
           peptide therapeutics
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Miloš Erak, Kathrin Bellmann-Sickert, Sylvia Els-Heindl, Annette G. Beck-Sickinger
      The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Structure-activity studies of a macrocyclic peptide inhibitor of histone
           lysine demethylase 4A
    • Abstract: Publication date: Available online 31 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Toby Passioura, Bhaskar Bhushan, Anthony Tumber, Akane Kawamura, Hiroaki Suga
      The combination of genetic code reprogramming and mRNA display is a powerful approach for the identification of macrocyclic peptides with high affinities to a target of interest. We have previously used such an approach to identify a potent inhibitor (CP2) of the human KDM4A and KDM4C lysine demethylases; important regulators of gene expression. In the present study, we have used genetic code reprogramming to synthesise very high diversity focused libraries (>1012 compounds) based on CP2 and, through affinity screening, used these to delineate the structure activity relationship of CP2 binding to KDM4A. In the course of these experiments we identified a CP2 analogue (CP2f-7) with ∼4-fold greater activity than CP2 in in vitro inhibition assays. This work will facilitate the development of more potent, selective inhibitors of lysine demethylases.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Optimization of Permeability in a Series of Pyrrolotriazine Inhibitors of
           IRAK4
    • Abstract: Publication date: Available online 17 January 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sébastien L. Degorce, Rana Anjum, Keith S. Dillman, Lisa Drew, Sam D. Groombridge, Christopher T. Halsall, Eva M. Lenz, Nicola A. Lindsay, Michele F. Mayo, Jennifer H. Pink, Graeme R. Robb, James S. Scott, Stephen Stokes, Yafeng Xue
      We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series1 led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
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      PubDate: 2018-02-05T07:38:30Z
       
  • An appraisal on synthetic and pharmaceutical perspectives of
           pyrazolo[4,3-d]pyrimidine scaffold
    • Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 2
      Author(s): Srinivasulu Cherukupalli, Girish A. Hampannavar, Sampath Chinnam, Balakumar Chandrasekaran, Nisar Sayyad, Francis Kayamba, Rajeshwar Reddy Aleti, Rajshekhar Karpoormath
      Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Podophyllotoxin derivatives as an excellent anticancer aspirant for future
           chemotherapy: A key current imminent needs
    • Abstract: Publication date: 15 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 2
      Author(s): Xu Zhang, K.P. Rakesh, C.S. Shantharam, H.M. Manukumar, A.M. Asiri, H.M. Marwani, Hua-Li Qin
      Cancer is one of the leading groups of threatened caused by abnormal state cell growth and second leading diseases involved in the major global death. To treat this, research looking for promising anticancer drugs from natural resource, or synthesized novel molecules by diverse group of scientists worldwide. Currently, drugs get into clinical practices and showing side effects with target actions which in turn leading to multidrug resistance unknowingly. Podophyllotoxin, a naturally occurring lignan and with hybrids have become one of the most attractive subjects due to their broad spectrum of pharmacological activities. Podophyllotoxin derivatives have been the centre of attention of extensive chemical amendment and pharmacological investigation in modern decades. Mainly, the innovation of the semi-synthetic anticancer drugs etoposide and teniposide has stimulated prolonged research interest in this structural phenotype. The present review focuses mainly onnew anticancer drugs from podophyllotoxin analogs, mechanism of action and their structure–activity relationships (SAR) as potential anticancer candidates for future discovery of suitable drug candidates.
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      PubDate: 2018-02-05T07:38:30Z
       
  • Theoretical Research in Structure Characteristics of Different Inhibitors
           and Differences of Binding Modes with CBP Bromodomain
    • Authors: Xue-Song Wang; Qing-Chuan Zheng
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xue-Song Wang, Qing-Chuan Zheng
      The CBP (CREB (cAMP responsive element binding protein) binding protein) bromodomain (BRD) could recognize and bind with acetyl K382 of human tumor suppressor protein p53 which the mutation of encoding gene might cause human cancers. CBP-BRD serves as a promising drug target for several disease pathways and a series of effective drug have been discovered. In this study, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GB/SA) approaches were performed to investigate the different binding modes between five inhibitors with CBP-BRD. Based on the energy and conformation analyses, a potent core fragment is chosen to act as the starting point for new inhibitor design by means of LUDI and rational drug design approaches. Then, T.E.S.T and molinspirition were applied to evaluate oral bioavailability and drug promiscuity of the new molecules. These results shed light on the idea for further inhibitor design.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.040
       
  • One-step Synthesis of Carbohydrate Esters as Antibacterial and Antifungal
           Agents
    • Authors: Madher N. AlFindee; Qian Zhang; Yagya Prasad Subedi; Jaya P. Shrestha; Yukie Kawasaki; Michelle Grilley; Jon Y. Takemoto; Cheng-Wei Tom Chang
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Madher N. AlFindee, Qian Zhang, Yagya Prasad Subedi, Jaya P. Shrestha, Yukie Kawasaki, Michelle Grilley, Jon Y. Takemoto, Cheng-Wei Tom Chang
      Carbohydrate esters are biodegradable, and the degraded adducts are naturally occurring carbohydrates and fatty acids which are environmentally friendly and non-toxic to human. A simple one-step regioselective acylation of mono-carbohydrates has been developed that leads to the synthesis of a wide range of carbohydrate esters. Screening of these acylated carbohydrates revealed that several compounds were active against a panel of bacteria and fungi, including Staphylococcus aureus. methicillin-resistant S. aureus (MRSA), Candida albicans, Cryptococcus neoformans, Aspergillus flavus and Fusarium graminearum. Unlike prior studies on carbohydrate esters that focus only on antibacterial applications, our compounds are found to be active against both bacteria and fungi. Furthermore, the synthetic methodology is suitable to scale-up production for a variety of acylated carbohydrates. The identified lead compound, MAN014, can be used as an antimicrobial in applications such as food processing and preservation and for treatment of bacterial and fungal diseases in animals and plants.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.038
       
  • Inhibition of protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase
           by xanthones from Cratoxylum cochinchinense, and their kinetic
           characterization
    • Authors: Zuopeng Li; Yeong Hun Song; Zia Uddin; Yan Wang; Ki Hun Park
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zuopeng Li, Yeong Hun Song, Zia Uddin, Yan Wang, Ki Hun Park
      Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1-12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC50s of (2.4-52.5 µM), and α-glucosidase with IC50 values of (1.7-72.7 µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50 = 2.4 µM for 3, 2.8 µM for 7) and α-glucosidase (IC50 = 4.8 µM for 3, 1.7 µM for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of α-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: K i app = 2.4 µM; k 5 = 0.05001 µM-1S-1 and k 6 = 0.02076µM-1S-1.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.043
       
  • A cell surface clicked navigation system to direct specific bone targeting
    • Authors: Young Kim; Zhe Zhang; Jae-Hyuck Shim; Tae Sup Lee; Ching-Hsuan Tung
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Young Kim, Zhe Zhang, Jae-Hyuck Shim, Tae Sup Lee, Ching-Hsuan Tung
      Cell therapies are promising up-and-coming therapeutic strategies for many diseases. For maximal therapeutic benefits, injected cells have to navigate their way to a designated area, including organ and tissue; unfortunately, the majority of therapeutic cells are currently administered without a guide or homing device. To improve this serious shortcoming, a functionalization method was developed to equip cells with a homing signal. Its application was demonstrated by applying an Azadibenzocyclooctyne-bisphosphonate (ADIBO-BP) and azide paired bioorthogonal chemistry on cells for bone specific homing. Jurkat T cells and bone marrow derived stromal cells (BMSCs) were cultured with tetraacetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) to place unnatural azido groups onto the cell’s surface; these azido groups were then reacted with ADIBO-BP. The tethered bisphosphonates were able to bring Jurkat cells to hydroxyapatite, the major component of bone, and mineralized SAOS-2 cells. The incorporated BP groups also enhanced the specific affinity of BMSCs to mouse femur bone fragments in vitro. The introduced navigation strategy is expected to have a broad application in cell therapy, because through the biocompatible ADIBO and azide reactive pair, various homing signals could be efficiently anchored onto therapeutic cells.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.037
       
  • A review on the hybrids of hydroxycinnamic acidas multi-target-directed
           ligands against Alzheimer's disease
    • Authors: Xiao Zhang; Xixin He; Qiuhe Chen; Junfeng Lu; Simona Rapposelli; Rongbiao Pi
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xiao Zhang, Xixin He, Qiuhe Chen, Junfeng Lu, Simona Rapposelli, Rongbiao Pi
      Alzheimer's disease (AD), a complex chronic progressive central nervous system degenerative disease and a public health problem of the world, often characters cognitive dysfunction accompaning aggression and depression, and may lead to death. More attentions should be paid on it because there is no modified strategy against AD till now. AD is featured with the loss of cholinergic neurons, the amyloid-beta peptide (Aβ) plaques and the neurofibrillary tangles and several hypotheses were established to explain the pathogenesis of AD. Hydroxycinnamic acids,including caffeic acid (CA) and ferulic acid (FA) are widely distributed in natural plants and fruits. CA and FA exert various pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, anti-amyloid aggregation and so on. All these pharmacological activities are associated with the treatment of AD. Here we summarized the pharmacological activities of CA and FA, and their hybrids as multi-target-directed ligands (MTDLs) against AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA- and FA-based MTDLs against AD.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.042
       
  • Structural optimization of N1-aryl-benzimidazoles for the discovery of new
           non-nucleoside reverse transcriptase inhibitors active against wild-type
           and mutant HIV-1 strains
    • Authors: Anna Maria Monforte; Laura De Luca; Maria Rosa Buemi; Fatima E. Agharbaoui; Christophe Pannecouque; Stefania Ferro
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anna Maria Monforte, Laura De Luca, Maria Rosa Buemi, Fatima E. Agharbaoui, Christophe Pannecouque, Stefania Ferro
      Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N1-aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse trascriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N1-aryl-2-arylthioacetamido-benzimidazoles and N1-aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A.. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.033
       
  • New Photodynamic Molecular Beacons (PMB) as potential cancer-targeted
           agents in PDT
    • Authors: Aurélie Stallivieri; Ludovic Colombeau; Jérôme Devy; Nicolas Etique; Carine Chaintreuil; Bauyrzhan Myrzakhmetov; Mathilde Achard; Francis Baros; Philippe Arnoux; Régis Vanderesse; Céline Frochot
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Aurélie Stallivieri, Ludovic Colombeau, Jérôme Devy, Nicolas Etique, Carine Chaintreuil, Bauyrzhan Myrzakhmetov, Mathilde Achard, Francis Baros, Philippe Arnoux, Régis Vanderesse, Céline Frochot
      Further improvements in Photodynamic therapy (PDT) necessitate that the dye targets more selectively tumour tissues or neovascularization than healthy cells. Different enzymes such as matrix metalloproteinases (MMPs) are overexpressed in tumour areas. Among these MMPs, gelatinases (MMP-2 and MMP-9) and its activator MMP-14 are known to play a key role in tumour angiogenesis and the growth of many cancers such as glioblastoma multiforme (GBM), an aggressive malignant tumour of the brain. These last years, the concept of photodynamic molecular beacons (PMB) became interesting for controlling the photosensitizer’s ability to generate singlet oxygen (1O2) close to target biomolecules as MMPs. We report herein novel PMBs triggered by MMP-2 and/or MMP-9 and/or MMP-14, comprising a photosensitizer and a singlet oxygen quencher linked by MMP cleavable peptide linker (H-GRIGFLRTAKGG-OH). First of all, we focused on the synthesis and the photophysical study of different derivatives photosensitizer-peptide. This preliminary work concluded on an influence of the nature and the distance from the peptide, but not of the position of the photosensitizer in these derivatives on the proteolytic enzymatic action. The nature of the quencher used (a blackberry quencher (BBQ-650) or a black hole quencher (BHQ3)) does not influence the enzymatic action. We also studied the influence of an additionnal PEG spacer. Finally, the synthesis, the singlet oxygen quenching efficiency and the enzymatic activation of these new MMP- cleavable-PMBs were compared.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.034
       
  • Structure-based Design, Synthesis, and Biological Evaluation of
           Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors
    • Authors: Akira Kaieda; Masashi Takahashi; Takafumi Takai; Masayuki Goto; Takahiro Miyazaki; Yuri Hori; Satoko Unno; Tomohiro Kawamoto; Toshimasa Tanaka; Sachiko Itono; Terufumi Takagi; Teruki Hamada; Mikio Shirasaki; Kengo Okada; Gyorgy Snell; Ken Bragstad; Bi-Ching Sang; Osamu Uchikawa; Seiji Miwatashi
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Akira Kaieda, Masashi Takahashi, Takafumi Takai, Masayuki Goto, Takahiro Miyazaki, Yuri Hori, Satoko Unno, Tomohiro Kawamoto, Toshimasa Tanaka, Sachiko Itono, Terufumi Takagi, Teruki Hamada, Mikio Shirasaki, Kengo Okada, Gyorgy Snell, Ken Bragstad, Bi-Ching Sang, Osamu Uchikawa, Seiji Miwatashi
      We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.031
       
  • Benzimidazole design, synthesis, and docking to build selective carbonic
           anhydrase VA inhibitors
    • Authors: Edita Čapkauskaitė; Audrius Zakšauskas; Virginijus Ruibys; Vaida Linkuvienė; Vaida Paketurytė; Marius Gedgaudas; Visvaldas Kairys; Daumantas Matulis
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Edita Čapkauskaitė, Audrius Zakšauskas, Virginijus Ruibys, Vaida Linkuvienė, Vaida Paketurytė, Marius Gedgaudas, Visvaldas Kairys, Daumantas Matulis
      The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.035
       
  • Identification of highly potent and orally available free fatty acid
           receptor 1 agonists bearing isoxazole scaffold
    • Authors: Zheng Li; Chunxia Liu; Wei Shi; Xingguang Cai; Yuxuan Dai; Chen Liao; Wenlong Huang; Hai Qian
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zheng Li, Chunxia Liu, Wei Shi, Xingguang Cai, Yuxuan Dai, Chen Liao, Wenlong Huang, Hai Qian
      The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.030
       
  • Discovery of New Thienopyrimidine Derivatives as Potent and Orally
           Efficacious Phosphoinositide 3-Kinase Inhibitors
    • Authors: Songwen Lin; Chunyang Wang; Ming Ji; Deyu Wu; Yuanhao Lv; Li Sheng; Fangbin Han; Yi Dong; Kehui Zhang; Yakun Yang; Yan Li; Xiaoguang Chen; Heng Xu
      Abstract: Publication date: Available online 23 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Songwen Lin, Chunyang Wang, Ming Ji, Deyu Wu, Yuanhao Lv, Li Sheng, Fangbin Han, Yi Dong, Kehui Zhang, Yakun Yang, Yan Li, Xiaoguang Chen, Heng Xu
      A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.025
       
  • Synthesis and biological evaluation of cyclopeptide GG-8-6 and its
           analogues as anti-hepatocellular carcinoma agents
    • Authors: Jie-Tao Chen; Ru Ma; Shi-Chang Sun; Xiao-Feng Zhu; Xiao-Li Xu; Qing Mu
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jie-Tao Chen, Ru Ma, Shi-Chang Sun, Xiao-Feng Zhu, Xiao-Li Xu, Qing Mu
      GG-8-6, cyclo-(Val-Leu-Pro-Ile-Leu-Leu-Leu-Val-Leu, compound 1), and its twelve analogues (compound 2 - 13) were synthesized based on the lead compound Grifficyclocin B, a cyclic peptide with anti-tumor activity which was isolated from the plants of Goniothalamus species (Annonaceae). The bioassay results showed that these synthetic cyclopeptides exhibited different extent of cytotoxicity against human hepatocellular carcinoma cell lines. Among them, GG-8-6 (1) was the most active compound with IC50 values of 6.38 μM and 12.22 μM against SMMC-7721 and HepG2, respectively. Further studies on the mechanism demonstrated that GG-8-6 (1) could induce apoptosis and G2/M arrest of HCC cells, and the activation of caspase pathways was probably involved. In vivo anti-tumor experiments showed that GG-8-6 (1) could significantly inhibit the growth of tumor in the mouse xenograft tumor model. At the dose of 40 mg/kg, the inhibition ratio was 67.9% without weight loss. Our results suggested that GG-8-6 (1), a new cyclic peptide, might be a potential candidate for developing new anti-HCC drug in the coming future.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.028
       
  • Induction of apoptosis by pyrazolo[3,4-d]pyridazine derivative in lung
           cancer cells via disruption of bcl-2/bax expression balance
    • Authors: Mervat S. Mohamed; Abdou O. Abdelhamid; Fahad M. Almutairi; Ayat G. Ali; Mai K. Bishr
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mervat S. Mohamed, Abdou O. Abdelhamid, Fahad M. Almutairi, Ayat G. Ali, Mai K. Bishr
      In the rapidly expanding era of cancer target therapy, regulators of apoptosis are emerging as attractive therapeutic targets. X-linked inhibitor of apoptosis (XIAP) is of specific interest owing to its characteristic overexpression in a wide variety of neoplasms, with a resultant survival advantage for tumor cells and treatment resistance. In this study, we examined three pyrazolo [3,4-d] pyridazine derivatives (PPDs) through molecular modeling and studied their modes of interaction with XIAP-BIR3 domain. PPD-1, which possessed the highest binding affinity with XIAP, was tested on A549 (lung cancer cell line); HCT-116 (colorectal carcinoma cell line); HEPG2 (liver carcinomacell line), HFB4 (normal human skin melanocyte cell line) and WI-38 (human embryonic lung fibroblasts). In comparison to cisplatin as a positive control, PPD-1 yielded remarkable cytotoxicity on all cancer cell lines, with the highest anti-tumor activity on A549 and a favorable therapeutic ratio. Flow cytometry studies concluded that PPD-1 treatment induces Sub G1 and G2/M cell cycle arrest and apoptosis. The percentage of apoptotic cells in PPD-1 treated A549 cells was considerably higher than that in untreated cells (10.06% vs 0.57%, respectively). To further investigate the mechanism of induction of apoptosis by PPD-1, Real time-PCR was used to quantify the expression levels of key apoptotic regulators. Significant overexpression of the effector capsase-3, pro-apoptotic bax and tumor suppressor gene p53 were noted as compared to untreated cells (7.19 folds, 7.28 folds, and 5.08 folds, respectively). Moreover, PPD-1 inhibited the expression of the anti-apoptotic bcl-2 gene to 0.22 folds. These findings demonstrate that PPD-1 treatment disrupts the Bcl-2/BAX balance in lung cancer cell lines, leading to apoptosis induction possibly through intrinsic mitochondria-dependent pathway. These novel insights elucidate the mechanism of PPD-1 cytotoxicity in lung cancer cell lines and offer a promising therapeutic approach that needs further study.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.026
       
  • Discovery of EBI-1051: a novel and orally efficacious MEK inhibitor with
           benzofuran scaffold
    • Authors: Biao Lu; Song Huang; Jingsong Cao; Qiyue Hu; Ru Shen; Hong Wan; Dan Wang; Jijun Yuan; Lei Zhang; Jiayin Zhang; Minsheng Zhang; Weikang Tao; Lianshan Zhang
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Biao Lu, Song Huang, Jingsong Cao, Qiyue Hu, Ru Shen, Hong Wan, Dan Wang, Jijun Yuan, Lei Zhang, Jiayin Zhang, Minsheng Zhang, Weikang Tao, Lianshan Zhang
      A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.019
       
  • Structure-Activity Relationships of Cryptopleurine Analogs with E-ring
           Modifications as Anti-Hepatitis C Virus Agents
    • Authors: Ying Wang; Shao-Ru Chen; Xiaoming Yang; Kuo-Hsiung Lee; Yung-Chi Cheng
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ying Wang, Shao-Ru Chen, Xiaoming Yang, Kuo-Hsiung Lee, Yung-Chi Cheng
      The tylophorine analog rac-cryptopleurine exhibited potent anti-hepatitis C virus (HCV) activity through allosteric regulation of ATPase activity of heat shock cognate protein 70 (Hsc70). We evaluated the impact of modifications on the E-ring of rac-cryptopleurine to the inhibitory activity against HCV replication and regulation of ATPase activity of Hsc70. Cryptopleurine analog YXM-110 with a 13α-hydroxyl group maintained activity against HCV and promoted ATP/ADP turnover of Hsc70; however, compounds with hydroxyl groups at other positions or with other orientations (YXM-109, YXM-139, and YXM-140) did not exhibit similar activities. Size modification or heteroatom incorporation of the E-ring led to loss of anti-HCV activity. Promotion of the chaperone activity of Hsc70 with carboxyl terminus Hsc70 interacting protein (CHIP) further enhanced the anti-HCV activity of rac-cryptopleurine and XYM-110. This structure-activity relationship (SAR) study refined structural design and optimization for developing rac-crytopleurine analogs as potent anti-HCV agents targeted against the host factor involved in HCV replication.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.027
       
 
 
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