Synthesis of novel natural product-like diaryl acetylenes as hypoxia inducible factor-1 inhibitors and antiproliferative agents

Shisheng Wang; Liqiang Liu; Xiuhan Guo; Guangzhe Li; Xu Wang; Huijuan Dong; Yueqing Li; Weijie Zhao

doi:10.1039/c9ra02525a

Synthesis of novel natural product-like diaryl acetylenes as hypoxia inducible factor-1 inhibitors and antiproliferative agents

RSC Adv. 2019 May 7;9(24):13878-13886. doi: 10.1039/c9ra02525a. eCollection 2019 Apr 30.

Authors

Shisheng Wang^{1

2}, Liqiang Liu¹, Xiuhan Guo^{1

2}, Guangzhe Li^{1

2}, Xu Wang¹, Huijuan Dong¹, Yueqing Li^{1

2}, Weijie Zhao^{1

2}

Affiliations

¹ Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology Dalian 116023 China liguangzhe@dlut.edu.cn.
² State Key Laboratory of Fine Chemicals, Dalian University of Technology Dalian 116023 China.

Abstract

The selaginellin derivatives are a type of novel natural pigments with an unusual alkynyl phenol skeleton from the genus Selaginella. Some of these natural compounds were previously reported to show important bioactivities, including anticancer activity, cardiovascular protection and phosphodiesterase-4 inhibition. We designed and synthesized fifteen biphenyl-containing diaryl acetylene derivatives mimicking the skeleton of natural alkynyl phenols. In MTT assay in cancer cells, compounds 1c, 2d, 2g, 2h, 2i and 2j exhibited potent antiproliferative activity. The evaluation of Hypoxia Inducible Factor-1 (HIF-1) pathway inhibitory activity in dual luciferase assay demonstrated that most tested compounds exhibited moderate to good activities. Compounds 1a, 2f and 2h displayed high HIF-1 inhibitory activities and relatively low cytotoxicity, demonstrating great potential as HIF-1 inhibitors. These results afford a new strategy for the discovery of new HIF-1 inhibitors and anti-proliferative agents from natural or synthetic diaryl acetylene derivatives.