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Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.鉴定咪唑并吡咯吡啶类化合物为新型强效 JAK1 抑制剂。
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MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells.新型微管抑制剂 MG-2477 通过抑制 Akt/mTOR 通路和延迟 A549 细胞凋亡诱导自噬。
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新型3-取代-7-苯基吡咯并[3,2-f]喹啉-9(6H)-酮作为具有多靶点抗增殖活性的单一实体

Novel 3-Substituted 7-Phenylpyrrolo[3,2-f]quinolin-9(6H)-ones as Single Entities with Multitarget Antiproliferative Activity.

作者信息

Carta Davide, Bortolozzi Roberta, Hamel Ernest, Basso Giuseppe, Moro Stefano, Viola Giampietro, Ferlin Maria Grazia

机构信息

Department of Pharmaceutical and Pharmacological Sciences, University of Padova , Via Marzolo, 5, 35131 Padova, Italy.

Laboratory of Oncohematology, Department of Women's and Children's Health, University of Padova , 35128 Padova, Italy.

出版信息

J Med Chem. 2015 Oct 22;58(20):7991-8010. doi: 10.1021/acs.jmedchem.5b00805. Epub 2015 Oct 7.

DOI:10.1021/acs.jmedchem.5b00805
PMID:26418966
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4629825/
Abstract

A series of chemically modified 7-phenylpyrrolo[3,2-f]quinolinones was synthesized and evaluated as anticancer agents. Among them, the most cytotoxic (subnanomolar GI50 values) amidic derivative 5f was shown to act as an inhibitor of tubulin polymerization (IC50, 0.99 μM) by binding to the colchicine site with high affinity. Moreover, 5f induced cell cycle arrest in the G2/M phase of the cell cycle in a concentration dependent manner, followed by caspase-dependent apoptotic cell death. Compound 5f also showed lower toxicity in nontumoral cells, suggesting selectivity toward cancer cells. Additional experiments revealed that 5f inhibited the enzymatic activity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK1. Computational studies showed that 5f can be properly accommodated in the colchicine binding site of tubulin as well as in the ATP binding clefts of all examined kinases. Our data indicate that the excellent antiproliferative profile of 5f may be derived from its interactions with multiple cellular targets.

摘要

合成了一系列化学修饰的7-苯基吡咯并[3,2-f]喹啉酮，并将其作为抗癌剂进行评估。其中，细胞毒性最强（亚纳摩尔级的GI50值）的酰胺衍生物5f通过与秋水仙碱位点高亲和力结合，表现为微管蛋白聚合的抑制剂（IC50，0.99 μM）。此外，5f以浓度依赖性方式诱导细胞周期在G2/M期停滞，随后导致半胱天冬酶依赖性凋亡细胞死亡。化合物5f在非肿瘤细胞中也表现出较低的毒性，表明对癌细胞具有选择性。进一步的实验表明，5f抑制多种激酶的酶活性，包括AURKA、FLT3、GSK3A、MAP3K、MEK、RSK2、RSK4、PLK4、ULK1和JAK1。计算研究表明，5f可以很好地容纳在微管蛋白的秋水仙碱结合位点以及所有检测激酶的ATP结合裂隙中。我们的数据表明，5f优异的抗增殖特性可能源于其与多个细胞靶点的相互作用。