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.

A 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 as PowerPoint slide