显示样式:     当前期刊: Bioorganic & Medicinal Chemistry Letters    加入关注    导出
我的关注
我的收藏
您暂时未登录!
登录
  • Synthesis, antitumor activity, and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Mizuki Yamada, Tsutomu Takahashi, Mai Hasegawa, Mio Matsumura, Kanna Ono, Ryota Fujimoto, Yuki Kitamura, Yuki Murata, Naoki Kakusawa, Motohiro Tanaka, Tohru Obata, Yasuyuki Fujiwara, Shuji Yasuike

    Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a-f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) and their 5-unsubstituted 1,2,3-triazoles (4a-f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a-f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a-f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a-f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a-f), but not all 5-unsubstituted 1,2,3-triazoles (4a-f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b-e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.

    更新日期:2017-11-24
  • Towards smart biocide-free anti-biofilm strategies:Click-based synthesis of cinnamide analogues as anti-biofilm compounds against marine bacteria.
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    C. Sall, M. Ayé, O. Bottzeck, A. Praud, Y. Blache

    A set of triazole-based analogues of N-coumaroyltyramine was designed to discover potential leads that may help in the control of bacterial biofilms. the most potent compounds act inhibitors of biofilm development with EC50 closed to ampicillin (EC50 = 11 microM) without toxic effect on bacterial growth even at high concentrations(100 microm)

    更新日期:2017-11-24
  • Discovery of new GSK-3β inhibitors through structure-based virtual screening
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Xiaodong Dou, Lan Jiang, Yanxing Wang, Hongwei Jin, Zhenming Liu, Liangren Zhang

    Glycogen synthase kinase-3β (GSK-3β) is an attractive therapeutic target for human diseases, such as diabetes, cancer, neurodegenerative diseases, and inflammation. Thus, structure-based virtual screening was performed to identify novel scaffolds of GSK-3β inhibitors, and we observed that conserved water molecules of GSK-3β were suitable for virtual screening. We found 14 hits and D1 (IC50 of 0.71 μM) were identified. Furthermore, the neuroprotection activity of D1∼D3 was validated on a cellular level. 2D similarity searches were used to find derivatives of high inhibitory compounds and an enriched structure-activity relationship suggested that these skeletons were worthy of study as potent GSK-3β inhibitors.

    更新日期:2017-11-24
  • Small molecule inhibitors of anthrax edema factor
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Guan-Sheng Jiao, Seongjin Kim, Mahtab Moayeri, April Thai, Lynne Cregar-Hernandez, Linda McKasson, Sean O'Malley, Stephen H. Leppla, Alan T. Johnson

    Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production.

    更新日期:2017-11-24
  • Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa

    BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.

    更新日期:2017-11-24
  • A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Johan Wannberg, Rebecka Isaksson, Ulf Bremberg, Maria Backlund, Jonas Sävmarker, Mathias Hallberg, Mats Larhed

    A series of AT2R ligands have been synthesized applying a quick, simple, and safe transesterification-type reaction whereby the sulfonyl carbamate alkyl tail of the selective AT2R antagonist C38 was varied. Furthermore, a limited number of compounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acid bioisosteres were synthesized and evaluated. By reducing the size of the alkyl chain of the sulfonyl carbamates, ligands 7a and 7b were identified with significantly improved in vitro metabolic stability in both human and mouse liver microsomes as compared to C38 while retaining the AT2R binding affinity and AT2R / AT1R selectivity. Eight of the compounds synthesized exhibit an improved stability in human microsomes as compared to C38.

    更新日期:2017-11-24
  • Anti-neuroinflammatory effects of sesquiterpenoids isolated from Nardostachys jatamansi
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-24
    Chi-Su Yoon, Kwan-Woo Kim, Sang-Chan Lee, Youn-Chul Kim, Hyuncheol Oh

    Two new nardosinone-type sesquiterpenoids, namely kanshone J (1) and kanshone K (2) along with seven known terpenoids (3–9) were isolated from the rhizomes and roots of Nardostachys jatamansi DC (Valerianaceae). The structures of these compounds were determined mainly by analysis of 1D-, 2D-NMR and MS data. In addition, the absolute configuration of compound 1 was assigned by application of the modified Mosher’s method. In an initial assay to evaluate their anti-neuroinflammatory effects, compounds 1–5 and 9 exhibited dose-dependent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 cells, with IC50 values ranging from 2.43 to 46.54 μM. Particularly, desoxo-narchinol A (3) and narchinol B (4) significantly inhibited LPS-induced NO overproduction in BV2 cells with IC50 values of 3.48 ± 0.47 and 2.43 ± 0.23 μM, respectively. Furthermore, compounds 3 and 4 exhibited anti-neuroinflammatory effects by inhibiting the production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) proteins, and pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), in LPS-stimulated BV2 and primary microglial cells.

    更新日期:2017-11-24
  • Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-23
    Taeko Kakizawa, Yosuke Ota, Yukihiro Itoh, Takayoshi Suzuki

    Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position. Enzymatic assays showed that PCPA peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors.

    更新日期:2017-11-24
  • Effect of side chain hydrophobicity and cationic charge on antimicrobial activity and cytotoxicity of helical peptoids
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-23
    Jiyoun Lee, Dahyun Kang, Jieun Choi, Wei Huang, Mayken Wadman, Annelise E. Barron, Jiwon Seo

    Peptoids are peptidomimetic polymers that are resistant to proteolysis and less prone to immune responses; thus, they can provide a practical alternative to peptides. Among the various therapeutic applications that have been explored, cationic amphipathic peptoids have demonstrated broad-spectrum antibacterial activity, including activity towards drug-resistant bacterial strains. While their potency and activity spectrum can be manipulated by sequence variations, bacterial selectivity and systemic toxicity need to be improved for further clinical development. To this aim, we incorporated various hydrophobic or cationic residues to improve the selectivity of the previously developed antibacterial peptoid 1. The analogs with hydrophobic residues demonstrated non-specific cytotoxicity, while those with an additional cationic residue showed improved selectivity and comparable antibacterial activity. Specifically, compared to 1, peptoid 7 showed much lower hemolysis and cytotoxicity, while maintaining the antibacterial activity. Therefore, we believe that peptoid 7 has the potential to serve as a promising alternative to current antimicrobial therapies.

    更新日期:2017-11-23
  • Discovery of molecular mechanism of a clinical herbal formula upregulating serum HDL-c levels in treatment of metabolic syndrome by in vivo and computational studies
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-21
    Meimei Chen, Fafu Yang, Jie Kang, Huijuan Gan, Xinmei Lai, Yuxing Gao

    Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD.

    更新日期:2017-11-22
  • AMP and adenosine are both ligands for adenosine 2B receptor signaling
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-20
    Jessica K. Holien, Benjamin Seibt, Veena Roberts, Evelyn Salvaris, Michael W. Parker, Peter J. Cowan, Karen M. Dwyer

    Adenosine is considered the canonical ligand for the adenosine 2B receptor (A2BR). A2BR is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A2BR signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A2BR. The computational modeling suggested that AMP interacts with more favorable energy to A2BR compared with adenosine. Furthermore, AMPαS, a non-hydrolyzable form of AMP, increased calcium uptake by Chinese hamster ovary (CHO) cells expressing the human A2BR, indicating preferential signaling via the Gq pathway. Therefore, a putative AMP-A2BR interaction is supported by the computational modeling data and the biological results suggest this interaction involves preferential Gq activation. These data provide further insights into the role of purinergic signaling in the pathophysiology of renal IRI.

    更新日期:2017-11-20
  • Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-17
    Masayori Hagimori, Takashi Temma, Shinji Kudo, Kohei Sano, Naoya Kondo, Takahiro Mukai

    Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (1–3) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50 = 8.5 nM) compared to compound 2, with amide linker, and compound 3, with sulfonamide linker. Using bromo-substituted carbamate 13 as a radioiodination precursor, [125I]1 was successfully prepared to high radiochemical purity (over 98%) and good specific radioactivity (4.1 GBq/μmol). These results suggest that radioiodinated compound 1 is potent as a novel MMP-12-targeted probe.

    更新日期:2017-11-20
  • Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-15
    Tsutomu Akama, Yong-Kang Zhang, Yvonne R. Freund, Pamela Berry, Joanne Lee, Eric E. Easom, Robert T. Jacobs, Jacob J. Plattner, Michael J. Witty, Rosemary Peter, Tim G. Rowan, Kirsten Gillingwater, Reto Brun, Bakela Nare, Luke Mercer, Musheng Xu, Jiangong Wang, Hao Liang

    Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.

    更新日期:2017-11-20
  • Structure-based design, synthesis, and binding mode analysis of novel and potent chymase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-16
    Junko Futamura-Takahashi, Taisaku Tanaka, Hajime Sugawara, Shinzo Iwashita, Seiichi Imajo, Yoshiaki Oyama, Tsuyoshi Muto

    Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1. .

    更新日期:2017-11-20
  • Discovery of benzotriazole-azo-phenol/aniline derivatives as antifungal agents
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-16
    Min Lv, Jingchun Ma, Qin Li, Hui Xu

    A series of benzotriazole-azo-phenol/aniline derivatives were prepared and evaluated for their antifungal activities against six phytopathogenic fungi such as Fusarium graminearum, Fusarium solani, Alternaria alternate, Valsa mali, Botrytis cinerea, and Curvularia lunata. Among them, compounds IIf, IIn, and IIr showed a broad-spectrum of potent antifungal activities. Especially some compounds displayed 3.5-10.8 folds more potent activities than carbendazim against A. alternata and C. lunata. Notably, compounds IIc, IIm, and IIr exhibited good protective and therapeutic effects against B. cinerea at 200 μg/mL. Their structure-activity relationships were also discussed.

    更新日期:2017-11-20
  • Factors affecting the uncaging efficiency of 500 nm light-activatable BODIPY caging group
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-16
    Minoru Kawatani, Mako Kamiya, Hironori Takahashi, Yasuteru Urano

    Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500 nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light.

    更新日期:2017-11-17
  • Isosteric ribavirin analogues: synthesis and antiviral activities.
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-15
    Nikolay I. Zhurilo, Mikhail V. Chudinov, Andrey V. Matveev, Olga S. Smirnova, Irina D. Konstantinova, Anatoly I. Miroshnikov, Alexander N. Prutkov, Lyubov E. Grebenkina, Natalya V. Pulkova, Vitaly I. Shvets

    The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.

    更新日期:2017-11-16
  • Design and Synthesis of A Biaryl Series As Inhibitors for the Bromodomains of CBP/P300
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-14
    Kwong Wah Lai, F. Anthony Romero, Vickie Tsui, Maureen H. Beresini, Gladys de Leon Boenig, Sarah M. Bronner, Kevin Chen, Zhongguo Chen, Edna F. Choo, Terry D. Crawford, Patrick Cyr, Susan Kaufman, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jeremy Murray, Weichao Shen, John Wai, Fei Wang, Caicai Zhu, Xiaoyu Zhu, Steven Magnuson

    A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.

    更新日期:2017-11-15
  • Synthesis and biological evaluation of 1-amino isochromans from 2-bromoethyl benzaldehyde and amines in acid medium
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-14
    Narjis Fatima, B.V. Subba Reddy, Gowravaram Sabitha, J.S. Yadav, K. Sudhakar, Chandra Shekar Putta

    We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Echerichia coli 4) Pseudomonas aeruginosa. Compounds 3e, 3n, 3m, 3l, 3k, 3j and 3b showed most potent in vitro activity against bacterial strains.

    更新日期:2017-11-15
  • Synthesis and in-vitro evaluations of 6-(hetero)-aryl-imidazo[1,2-b]pyridazine -3- sulfonamide’s as an inhibitor of TNF-α production.
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-13
    Shivaji.S. Pandit, Mahesh R. Kulkarni, Yashwant B. Pandit, Nitin P. Lad, Vijay M. Khedkar

    Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50 = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-Sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π- π) stacking, hydrogen-bonding interactions.

    更新日期:2017-11-14
  • Selective incorporation of foreign functionality into fibrin gels through a chemically modified DNA aptamer
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-11
    Hiroto Fujita, Yusuke Inoue, Masayasu Kuwahara

    We found for the first time that a thrombin-binding DNA aptamer (TBA) is selectively entrapped in fibrin gels during the gel growth reaction catalyzed by thrombin. Furthermore, using this phenomenon, we successfully demonstrated multiple incorporation of amphiphilic aliphatic groups into fibrin gels via chemically modified TBA.

    更新日期:2017-11-13
  • Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-01
    Xiao Hu, Yanhua He, Liping Wu, Yujun Hao, Zhenghe Wang, Weiping Zheng

    To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.

    更新日期:2017-11-13
  • Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-11
    Anthony B. Pinkerton, Eduard Sergienko, Yalda Bravo, Russell Dahl, Chen-Ting Ma, Qing Sun, Michael R. Jackson, Nicholas D.P. Cosford, José Luis Millán

    Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.

    更新日期:2017-11-11
  • Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud.
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-11
    Namki Cho, Yongle Du, Ana Lisa Valenciano, Maria L. Fernández-Murga, Michael Goetz, Jason Clement, Maria B. Cassera, David G.I. Kingston

    A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2 – 4 and the two lycorane alkaloids 5–6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.

    更新日期:2017-11-11
  • Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-11
    Kamala K. Vasu, Chander Singh Digwal, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, Sneha Patel, Milee Agarwal

    A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ± 0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.

    更新日期:2017-11-11
  • Synthesis and evaluation of C2 functionalized analogs of the α-tubulin-binding natural product pironetin
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-11
    David S. Huang, Henry L. Wong, Gunda I. Georg

    Pironetin is an α-tubulin-binding natural product with potent antiproliferative activity against several cancer cell lines that inhibits cell division by forming a covalent adduct with α-tubulin via a Michael addition into the natural product’s α,β-unsaturated lactone. We designed and prepared analogs carrying electron-withdrawing groups at the α-position (C2) of the α,β-unsaturated lactone with the goal to generate potent and selective binding analogs. We prepared derivatives containing halogens, a phenyl, and a methyl group at the C2 position to evaluate the structure-activity relationship at this position. Testing of the analogs in ovarian cancer cell lines demonstrated 100–1000-fold decreased antiproliferative activity.

    更新日期:2017-11-11
  • Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-10
    Bao-Lei Wang, Li-Yuan Zhang, Xing-Hai Liu, Yi Ma, Yan Zhang, Zheng-Ming Li, Xiao Zhang

    A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with Ki value of (0.38 ± 0.25), (6.59 ± 2.75) and (8.46 ± 3.99) μmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis.

    更新日期:2017-11-11
  • Drug-target interactions that involve the replacement or displacement of magnesium ions
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-03
    Nicholas A. Meanwell

    Metal ions play important roles in protein and RNA structure and function and the construction of ligands frequently focuses on the exploitation of functionality designed to engage a metal. However, there are circumstances where functionality can be incorporated into a ligand to emulate the metal ion, allowing target engagement by displacing or replacing the metal and directly interacting with the metal-binding elements in the target. In this Digest, we illustrate protein and RNA modulators that exploit this design principle, with all of the examples based on the displacement or replacement of a magnesium ion, and which can confer a potency advantage. Moreover, this approach relies upon an inversion of the physical chemical properties of a more conventional metal-binding ligand.

    更新日期:2017-11-11
  • Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-10
    Shun-ichi Wada, Anna Takesada, Yurie Nagamura, Eri Sogabe, Rieko Ohki, Junsuke Hayashi, Hidehito Urata

    The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-D-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells.

    更新日期:2017-11-10
  • Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-10
    Lin You, Hong Zhu, Chun Wang, Fang Wang, Yongjun Li, Yan Li, Yonglin Wang, Bin He

    Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2.

    更新日期:2017-11-10
  • Uracil-Amino Acid as a Scaffold for β-Sheet Peptidomimetics: Study of Photophysics and interaction with BSA Protein
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-10
    Subhendu Sekhar Bag, Afsana Yashmeen

    We report herein the uracil-di-aza-amino acid (UrAA) as a new family of molecular scaffold to induce β-hairpin structure with H-bonded β-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine (TPyAlaDo and/or TMNapAlaDo) are embedded into two arms of the uracil-amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the β-hairpin structures for both the peptides. Study of photophysical property reveals that the pentapeptide containing fluorescent triazolyl unnatural amino acids TMNapAlaDo and TPyAlaDo at the two termini exhibits dual path entry to exciplex emission-either via FRET from TMNapAlaDo to TPyAlaDo or via direct excitation of a FRET acceptor, TPyAlaDo. The other pentapeptide with TPyAlaDo/ TPyAlaDo pair shows excimer emission. Furthermore, both the peptides maintaining their fundamental photophysics are found to interact with BSA as only a test biomolecule.

    更新日期:2017-11-10
  • Identification of a Diverse Synthetic Abietane Diterpenoid Library and Insight into the Structure-activity Relationships for Antibacterial Activity
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-09
    Wei Hou, Guanjun Zhang, Zhi Luo, Di Li, Haoqiang Ruan, Benfang Helen Ruan, Lin Su, Hongtao Xu

    A diverse natural product-like (NPL) synthetic abietane diterpenoid library containing 86 compounds were obtained and the SARs were studied based on their antibacterial potential. Further in vitro cytotoxic and in silico drug-like properties evaluation showed that the potent antibacterial compound 84 had good drug-like properties and displayed low cytotoxicity toward noncancerous mammalian cells, indicating the study of AA and DHAA might be a good starting point for the search of novel antimicrobial molecules. Future work should be focused on the optimization of their potency and selectivity.

    更新日期:2017-11-10
  • New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-09
    Anne Brethon, Laurent Chantalat, Olivier Christin, Laurence Clary, Jean-François Fournier, Marcus Gastreich, Craig Harris, Tatiana Isabet, Jonathan Pascau, Etienne Thoreau, Didier Roche, Vincent Rodeschini

    Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.

    更新日期:2017-11-10
  • NOTA Analogue: a First Dithiocarbamate Inhibitor of Metallo-β-lactamases
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-07
    En Zhang, Ming-Ming Wang, Shu-Chao Huang, Shuai-Min Xu, De-Yun Cui, Yuan-Li Bo, Peng-Yan Bai, Yong-Gang Hua, Chun-Ling Xiao, Shangshang Qin

    The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the β-lactam antibiotics, the metallo-β-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7-tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of blaNDM-1. The compound 5 was non-hemolytic, even at a concentration of 1000 µg/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63±1.27 μM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs.

    更新日期:2017-11-10
  • Design, synthesis and biological evaluation of glutamic acid derivatives as anti-oxidant and anti-inflammatory agents
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-07
    Suvarna H. Pagire, Eunhye Lee, Haushabhau S. Pagire, Eun Jung Bae, Soo Jung Ryu, Dahye Lee, Min Hee Kim, Geum Ran Kim, Kyu-Seok Hwang, Sukyung Ahn, Jin Hee Maeng, Jin Sook Song, Myung Ae Bae, Don Hang Lee, Jin Hee Ahn

    A series of glutamic acid derivatives was synthesized and evaluated for their antioxidant activity and stability. We found several potent and stable glutamic acid derivatives. Among them, compound 12b exhibited good in vitro activity, chemical stability and cytotoxicity. A prototype compound 12b showed an anti-inflammatory effect in LPS-stimulated RAW 264.7 cell lines and in a zebrafish model.

    更新日期:2017-11-10
  • Glycyrrhiza glabra extract and quercetin reverses cisplatin resistance in triple-negative MDA-MB-468 breast cancer cells via inhibition of cytochrome P450 1B1 enzyme
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-07
    Rajni Sharma, Linda Gatchie, Ibidapo S. Williams, Shreyans K. Jain, Ram A. Vishwakarma, Bhabatosh Chaudhuri, Sandip B. Bharate

    The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. Herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 µg/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC50 values of 2.2 and 15 µM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC50 > 20 µM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies.

    更新日期:2017-11-10
  • (E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-06
    Neill J. Horley, Kenneth J.M. Beresford, Supriya Kaduskar, Prashant Joshi, Glen J.P. McCann, Ketan C. Ruparelia, Ibidapo S. Williams, Linda Gatchie, Vinay R. Sonawane, Sandip B. Bharate, Bhabatosh Chaudhuri

    The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in SacchrosomesTM and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10 fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent.

    更新日期:2017-11-10
  • Synthesis and antidepressant activity of a series of arylalkanol and aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-06
    Zheng-Song Gu, Ying Xiao, Qing-Wei Zhang, Jian-Qi Li

    A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model.

    更新日期:2017-11-10
  • Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-06
    Allan M. Prior, Xufen Yu, Eun-Jung Park, Tamara P. Kondratyuk, Yan Lin, John M. Pezzuto, Dianqing Sun

    In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3’-nitrogen coordinating with the heme group.

    更新日期:2017-11-10
  • Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-06
    Alexander Flohr, Roman Hutter, Barbara Mueller, Claudia Bohnert, Mélanie Pellisson, Hervé Schaffhauser

    Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer’s disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM’s) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM’s offer the potential of “use-dependent” attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM’s. With these novel M1-PAM’s, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM’s have become available

    更新日期:2017-11-10
  • New terpenoids and thiophene derivatives from the aerial parts of Artemisia sieversiana
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-01
    Xu-Dong Zhou, Chen Zhang, Shan He, Bin Zheng, Ke-Wu Zeng, Ming-Bo Zhao, Yong Jiang, Peng-Fei Tu

    One new highly oxygenated nortriterpene, named sieverlactone (1), one new sesquiterpene, 1β,10β-epoxy-8α-acetoxyachillin (2), one new natural product, 5-propinyl-thiophene-2-carboxylic acid (3), and one new thiophene, 3-hydroxy-5-propinyl-2-acetyl-thiophene (4), together with 10 other known compounds (5−14), were isolated from the dried aerial parts of Artemisia sieversiana. Their structures were elucidated by a combination of extensive spectroscopic analysis, including 1D, 2D NMR spectroscopic and mass spectrometric data. Meanwhile, the stereochemistry of 1 and 2 was confirmed by single-crystal X-ray diffraction technique using Cu radiation. All the isolates were evaluated for their anti-neuroinflammatory effects on the lipopolysaccharide-induced nitric oxide production in BV-2 murine microglial cells. Compounds 2, 5, and 6 exhibited the significant activities with IC50 values of 6.5 ± 0.5, 11.9 ± 0.7, and 10.1 ± 0.3 μM, respectively, comparable to the positive control, quercetin, with an IC50 value of 16.3 ± 0.4 μM.

    更新日期:2017-11-10
  • Design, synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-04
    Zhen Wang, Li Ping Cheng, Xing Hua Zhang, Wan Pang, Liang Li, Jin Long Zhao
    更新日期:2017-11-05
  • Aspergillus candidus is a newly recognized source of sphaeropsidin A: Isolation, semi-synthetic derivatization and anticancer evaluation
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-04
    Yan Li, Robert Scott, Annie R. Hooper, Geoffrey A. Bartholomeusz, Alexander V. Kornienko, Gerald F. Bills
    更新日期:2017-11-05
  • Highly selective peroxisome proliferator-activated receptor δ (PPAR δ) modulator demonstrates improved safety profile compared to GW501516
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-04
    Bharat Lagu, Arthur F. Kluge, Matthew M. Goddeeris, Effie Tozzo, Ross A. Fredenburg, Shekar Chellur, Ramesh S. Senaiar, Mahaboobi Jaleel, D. Ravi Krishna Babu, Nirbhay K. Tiwari, Taisuke Takahashi, Michael A. Patane
    更新日期:2017-11-05
  • 更新日期:2017-11-05
  • The Discovery and Optimization of Naphthalene-Linked P2-P4 Macrocycles as Inhibitors of HCV NS3 Protease
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-11-03
    Michael Bowsher, Sheldon Hiebert, Rongti Li, Alan X. Wang, Jacques Friborg, Fei Yu, Dennis Hernandez, Ying-Kai Wang, Herbert Klei, Ramkumar Rajamani, Kathy Mosure, Jay O. Knipe, Nicholas A. Meanwell, Fiona McPhee, Paul M. Scola
    更新日期:2017-11-05
  • 更新日期:2017-11-01
  • 更新日期:2017-11-01
  • Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-31
    Nagarajan Muthukaman, Macchindra Tambe, Sanjay Deshmukh, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G. Kattige, Monali Pisat, Pooja Sawant, Srinivasa Honnegowda, Vikas Karande, Abhay Kulkarni, Dayanidhi Behera, Satyawan B. Jadhav, Ramchandra R. Sangana, Girish S. Gudi, Neelima Khairatkar-Joshi, Laxmikant A. Gharat
    更新日期:2017-11-01
  • 更新日期:2017-11-01
  • Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti-osteosarcoma activity
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-31
    Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang
    更新日期:2017-11-01
  • Two new dammarane-type triterpene saponins from Korean red ginseng and their anti-inflammatory effects
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-31
    Le Ba Vinh, Yunjeong Lee, Yoo Kyong Han, Jong Seong Kang, Jung Up Park, Young Ran Kim, Seo Young Yang, Young Ho Kim
    更新日期:2017-10-31
  • Synthesis of 14-deoxy-11,12-didehydroandrographolide analogues as potential cytotoxic agents for cholangiocarcinoma
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-30
    Sudarat Sombut, Rada Bunthawong, Uthaiwan Sirion, Teerapich Kasemsuk, Pawinee Piyachaturawat, Kanoknetr Suksen, Apichart Suksamrarn, Rungnapha Saeeng
    更新日期:2017-10-31
  • Design, Synthesis and in vitro anti-tuberculosis activity of Benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Yasodakrishna Sajja, Sowmya Vanguru, Hanmanth Reddy Vulupala, Rajashaker Bantu, Perumal Yogeswari, Dharmarajan Sriram, Lingaiah Nagarapu
    更新日期:2017-10-30
  • Fragment-Based Design, Synthesis, Biological Evaluation, and SAR of 1H-benzo[d]imidazol-2-yl)-1H-indazol Derivatives as Potent PDK1 Inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L. Warner, Sunil Sharma, David J. Bearss, Hariprasad Vankayalapati
    更新日期:2017-10-28
  • Potential antimicrobial agents from triazole-functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Rajitha Bollu, Saleha Banu, Rajashaker Bantu, Gopi Reddy A, Lingaiah Nagarapu, K. Sirisha, C. Ganesh Kumar, Shravan Kumar Gunda, Kamal Shaik
    更新日期:2017-10-28
  • Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Xiaozhen Wang, Yuji Wang, Jianhui Wu, Lin Gui, Xiaoyi Zhang, Meiqing Zheng, Yaonan Wang, Shurui Zhao, Ze Li, Ming Zhao, Shiqi Peng
    更新日期:2017-10-28
  • Indirubin derivatives protect against endoplasmic reticulum stress- induced cytotoxicity and down-regulate CHOP levels in HT22 cells
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Yasuhiro Kosuge, Hiroaki Saito, Tatsuki Haraguchi, Yoshimi Ichimaru, Sachiyo Ohashi, Hiroko Miyagishi, Shunsuke Kobayashi, Kumiko Ishige, Shinichi Miyairi, Yoshihisa Ito
    更新日期:2017-10-28
  • Introduction of 2-O-benzyl abasic nucleosides to the 3′-overhang regions of siRNAs greatly improves nuclease resistance
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-28
    Yuki Nagaya, Yoshiaki Kitamura, Aya Shibata, Masato Ikeda, Yukihiro Akao, Yukio Kitade
    更新日期:2017-10-28
  • Novel highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulators with pharmacokinetic properties suitable for once-daily oral dosing
    Bioorg. Med. Chem. Lett. (IF 2.454) Pub Date : 2017-10-27
    Bharat Lagu, Arthur F. Kluge, Ross A. Fredenburg, Effie Tozzo, Ramesh S. Senaiar, Mahaboobi Jaleel, Sunil K. Panigrahi, Nirbhay K. Tiwari, Narasimha R. Krishnamurthy, Taisuke Takahashi, Michael A. Patane
    更新日期:2017-10-28
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
期刊列表
复旦大学施章杰课题组招聘启事
2017年“高被引科学家”,化学/材料领域完整名单
期刊版块即将升级,期待您的宝贵意见
Angew. Chem. Int. Ed. 10月文章访问量Top10
征稿通知:2017年绿色复合材料与纳米技术国际会议
2017年中科院JCR分区化学大类列表
【问答】动力学手性的概念具有什么重要意义?
试剂库存管理
化合物查询
down
wechat
bug