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.