Novel securinine derivatives as topoisomerase I based antitumor agents

•Novel securinine derivatives bearing β′-hydroxy-α,β-unsaturated ketones were synthesized.•Two compounds with significant Topo I inhibitory activity and potent anti-proliferative activity were identified.•The interference in the interaction of Topo I with DNA is identified as their action mechanism.

DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing β′-hydroxy-α,β-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I.

Graphical abstractA series of novel securinine derivatives bearing β′-hydroxy-α, β-unsaturated ketone moiety were synthesized and their Topo I inhibitory and antitumor activities were evaluated. Among them, 4a-1 and 4a-6 exhibited significant Topo I inhibitory activity and potent anti-proliferative activity. Their Topo I inhibitory mechanism was identified as interference in the interaction of Topo I with DNA.Figure optionsDownload full-size imageDownload as PowerPoint slide