Isolation and identification of novel natural products that inhibit P300/HIF-1α interaction

Abstract

Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor for initiating a response against low oxygen environments in many solid tumors. Under hypoxic conditions, subunit HIF-1α dimerizes with subunit HIF-1β and binds to the multi-domain protein and transcriptional coactivator, p300. Inhibition of the p300/HIF-1α interaction results in the suppression of HIF-1 transcriptional activity during hypoxia. An extract of the marine ascidian Eudistoma sp. was identified as active in a high throughput screen for inhibitors of the p300/HIF-1α interaction. Three novel heterocylic alkaloids were isolated from the extract and their structures elucidated using both spectroscopic analyses and synthesis. The core scaffold of these alkaloids contains an unprecedented fused ring system with embedded guanidine and amidine functionalities. These compounds showed activity inhibiting the binding domains of p300 and HIF-1α.