Document Report Card

ID: ALA1142538

Journal: J Med Chem

Title: Structure-activity relationship studies of phenanthridine-based Bcl-XL inhibitors.

Authors: Bernardo PH, Wan KF, Sivaraman T, Xu J, Moore FK, Hung AW, Mok HY, Yu VC, Chai CL.

Abstract: Despite their structural similarities, the natural products chelerythrine ( 5) and sanguinarine ( 6) target different binding sites on the pro-survival Bcl-X L protein. This paper details the synthesis of phenanthridine-based analogues of the natural products that were used to probe this difference in binding profiles. The inhibitory constants for these compounds were then measured in a fluorescence polarization assay against Bcl-X L and the tagged Bak-BH3 peptide. The results led to structure-activity relationship studies, which identified the structural motifs required for binding-site specificity as well as inhibitory activity. We also identified synthetic analogues of the natural products that display similar binding modes but with more potent IC 50 values.

CiteXplore: 18925736

DOI: 10.1021/jm8005433