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

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.

Automated summary

Novel dual PDE4/tubulin inhibitor 4r, derived from trimethoxyphenylbenzo[d]oxazoles, exhibited satisfactory antiproliferative activities against glioma and lung cancer cells by inducing apoptosis and disrupting the microtubule network. Its mechanism of action involved down-regulation of cyclin B1 and its upstream regulator gene cdc25C.