HIF-1 plays a significant role in the adaptation of tumor cells to hypoxia by activating the transcription of genes involved in critical aspects of cancer, making it a leading target for the treatment of cancer. Despite several small molecules have been reported to inhibit the HIF-1 signaling pathway, these compounds exhibit relatively low HIF-1 inhibitory activity. In addition, most of them lack the desired selectivity or toxicity profiles required for a useful therapeutic agent. Therefore, development of potent and selective HIF-1 inhibitors is urgently needed. Manassantin A, a dineolignan isolated from <i>Saururus cernuus</i> L. (Saururaceae) has been shown to be a potent inhibitor of HIF-1α <i>in vitro</i> with minimal cytotoxicity. Previously, we reported a convergent and efficient synthesis of manassantin A, which enables the creation of various analogues. This presentation will describe our medicinal chemistry efforts for design, synthesis, and biological evaluation of manassantin analogues to establish structure-activity relationships of the natural product.

Design, synthesis, and biological evaluation of manassantin analogues for HIF-1α inhibition

249th National Meeting (2015)

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