Structure–activity studies on seco-pancratistatin analogs: Potent inhibitors of human cytochrome P450 3A4

Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are reported. Structure–activity relationship (SAR) studies identified potent and selective inhibitors of human cytochrome P450 3A4 (CYP3A4) and revealed several core pharmacophoric elements. These studies identify potential roadblocks and will guide the further development of a viable selective clinical pancratistatin derivative.

The cytochrome P450 3A4 inhibitory activity of two fully synthetic series of seco-analogs of the lycorane-type anticancer amaryllidaceae alkaloids is presented. Potent inhibitors are identified and a comprehensive and consistent view of the P450 pharmacophore is revealed in this important series involving a double bond or small H-bond acceptor at the C1 position in conjunction with lipophilic substitution at C2, C3 and/or C4.Figure optionsDownload as PowerPoint slide