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

Jie Liu; Wan Ye; Jiang-Ping Xu; Hai-Tao Wang; Xiao-Fang Li; Wen-Ya Wang; Zhong-Zhen Zhou

doi:10.1016/j.ejmech.2021.113700

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. Epub 2021 Jul 15.

Authors

Jie Liu¹, Wan Ye¹, Jiang-Ping Xu², Hai-Tao Wang¹, Xiao-Fang Li³, Wen-Ya Wang⁴, Zhong-Zhen Zhou⁵

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.

MeSH terms

Apoptosis / drug effects*
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Glioma / drug therapy*
Glioma / metabolism
Glioma / pathology
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Molecular Structure
Oxazoles / chemical synthesis
Oxazoles / chemistry
Oxazoles / pharmacology*
Phosphodiesterase 4 Inhibitors / chemical synthesis
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology*
Structure-Activity Relationship
Tubulin / metabolism*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*
Tumor Cells, Cultured

Substances

Oxazoles
Phosphodiesterase 4 Inhibitors
Tubulin
Tubulin Modulators
Cyclic Nucleotide Phosphodiesterases, Type 4