2. Academic Validation
  3. 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

  • Eur J Med Chem. 2021 Nov 15:224:113700. doi: 10.1016/j.ejmech.2021.113700.
Jie Liu 1,  Wan Ye 1,  Jiang-Ping Xu 2,  Hai-Tao Wang 1,  Xiao-Fang Li 3,  Wen-Ya Wang 4,  Zhong-Zhen Zhou 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Key Laboratory of Mental Health of the Ministry Education, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, PR China.
  • 4 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: wangwy@smu.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Pharmacy Department, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhouzz@smu.edu.cn.
PMID: 34311158 DOI: 10.1016/j.ejmech.2021.113700
Abstract

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.

Keywords

Antiproliferative activities; Apoptosis; Cell cycle arrest; Dual PDE4/Tubulin inhibitor; trimethoxyphenylbenzo[d]oxazole.

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