Semisynthesis of Glycosmis pentaphylla Alkaloid Derivatives: Pyranoacridone-Hydroxamic Acid Cytotoxic Conjugates with HDAC and Topoisomerase II α Dual Inhibitory Activity.

Inspired by our previous efforts in the semisynthetic modification of naturally occurring pyranoacridones, we report the targeted design and semisynthesis of dual inhibitors of HDAC and topoisomerase II α (Topo II α) derived from Glycosmis pentaphylla des-N-methylacronycine (1) and noracronycine (8) pyranoacridone alkaloids. Designed from the clinically approved SAHA, the cytotoxic pyranoacridone nuclei from the alkaloids served as the capping group, while a hydroxamic acid moiety functioned as the zinc-binding group. Out of 16 compounds evaluated in an in vitro cytotoxicity assay, KT32 (10c) with noracronycine (8) as the capping group and five-carbon linker hydroxamic acid side chains showed good cytotoxic activity with IC50 values of 1.0, 1.5, and 0.3 μM on MCF-7, CALU-3, and SCC-25 cell lines, respectively. KT32 (10c) showed potent HDAC inhibitory activity and partial Topo II α inhibitory activity in both enzyme assays. The SAR results strongly aligned with the predicted binding affinities from the molecular docking study. KT32 (10c) was further explored for a preliminary mechanistic understanding of SCC-25 cell lines. Flow cytometry analysis suggests that KT32 (10c) induces cell death through apoptosis, as evidenced by the substantial increase in the population of late apoptotic cells.