Benzo[ d]isoxazole Derivatives as Hypoxia-Inducible Factor (HIF)-1α Inhibitors

Zian Xue; Huiti Li; Wenhao Xie; Ying Xu; Lu Zhou; Zhi-Bei Qu

doi:10.1021/acsmedchemlett.2c00308

Benzo[ d]isoxazole Derivatives as Hypoxia-Inducible Factor (HIF)-1α Inhibitors

ACS Med Chem Lett. 2022 Sep 13;13(12):1864-1869. doi: 10.1021/acsmedchemlett.2c00308. eCollection 2022 Dec 8.

Authors

Zian Xue¹, Huiti Li¹, Wenhao Xie¹, Ying Xu², Lu Zhou¹, Zhi-Bei Qu¹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200120, China.
² Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Abstract

Hypoxia-inducible factor, also known as HIF, is a transcriptional factor universally found in mammalian cells. HIF-1 is one of the HIF-families and acts as a heterodimer consisting of α and β subunits. It is found to play significant roles in pathologic conditions such as tumor development and metastasis. Here, we first report benzo[d]isoxazole analogues as HIF-1α transcription inhibitors. Thereby, we designed and synthesized 26 benzo[d]isoxazole derivatives and evaluated their inhibitory activities against HIF-1α transcription in HEK293T cells by a dual-luciferase gene reporter assay. Among them, compounds 15 and 31 showed the best efficacy in a cell-based assay with an IC₅₀ value of 24 nM and have potential antitumor effects for further development.