Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors.

Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.

Design, synthesis, and biological evaluation of ß-carboline 1,3,4-oxadiazole based hybrids as HDAC inhibitors with potential antitumor effects.

A series of novel ß-carboline 1,3,4-oxadiazole based hybrids were designed, synthesized, and tested for cytotoxicity and HDAC inhibition. Among the target compounds, compound ZDLT-1 displayed high inhibitory activity for class I HDACs 1, 2, and 3, and potent anti-proliferative activity against HCT116 cells with an IC50 value of 0.173 ± 0.018 µM, it also exhibited better inhibitory activity with an IC50 value of 6 nM for HDAC6 than SAHA (IC50 = 15 nM). Furthermore, the pharmacological experiment of Hoechst staining, colony formation, cell apoptosis assay, and wound healing scratch assay indicated that compound ZDLT-1 was a potent cytotoxic agent against HCT116 cells with cell apoptosis induction. Further, in silico prediction of physicochemical properties, drug-likeness, and ADME parameters suggested that compound ZDLT-1 is a promising anticancer agent. Taken together, the high potency cytotoxicity and class I HDACs inhibitory activity of compound ZDLT-1, which with the ß-carboline 1,3,4-oxadiazole based hybrids as potent anticancer agents could be nominated for further modification and optimization.