Discovery of novel trimethoxyphenylbenzo[d]oxazoles as dual tubulin/PDE4 inhibitors capable of inducing apoptosis at G2/M phase arrest in glioma and lung cancer cells
Discovery of novel trimethoxyphenylbenzo[d]oxazoles as dual tubulin/PDE4 inhibitors capable of inducing apoptosis at G2/M phase arrest in glioma and lung cancer cells
复制标题
发现新型三甲氧基苯基苯并[d]恶唑作为双微管蛋白/PDE4抑制剂，能够诱导神经胶质瘤和肺癌细胞G2/M期停滞的细胞凋亡。
DOI：
10.1016/j.ejmech.2021.113700
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发表时间：
2021-07-24
影响因子：
6.7
通讯作者：
Zhou, Zhong-Zhen
中科院分区：
文献类型：
--
作者：
Liu, Jie;Ye, Wan;Zhou, Zhong-Zhen
为了发现具有新型骨架结构的PDE4/微管蛋白双重缓蚀剂，通过将TH03的三甲氧基苯基迁移到苯并[d]恶唑上，设计并合成了7-三甲氧基苯并[d]恶唑4a-u和4-三甲氧基苯并[d]恶唑5a h。在这些化合物中，约有一半对胶质瘤(U251)和肺癌(A549和H460)细胞具有良好的抗增殖活性。三甲氧基苯基苯并[d]恶唑类化合物的构效关系表明，含吲哚-5-基侧链的4R化合物是一种新型的PDE4/微管蛋白双重抑制剂，对胶质瘤细胞(IC50=300+/-50 nM)和肺癌细胞(平均IC50=39.5 nM)具有良好的抗增殖活性。进一步研究发现，4R可诱导细胞周期停滞于G2/M期，破坏微管网络。初步的作用机制表明，4R下调A549细胞周期蛋白B1及其上游调控基因cdc25C的表达。(C)2021年爱思唯尔·马森公司。版权所有。
To discover PDE4/tubulin dual inhibitors with novel skeleton structures, 7-trimethoxyphenylbenzo [d] oxazoles 4a-u and 4-trimethoxyphenylbenzo[d]oxazoles 5a h were designed and synthesized by migrating the trimethoxyphenyl group of TH03 to the benzo[d]oxazole moiety. Among these compounds, approximately half of them displayed good antiproliferative activities against glioma (U251) and lung cancer (A549 and H460) cell lines. The structure-activity relationships of trimethoxyphenylbenzo[d] oxazoles led to the identification of 4r bearing indol-5-yl side-chain as a novel dual PDE4/tubulin inhibitor, which exhibited satisfactory antiproliferative activities against glioma (IC50 = 300 +/- 50 nM) and lung cancer (average IC50 = 39.5 nM) cells. Further investigations revealed that 4r induced apoptosis at G2/M phase arrest and disrupted the microtubule network. The preliminary mechanism of action showed that 4r down-regulated the expression of cyclin B1 and its upstream regulator gene cdc25C in A549. (C) 2021 Elsevier Masson SAS. All rights reserved.