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  • Erythrofordins D and E, two new cassaine-type diterpenes from Erythrophleum suaveolens
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-10
    Tanja Grkovic, Jason R. Evans, Rhone K. Akee, Liang Guo, Myrtle Davis, Johnson Jato, Paul G. Grothaus, Michelle Ahalt-Gottholm, Melinda Hollingshead, Jerry M. Collins, David J. Newman, Barry R. O'Keefe

    Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI50 value of 2.45 and 0.71 µM, mean TGI value of 9.77 and 2.29 µM, and a mean LC50 of 26.92 and 11.48 µM for 1 and 2 respectively. Using the COMPARE algorithm, the new compounds were found to have similar NCI-60 response profiles to the known cardiac glycosides hyrcanoside and strophanthin. In addition, in an assay examining the viability and contractile function in human cardiomyocytes derived from induced pluripotent stem-cells, erythrofordins showed cardiotoxicity effects at concentrations as low as 0.03 µg/mL.

    更新日期:2018-12-10
  • A new class of pentapeptide KISS1 receptor agonists with hypothalamic–pituitary–gonadal axis activation
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-10
    Naoki Nishizawa, Taiji Asami, Kimiko Nishibori, Yoshihiro Takatsu, Atsuko Suzuki, Kazutaka Ushio, Shin-ichi Matsumoto, Yuji Shimizu, Masashi Yamaguchi, Masami Kusaka, Hisanori Matsui, Tetsuya Ohtaki, Chieko Kitada

    The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.

    更新日期:2018-12-10
  • Synthesis and characterization of a photoresponsive doxorubicin/combretastatin A4 hybrid prodrug
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-10
    Wei Liu, Li Liang, Lifeng Zhao, Huan Tan, Jie Wu, Qihui Qin, Xiaojun Gou, Xiaohua Sun

    To explore the application of photoremovable protecting groups (PPGs) in the field of combination chemotherapy, we designed and synthesized a photoresponsive hybrid prodrug 4 that bearing both doxorubicin (DOX) and combretastatin A4 (CA4). Light triggered drug release investigation found that DOX release was mainly accomplished by 405 nm light while CA4 release was mainly triggered by 365 nm light, i.e., prodrug 4 exhibited a quasi-sequential release behavior when a sequential light irradiation strategy was applied. Cell viability evaluation confirmed the increased cytotoxicity of prodrug 4 compared with individual drugs towards MDA-MB-231cells, indicating that a synergistic effect was achieved.

    更新日期:2018-12-10
  • Discovery of N-substituted 7-azaindoles as Pan-PIM kinases inhibitors - Lead optimization- Part III
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-10
    Claude Barberis, James Pribish, Elina Tserlin, Alexandre Gross, Mark Czekaj, Matthieu Barragué, Paul Erdman, Sachin Maniar, John Jiang, Luke Fire, Vinod Patel, Andrew Hebert, Mikhail Levit, Anlai Wang, Frank Sun, Shih-Min A. Huang

    N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.

    更新日期:2018-12-10
  • Design, synthesis of novel purin-6-one derivatives as phosphodiesterase 2 (PDE2) inhibitors: the neuroprotective and anxiolytic-like effects
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-10
    Xian-Feng Huang, Yi-Jing Cao, Jing Zhen, Da-Wei Zhang, Ren Kong, Wen-Tao Jiang, Ying Xu, Guo-Qiang Song, Heng-Ming Ke, Li Liu

    Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC50: 72 and 81 nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors.

    更新日期:2018-12-10
  • Discovery of new indole-based acylsulfonamide Nav1.7 inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-06
    Yong-Jin Wu, Brian Venables, Jason Guernon, Jie Chen, Sing-Yuen Sit, Ramkumar Rajamani, Ronald J. Knox, Michele Matchett, Rick L. Pieschl, James Herrington, Linda J. Bristow, Nicholas A. Meanwell, Lorin A. Thompson, Carolyn Dzierba

    Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.

    更新日期:2018-12-07
  • Identification of 2-(2'-fluoro-[1,1'-biphenyl]-2-yl)acetamide as a Sodium Valproate-like broad spectrum anti-epileptic drug candidate
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-07
    Tomoyuki Tanaka, Nana Yajima, Tomoko Kiyoshi, Yoshiki Miura, Yoshifumi Inoue, Takuya Nishimaki, Seiji Iwama

    By further optimizing compound A [2'-fluoro-N-methyl-[1,1'-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2'-fluoro-[1,1'-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.

    更新日期:2018-12-07
  • Ganocapenoids A–D: Four new aromatic meroterpenoids from Ganoderma capense
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-05
    Guang-Feng Liao, Ze-Hong Wu, Ying Liu, Yong-Ming Yan, Ru-Mei Lu, Yong-Xian Cheng

    Four new aromatic meroterpenoids, Ganocapenoids A–D (1–4), together with twelve known analogues (5–16) were isolated from the fruiting bodies of Ganoderma capense. The structures of new compounds were determined through spectroscopic methods including 1D and 2D NMR and MS analyses. Their absolute configurations were assigned by ECD calculations and specific rotation comparison. The biological activities of these substances toward regulation of lipid metabolism, neurite outgrowth-promoting activity, and AchE inhibition were assessed. Compound 15 was found to be able to block lipid accumulation at a concentration of 20 μM, and compounds 4a, 4b, and 11 show moderate neurite outgrowth-promoting activity at 10 μM, while compounds 3, 6, 11, and 13 exhibit potent AchE inhibition with the IC50 values of 28.6 ± 1.9, 18.7 ± 1.6, 8.2 ± 0.2, 26.0 ± 2.9 μM, respectively.

    更新日期:2018-12-06
  • Synthesis, biological evaluation and molecular docking study of 1,2,3-1H-triazoles having 4H-pyrano[2,3-d]pyrimidine as potential Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-06
    Nguyen Dinh Thanh, Do Son Hai, Nguyen Thi Thu Ha, Do Tien Tung, Cao Thi Le, Hoang Thi Kim Van, Vu Ngoc Toan, Duong Ngoc Toan, Le Hai Dang

    Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam N−H bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-d]pyrimidine compounds has been accomplished by reaction with tetra-O-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1H-1,2,3-triazoles 8a-y were screened for their in vitro Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds 8v, 8x, and 8y showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) in vitro and in silico studies suggested that the interaction of Arg63 amino acids with anion type of para-hydroxyl group via a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.

    更新日期:2018-12-06
  • Substrate specificity of tuliposide-converting enzyme, a unique non-ester-hydrolyzing carboxylesterase in tulip: effects of the alcohol moiety of substrate on the enzyme activity
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-06
    Yasuo Kato, Takashi Futanaga, Taiji Nomura

    6-Tuliposides A (PosA) and B (PosB) are glucose esters accumulated in tulip (Tulipa gesneriana) as major defensive secondary metabolites. Pos-converting enzymes (TgTCEs), which we discovered previously from tulip, catalyze the conversion reactions of PosA and PosB to antimicrobial tulipalins A (PaA) and B (PaB), respectively. The TgTCEs, belonging to the carboxylesterase family, specifically catalyze intramolecular transesterification, but not hydrolysis. In this report, we synthesized analogues of Pos with various alcohol moieties, and measured the TgTCE activity together with a determination of the kinetic parameters for these analogues with a view to probe the substrate recognition mechanism of the unique non-ester-hydrolyzing TgTCEs. It was found that d-glucose-like structure and number of the hydroxyl group in alcohol moiety are important for substrate recognition by TgTCEs. Among the analogues examined, 1,2-dideoxy analogues of PosA and PosB were found to be recognized by the TgTCEs more specifically than the authentic substrates by lowering Km values. The present results will provide a basis for designing simple, stable synthetic substrate analogues for crystallographic analysis of TgTCEs.

    更新日期:2018-12-06
  • Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-06
    Yachuang Wu, Xiudong Ding, Sicong Xu, Yifeng Yang, Xue Zhang, Chu Wang, Hong Lei, Yanfang Zhao

    Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a-6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 ug/mL against S.aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5 µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC50 value of 91.04 μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.

    更新日期:2018-12-06
  • Synthesis of 2́-O-(N-methylcarbamoylethyl) 5-methyl-2-thiouridine and its application to splice-switching oligonucleotides
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-04
    Yoshiaki Masaki, Keishi Yamamoto, Takeshi Inde, Keita Yoshida, Atsuya Maruyama, Tetsuya Nagata, Jun Tanihata, Shin'ichi Takeda, Mitsuo Sekine, Kohji Seio

    The effect of 2́-O-(N-methylcarbamoyl)ethyl (MCE) modification on splice-switching oligonucleotides (SSO) was systematically evaluated. The incorporation of five MCE nucleotides at the 5́-termini of SSOs effectively improved the splice switching effect. In addition, the incorporation of 2́-O-(N-methylcarbamoylethyl)-5-methyl-2-thiouridine (s2TMCE), a duplex-stabilizing nucleotide with an MCE modification, into SSOs further improved splice switching. These SSOs may be useful for the treatment of genetic diseases associated with splicing errors.

    更新日期:2018-12-05
  • Design, synthesis and characterization of novel N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors leading to the identification of the selective compound, AC1903
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-04
    Swagat H. Sharma, Juan Lorenzo Pablo, Monica Suarez Montesinos, Anna Greka, Corey R. Hopkins

    The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.

    更新日期:2018-12-05
  • Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-04
    Megan E. Dumas, Geng-Yuan Chen, Nicole Kendrick, George Xu, Scott A. Larsen, Somnath Jana, Alex G. Waterson, Joshua A. Bauer, William Hancock, Gary A. Sulikowski, Ryoma Ohi

    The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.

    更新日期:2018-12-05
  • A Novel Tetrazole Analogue of Resveratrol is a Potent Anticancer Agent
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-04
    Shobanbabu Bommagani, Narsimha Reddy Penthala, Meenakshisundaram Balasubramaniam, Sudhakiranmayi Kuravi, Eloisi Caldas-Lopes, Monica L. Guzman, Ramesh Balusu, Peter A. Crooks

    A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values <10 nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogs 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.

    更新日期:2018-12-05
  • Advances in Lead Generation
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-03
    Joerg Holenz, Patrick Stoy

    Lead Generation represents a critical drug discovery phase where chemical starting points and their respective mechanism of action, quality, and potential liabilities are largely predefined. Recent advances such as DNA-encoded libraries or fragment-, chemical biology-, and virtual screening-based approaches are today as common as traditional High Throughput Screening. Innovations in characterizing lead quality have allowed more informed decision-making by discovery teams. The key challenge today is to individually tailor the right mix of methods for each project to facilitate data integration with the purpose of creating multiple high-quality lead series, ultimately translating to reduced chemistry-related pipeline attrition.

    更新日期:2018-12-04
  • Semi-synthesis and anti-tumor activity of novel 25-OCH3-PPD derivatives incorporating aromatic moiety
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-03
    Fan-Zhi Qu, Sheng-Nan Xiao, Xu-De Wang, Yan Zhang, Guang-Yue Su, Yu-Qing Zhao

    Previously we have reported that 25-OCH3-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC50 < 15 µM, 5-fold to 10-fold increases than 25-OCH3-PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC50 = 6.7 ± 0.8, 4.3 ± 0.8 and 5.8 ± 0.6 µM, respectively). Structure-activity relationships demonstrated that having aromatic ester at the C3 position could improve the bioactivity. The data provided new insights into exploring novel antiproliferative lead compounds.

    更新日期:2018-12-04
  • Bioactive Polyoxygenated Cembranoids from a Novel Hainan Chemotype of the Soft Coral Sinularia flexibilis
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-03
    Qihao Wu, Xu-Wen Li, Heng Li, Li-Gong Yao, Wei Tang, Ze-Hong Miao, Hong Wang, Yue-Wei Guo

    Different chemotypes of Sinularia flexibilis exist in the Hainan island. Thus, a collection of this soft coral from a location different from the one of our previous study afforded three novel cembranoid esters featuring a n-butyl alcohol moiety, a structural element rare in natural products of both terrestrial and marine origin. The structures of the new compounds were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported diepoxycembrene (9) was first time determined by the X-ray diffraction analysis. In bioassays, compounds 6−8 exhibited strong anti-inflammatory effect with IC50 values of 2.7, 4.7, and 4.2 μM, respectively, whereas compound 5 displayed cytotoxicity against several cancer cells with IC50 values ranging from 8.9 to 27.4 μM. A preliminary structural-activity relationship (SAR) was also described.

    更新日期:2018-12-04
  • Turning natural products into insecticide candidates: Design and semisynthesis of novel fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides against two crop-threatening insect pests
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-03
    Yong Guo, Jiangping Fan, Qian Zhang, Chongnan Bao, Zhiyan Liu, Ruige Yang

    To improve the insecticidal activities of fraxinellone, two series of fraxinellone-based N-(1,3-thiazol-2-yl)carboxamides containing 25 compounds were prepared by structural modification. Their structures were determined by melting point, optical rotation, IR, 1H NMR and ESI-MS. The steric configurations of compounds 6i, 7d and 7i were unambiguously confirmed by X-ray diffraction further. The bioassay showed that compounds 6b and 6i exhibited more potent larvicidal and growth inhibitory activities against Plutella xylostella Linnaeus and Mythimna separata Walker, respectively. Moreover, compounds 6b and 6i also displayed low cytotoxicity to noncancerous mammalian cells. The structure–activity relationships (SARs) of all target compounds were also observed.

    更新日期:2018-12-03
  • Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) – Part 1
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-12-01
    Joanne Osborne, Kristian Birchall, Denise J. Tsagris, Stephen J. Lewis, Ela Smiljanic-Hurley, Debra L. Taylor, Alison Levy, Dario R. Alessi, Edward G. McIver

    Parkinson’s disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further development.

    更新日期:2018-12-01
  • Synthesis and biological evaluation of novel analogues of Gly-L-Pro-L-Glu (GPE) as neuroprotective agents
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-29
    Lisa Marinelli, Erika Fornasari, Antonio Di Stefano, Hasan Turkez, Salvatore Genovese, Francesco Epifano, Giuseppe Di Biase, Erica Costantini, Chiara D'Angelo, Marcella Reale, Ivana Cacciatore

    This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1-3) as potential candidates to counteract neuroinflammation processes in Alzheimer’s disease.GPE 1-3 pseudotripeptides are synthetic derivatives of Gly-L-Pro-L-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t1/2 > 4 h) than GPE (t1/2 = 30 min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1-3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1β, IL-18, and TNF-α) in Aβ25-35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties.

    更新日期:2018-11-29
  • Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-28
    Marcus J.C. Long, Ann P. Lawson, Rick Baggio, Yu Qian, Lior Rozhansky, Domenico Fasci, Farid El Oualid, Eranthie Weerapana, Lizbeth Hedstrom

    Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB inhibitors.

    更新日期:2018-11-28
  • 5-Substituted-N-pyridazinylbenzamides as Potent and Selective LRRK2 Inhibitors: Improved Brain Unbound Fraction Enables Efficacy
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-28
    Xiao Ding, Luigi Piero Stasi, Xuedong Dai, Kai Long, Cheng Peng, Baowei Zhao, Hailong Wang, Changhui Sun, Huan Hu, Zehong Wan, Karamjit S. Jandu, Oliver J. Philps, Yan Chen, Lizhen Wang, Qian Liu, Colin Edge, Yi Li, Kelly Dong, Feng Ren

    We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h.

    更新日期:2018-11-28
  • Practical One-step Glucuronidation via Biotransformation
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-28
    Takashi Ohnuki, Masahiko Ejiri, Masaaki Kizuka, Mie Fujiwara, Takahide Nishi

    We herein report a practical one-step glucuronidation method by biotransformation using Streptomyces sp. SANK 60895. This novel direct method of biotransformation has been shown to be more practical and scalable for glucuronidation than previously reported chemical and enzymatic procedures given its simplicity, high β-selectivity, cost-effectiveness, and reproducibility. We applied the present method to the synthesis of acyl glucuronide and hydroxy-β-glucuronide of mycophenolic acid and compound 4, respectively. This method was also shown to be applicable to the N-glucuronidation of various compounds.

    更新日期:2018-11-28
  • Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-27
    Nan Zheng, Qun Hao, Kuaile Lin, Jing Pan, Yingxia Li, Weicheng Zhou

    A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines in vitro. Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC50 value of 4.2 nM. In particular, 8 and 9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.

    更新日期:2018-11-28
  • Synthesis and Evaluation of 2,5-diamino and 2,5-dianilinomethyl pyridine analogues as potential CXCR4 antagonists
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-27
    S. Virani, Z. Liang, Y. Yoon, H. Shim, S.R. Mooring

    CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.

    更新日期:2018-11-28
  • Prodrugs of the Cancer Cell Selective Anti-Cancer Agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) Are Orally Efficacious in a Mouse Model of Resistant Colon Cancer
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-27
    Cheng Shang See, Mayumi Kitagawa, Pei-Ju Liao, Kyung Hee Lee, Jasmine Wong, Sang Hyun Lee, Brian W. Dymock

    A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.

    更新日期:2018-11-28
  • Synthesis and antitumor activity of biotinylated camptothecin derivatives as potent cytotoxic agents
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-27
    Cheng-Ting Zi, Liu Yang, Feng-Qing Xu, Fa-Wu Dong, Rui-Jing Ma, Yan Li, Jun Zhou, Zhong-Tao Ding, Zi-Hua Jiang, Jiang-Miao Hu

    A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 0.13 to 21.53 μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC50 = 0.13 – 3.31 μM) and compound 18 (IC50 = 0.23 – 1.48 μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.

    更新日期:2018-11-27
  • Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-24
    Debnath Bhuniya, Rajendra K. Kharul, Atul Hajare, Nadim Shaikh, Sandeep Bhosale, Sandip Balwe, Fouzia Begum, Siddhartha De, Sonalee Athawankar, Dhananjay Joshi, Vamsi Madgula, Kaushal Joshi, Amol A. Raje, Ashwinkumar V. Meru, Amol Magdum, Kasim A. Mookhtiar, Rashmi Barbhaiya

    Conceptual design and modification of urea moiety in chemotype PF-3845/ 04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Table 1, Table 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3 to 30 mg/kg po for 7 days. The effects at 30 mg/kg are comparable to that of PF-04457845 (10 mg/kg) and Tramadol (40 mg/kg).

    更新日期:2018-11-26
  • Diversity-oriented synthesis of bicyclic fragments containing privileged azines
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-24
    Nicola Luise, Paul G. Wyatt

    An innovative and efficient reagent- and scaffold-based diversity oriented synthesis (DOS) of a fragment set was developed for fragment-based drug discovery (FBDD) programs. Twelve diverse, functionalized and bicyclic scaffolds were rapidly accessed by adopting a convenient synthetic toolkit around three privileged azine cores in order to effectively modulate biomolecules. These structures are characterized by both key motifs for interacting with diverse biological targets via hydrogen bonds and useful points of growth for subsequent fragment optimization.

    更新日期:2018-11-26
  • Design, Synthesis and Evaluation of N2,N4-diaminoquinazoline Based Inhibitors of Phosphodiesterase Type 5
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-22
    Nattakarn Pobsuk, Tamkeen Urooj Paracha, Nattiya Chaichamnong, Nattapas Salaloy, Praphasri Suphakun, Supa Hannongbua, Kiattawee Choowongkomon, Dumrongsak Pekthong, Krongkarn Chootip, Kornkanok Ingkaninan, M. Paul Gleeson

    We describe the design, synthesis and evaluation of a series of N2,N4-diaminoquinazoline analogues as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC50 = 0.072±0.008 µM) and exhibited 4.61 fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC50s of 1.63±0.72 µM and 2.28±0.74 µM respectively.

    更新日期:2018-11-24
  • Sanguiin H-11 from Sanguisorbae radix protects HT22 murine hippocampal cells against glutamate-induced death
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-22
    Ji Hoon Song, Song-Yi Kim, Gwi Seo Hwang, Youn-Sub Kim, Hyun Young Kim, Ki Sung Kang

    Excessive glutamate level induces neuronal death in acute brain injuries and chronic neurodegenerative diseases. Natural compounds from medicinal and food plants have been attracting interest as a treatment for neurological disorders. Sanguiin H-11 (SH-11), a hydrolysable ellagitannin, inhibits neutrophil movement and nitric oxide activity. However, its neuroprotective effect has not been studied. Therefore, the present study examined the protective effect of SH-11 from Sanguisorbae radix and its mechanism against glutamate-induced death in HT22 cells. Our results showed that SH-11 possessed a strong antioxidant activity and prevented glutamate-induced death in HT22 cells. As a strong antioxidant, SH-11 significantly reduced glutamate-induced increases in intracellular reactive oxygen species accumulation and calcium ion influx. Western blotting analysis showed that glutamate-induced phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-related kinases 1/2, c-Jun N-terminal kinase, and p38, was significantly decreased by SH-11. Furthermore, SH-11 significantly decreased the number of annexin V-positive HT22 cells, which is indicating apoptotic cell death. In conclusion, our results suggested that SH-11 exerted a potent neuroprotective activity against glutamate-mediated apoptotic cell death by inhibiting oxidative stress-mediated MAPK activation.

    更新日期:2018-11-24
  • Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-22
    Carlos J.A. Ribeiro, Jayakanth Kankanala, Jiashu Xie, Jessica Williams, Hideki Aihara, Zhengqiang Wang

    Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure-activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC50 < 50 µM), with 17z showing excellent cell permeability and no cytotoxicity.

    更新日期:2018-11-24
  • Design, synthesis and biological evaluation of benzimidazole derivatives as novel human Pin1 inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-23
    Tianyi Ma, Min Huang, Aihua Li, Feng Zhao, Deyi Li, Dan Liu, Linxiang Zhao

    In this work, a series of novel benzimidazole derivatives were designed and synthesized as Pin1 inhibitors. Protease-coupled assay was used to investigate the Pin1 inhibitory potency of all synthesized compounds. Thirteen of them showed preferable Pin1 inhibitory effects with IC50 values lower than 5 μM, and 12a, 15b, 15d and 16c exhibited the most promising Pin1 inhibitory activity at low micromolar level (0.33∼1.00 μM) than the positive control compound Juglone. Flow cytometry results showed that treating PC-3 cells with 16c caused slight cycle arrest in a concentration-dependent manner. The structure-activity relationships of R1, R2, R3 and linker of the benzimidazole derivatives were analyzed in detail, which would help further exploration of new Pin1 inhibitors.

    更新日期:2018-11-24
  • BH3 mimetics derived from Bim-BH3 domain core region show PTP1B inhibitory activity
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-23
    Xiao Lu, Lijuan Wu, Xiaochun Liu, Shulin Wang, Chuanliang Zhang

    A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity(KD=8.38nmol/L), inhibitory activity (IC50=1.20μmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.

    更新日期:2018-11-24
  • Identification of potent bovine viral diarrhea virus inhibitors by a structure-based virtual screening approach
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-23
    Eliana F. Castro, Juan J. Casal, María J. España de Marco, Leandro Battini, Matías Fabiani, Gabriela A. Fernández, Ana M. Bruno, Lucía V. Cavallaro, Mariela Bollini

    Bovine viral diarrhea virus (BVDV) is a pestivirus whose infection in cattle is globally distributed. The use of antivirals could complement vaccination as a tool of control and reduce economic losses. The RNA-dependent RNA polymerase (RdRp) of the virus is essential for its genome replication and constitutes an attractive target for the identification of antivirals. With the aim of obtaining selective BVDV inhibitors, the crystal structure of BVDV RdRp was used to perform a virtual screening. Approximately 15,000 small molecules from commercial and in-house databases were evaluated and several structurally different compounds were tested in vitro for antiviral activity. Interestingly, of twelve evaluated compounds, five were active and displayed EC50 values in the sub and low-micromolar range. Time of drug addition experiment and measured intracellular BVDV RNA showed that compound 7 act during RNA synthesis. Molecular Dynamics and MM/PBSA calculation were done to characterize the interaction of the most active compounds with RdRp, which will allow future ligand optimization. These studies highlight the use of in silico screening to identify a new class of BVDV inhibitors.

    更新日期:2018-11-24
  • Identification of Fluorinated (R)-(-)-Aporphine Derivatives as Potent and Selective Ligands at Serotonin 5-HT2C Receptor
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-23
    Yulong Xu, Anna W. Sromek, John L. Neumeyer

    A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT2 receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT2C hit ligands with highly selectivity over other 5-HT2 receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.

    更新日期:2018-11-24
  • Potent inhibitors of malarial P. falciparum protein kinase G: improving the cell activity of a series of imidazopyridines
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-20
    Jonathan M. Large, Kristian Birchall, Nathalie S. Bouloc, Andy T. Merritt, Ela Smiljanic-Hurley, Denise J. Tsagris, Mary C. Wheldon, Keith H. Ansell, Peter J. Coombs, Catherine A. Kettleborough, David Whalley, Lindsay B. Stewart, Paul W. Bowyer, David A. Baker, Simon A. Osborne

    Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.

    更新日期:2018-11-21
  • A thiol-inducible and quick-response DNA cross-linking agent
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-19
    Yuanzhen Xu, Hongbo Wei, Jianjun Chen, Kun Gao

    Three new 2,4-dinitrobenzenesulfonyl derivatives 1–3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4–6) within 5 minutes. The quick response of 1–3 toward thiols was determined by 1H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group.

    更新日期:2018-11-20
  • Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-19
    Yu-Yon Kim, Jaeyul Choi, Kyungjin Choi, Changhee Park, Young Hoon Kim, Kwee Hyun Suh, Young Jin Ham, Sun Young Jang, Kyu-Hang Lee, Kwang Woo Hwang

    Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.

    更新日期:2018-11-20
  • New Approaches for the Treatment of Alzheimer’s Disease
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-19
    Paul V. Fish, David Steadman, Elliott D. Bayle, Paul Whiting

    Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.

    更新日期:2018-11-20
  • Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-20
    Anna N. Tevyashova, Elena N. Bychkova, Alexander M. Korolev, Elena B. Isakova, Elena P. Mirchink, Ilya A. Osterman, Réka Erdei, Zsolt Szücs, Gyula Batta

    One of the promising directions of the combined approach is the design of dual-acting antibiotics - heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin’s activity for the treatment of mice with Staphylococcus aureus sepsis.

    更新日期:2018-11-20
  • Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening of an in-house small molecule library for anti-lung cancer therapeutics
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-17
    Fuyun Guo, Shufen Zhao, Xiao'e Li

    Pyruvate dehydrogenase kinases (PDKs) are widely over-expressed in various human solid cancers, making them attractive therapeutic targets for cancer treatment. Herein, we report the identification of structurally novel PDKs inhibitors by screening of an in-house small molecule library. Biochemical assay indicated that the identified compounds 1-4 inhibited PDK1 activity with EC50 values of 0.50, 1.99, 4.64, and 0.42 µM, respectively. The ITC analysis suggested that the identified compounds 1-4 were pan-isoform PDK inhibitors, which bound to and inhibited the four PDK isoforms. Moreover, 1-4 dose-dependently reduced pyruvate dehydrogenase complex phosphorylation in NCI-H1975 cell. Molecular docking suggested that the most potent compound 4 docked well in the ATP binding pocket of the four PDK isoforms, forming direct hydrogen bond interactions with the conserved amino acids Thr and Asp in ATP binding pocket of PDKs. The cell viability assay demonstrated that 4 potently blocked NCI-H1975 cell proliferation (IC50 = 3.32 µM), but had little effect on human normal lung cell MRC-5 even with the tested concentration up to 40 µM. All the data demonstrated that 4 was a promising lead for the development of structurally novel PDKs inhibitor for the cancer treatment.

    更新日期:2018-11-17
  • Synthesis and biological evaluation of 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives as novel anti-tubercular agents
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-17
    Kasa Shiva Raju, Sandeep AnkiReddy, Gowravaram Sabitha, Vagolu Siva Krishna, Dharmarajan Sriram, Kunduru Bharathi Reddy, Someswar Rao Sagurthi

    A series of novel 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives have been synthesized in good to excellent yields. Through the copper-catalyzed azide-alkyne cycloaddition via reaction of 7-(prop-2-ynyl)-7H-pyrrolo[2,3-d]pyrimidine and aryl, heteroaryl and alkyl azides in the presence of CuSO4.5H2O and sodium ascorbate. These compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Most of these pyrrolopyrimidine-triazole hybrids exhibited good anti tubercular activity. The antimycobacterial assay results showed that the minimum inhibitory concentration of compounds 4q and 4r were 0.78µg/mL. The molecular docking results also had shown highest Moldock score for same compounds. These novel compounds exhibited good inhibition activities and further structure-activity studies of the derivatives had shown promising features to use in antitubercular therapy

    更新日期:2018-11-17
  • Synthesis and biological evaluation of clovamide analogues with catechol functionality as potent Parkinson’s disease agents in vitro and in vivo
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-15
    Jia-Hao Feng, Xiao-Long Hu, Xian-Yu Lv, Bao-Lin wang, Jun Lin, Xiao-Qi Zhang, Wen-Cai Ye, Fei Xiong, Hao Wang

    •In this study, seven clovamide analogues (1-7) were designed and synthesized, and the neuroprotection of 1-7 as well as 8-15 (prepared in our previous work) against H2O2-induced oxidative stress was evaluated in SH-SY5Y cells. Results showed that 1-7 with catechol groups exhibited better neuroprotective effects than 8-15, and their EC50 values ranged from 4.26 to 23.83 μM, especially 1, indicating that the moiety of catechol governed the activities of these compounds. Furthermore, oral administration of 1 (10 or 20 mg/kg) was demonstrated to possess anti-PD effect through alleviating apoptosis and oxidative stress in vitro and in vivo, and to up-regulate the expression of heme oxygenase-1 (HO-1) via PI3K/AKT/mTOR pathway. Finally, the pharmacokinetic (PK) assessment of 1 was determined in rats. These findings suggested that 1 might be an effective candidate for PD therapy.

    更新日期:2018-11-16
  • On the origin of the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold’s unique group II selectivity for the mGlu receptors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-16
    Junliang Hao, Qi Chen

    Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of L-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold’s unique group II selectivity that explores the subtle distance differences between the α-carbon of L-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu2).

    更新日期:2018-11-16
  • Molecular Features Characterizing Non-peptide Selectivity to the Human B1 and B2 Bradykinin Receptors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-14
    B. Rasaeifar, C.S. Lupala, P. Gomez-Gutierrez, Juan J. Perez

    Bradykinin is produced in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases. Actions of this peptide are mediated through two different G-protein coupled receptors, named B1 and B2 that have different pharmacological characteristics. The former is up-regulated during inflammation episodes or tissue trauma whereas, the latter is constitutively expressed in a variety of cell types. In a previous work we have characterized the molecular features that explain the observed structure-activity results for both receptors by means of molecular modeling studies, using diverse ligands for both receptors. These results were summarized in the form of two different pharmacophores that provided new insights to be used for the design of novel molecules with antagonistic profile. In the present work, we compare these pharmacophores to understand the features that characterize ligand selectivity to the two bradykinin receptors. The study shows that most of the residues involved in the binding pocket are similar in both receptors and consequently are the pharmacophores obtained. The main difference between the two pharmacophores remains on point #5 that involves a polar moiety for the B1 receptor and an aromatic ring for the B2 receptor. Accordingly, analysis of the prospective bound conformation of several non-selective small molecule ligands of the bradykinin receptors permits to conclude that fulfilment of point#5 is a requirement to produce selective ligands. However, the study also shows that this is a necessary condition only, since ligands need also to be bulky enough to avoid binding to these receptors in diverse poses. These results provide new insights for a better understanding of the molecular features that ligands are required to exhibit to be selective bradykinin ligands.

    更新日期:2018-11-15
  • Resorcinol alkyl glucosides as potent tyrosinase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-14
    Wakana Ishioka, Sayaka Oonuki, Takehiro Iwadate, Ken-ichi Nihei

    Resorcinol alkyl glucosides 7–12 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4-dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 7–12 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC50) of tetradecyl derivative 12 was 0.39 μM, making it the most potent of the compounds synthesized. The IC50 of 8 (3.62 μM) with a propyl spacer was ca 10 times that of 7 (35.9 μM) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C3.

    更新日期:2018-11-15
  • Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-14
    Hikaru Kato, Ahmed H. El-Desoky, Yuya Takeishi, Tatsuo Nehira, Esther D. Angkouw, Remy E. P. Mangindaan, Nicole J. de Voogd, Sachiko Tsukamoto

    A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.

    更新日期:2018-11-15
  • The development of myeloperoxidase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-15
    Semira Galijasevic

    Myeloperoxidase (MPO), an abundant hemoprotein present in neutrophils and monocytes, plays a significant role in immune surveillance and host defense mechanisms. However, increased MPO activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. As a result, search for active compounds that can efficiently inhibit MPO activity and subsequently decrease inflammatory events has been focus of the current research. This perspective provides an overview of the development of MPO inhibitors, their mechanism of action and the review of molecules that were in clinical trials as promising MPO inhibitors.

    更新日期:2018-11-15
  • Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-14
    Feifei Yang, Peipei Shan, Na Zhao, Di Ge, Kongkai Zhu, Cheng-shi Jiang, Peifeng Li, Hua Zhang

    Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.

    更新日期:2018-11-14
  • Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-12
    Robert A Mook, Jiangbo Wang, Xiu-Rong Ren, Hailan Piao, H. Kim Lyerly, Wei Chen

    Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide’s inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.

    更新日期:2018-11-13
  • Seco-4-methyl-DCK Derivatives as Potent Chemosensitizers
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-12
    Yalan Guo, Ke Wang, Xiaoyu Chen, Haihong Li, Qi Wan, Susan Morris-Natschke, Kuo-Hsiung Lee, Ying Chen

    Twenty-five seco-4-methyl-DCK derivatives were designed, synthesized and evaluated for chemoreversal activity when combined with paclitaxel or vincristine in two drug-resistant cancer cell lines (A2780/T and KB-V) respectively. Most of the new compounds displayed moderate to significant MDR reversal activities in the P-gp overexpressing A2780/T and KB-V cells. Especially, compounds 7o and 7y showed the most potent chemosensitization activities with more than 496 and 735 reversal ratios at a concentration of 10 μM. Unexpectedly the newly synthesized compounds did not show chemosensitization activities observed in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, these compounds did not exhibit significant antiproliferative activities against nontumorigenic cell lines (HUVEC, HOSEC and T29) compared to the positive control verapamil at the tested concentration, which suggested better safety than verapamil. The pharmacological actions of the compounds will be studied further to explore their merit for development as novel candidates to overcome P-gp mediated MDR cancer.

    更新日期:2018-11-13
  • Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-13
    Christopher A. Luckhurst, Omar Aziz, Vahri Beaumont, Roland W. Bürli, Perla Breccia, Michel C. Maillard, Alan F. Haughan, Marieke Lamers, Phil Leonard, Kim L. Matthews, Gilles Raphy, Andrew J. Stott, Ignacio Munoz-Sanjuan, Beth Thomas, Michael Wall, Grant Wishart, Dawn Yates, Celia Dominguez

    We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼ 8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.

    更新日期:2018-11-13
  • A carbapenem-based fluorescence assay for the screening of metallo-β-lactamase inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-13
    Xiana Qian, Shuangzhan Zhang, Shuyuan Xue, Wuyu Mao, Minqiu Xu, Weipan Xu, Hexin Xie

    Reported herein is a fluorescence assay for the rapid screening of metallo-β-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.

    更新日期:2018-11-13
  • Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-13
    Fang Yang, Cai-Ping He, Peng-Cheng Diao, Kwon Ho Hong, Jin-Jun Rao, Pei-Liang Zhao

    Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 μM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 μM, which was almost as active as that of CA-4 (IC50 = 4.2 μM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.

    更新日期:2018-11-13
  • Discovery of Covalent Enzyme Inhibitors Using Virtual Docking of Covalent Fragments
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-09
    Sandipan Roy Chowdhury, Steven Kennedy, Kai Zhu, Rama Mishra, Patrick Chuong, Alyssa-uyen Nguyen, Stefan G. Kathman, Alexander V. Statsyuk
    更新日期:2018-11-10
  • Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-09
    Anton Shetnev, Angelina Osipyan, Sergey Baykov, Alexander Sapegin, Zhanna Chirkova, Michail Korsakov, Anél Petzer, Idalet Engelbrecht, Jacobus P. Petzer
    更新日期:2018-11-10
  • Synthesis and Biological Activities Evaluation of Sanjuanolide and its Analogues
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-10
    Jiadai Zhai, Lin Fu, Yuanyuan Li, Rui Zhao, Rui Wang, Hongkuan Deng, Hongliang Liu, Ling Kong, Zhiwei Chen, Feng Sang
    更新日期:2018-11-10
  • Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5
    Bioorg. Med. Chem. Lett. (IF 2.442) Pub Date : 2018-11-10
    Andrew S. Felts, Katrina A. Bollinger, Christopher J. Brassard, Alice L. Rodriguez, Ryan D. Morrison, J. Scott Daniels, Anna L. Blobaum, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Kyle A. Emmitte, Craig W. Lindsley
    更新日期:2018-11-10
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.
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