Design, Synthesis and Biological Evaluation of Novel HIF1α Inhibitors.

Elevated levels of hypoxia inducible factor-1 (HIF1) are linked to tumor metastasis, angiogenesis, poor patient prognosis and response to chemotherapy. HIF1α is a master regulator of the hypoxic response, including in cancer cells, through transcriptional activation of several target genes. Previously, we identified compound CJ-3k with high anti-HIF1α activity based on the structure of a well-known HIF1α inhibitor, YC-1. In this study, the CJ-3k scaffold was systematically modified to explore the structure-activity relationships. Fifty-three new CJ-3k analogs were synthesized and screened for their anti-HIF-1α activity in a luciferase-transfected human breast cancer cell line (MDA-MB-231). Some of these new analogs have a significantly greater activity than that of CJ-3k and hold potential for development as new therapeutic agents for the treatment of cancer. Copyright