Molecular Design, Synthesis and Docking Study of Alkyl and Benzyl Derivatives of Robustic Acid as Topoisomerase I Inhibitors

Abstract

Robustic acid is reported to be a bioactive compound, isolated from the medicinal plant Dalbergia benthamii Prain. Ten alkyl and benzyl derivatives (2a–2j) of robustic acid were designed and synthesized based on molecular docking approaches. The biological activities of most of the synthesized compounds (such as 2g, 2h, and 2i) were closely consistent with the docking results. In particular, 4‐O‐phenylpropyl substituted compound 2g displayed potent topoisomerase I inhibitory activity as well as cytotoxicity against SMMC‐7721, HepG2, and HeLa cell lines. Further biological testing suggests that compound 2g acted mainly by an arrest of the tumor cells in G1 phase of the cell cycle and suppressed cell proliferation by inducing apoptosis. The findings of this study are encouraging with respect to potential utilization of these compounds as new topoisomerase I inhibitors.

Antitumor Activity and Mechanism of Robustic Acid from Dalbergia benthami Prain via Computational Target Fishing

“…Supplementary Materials: The following are available online. Supplementary File: MS, 1 H-NMR and 13 C-NMR spectra of compounds of RA.…”

“…It has been reported that the Topo I inhibitor activity could be the basis of anti-tumor activity [ 16 , 17 ]. In the previous report, we chose the conformation with the highest score (7.89) for analysis [ 13 ], and the differences with this manuscript were the hydrophobic residue and bond length. Nevertheless, they all indicated that the hydrophobic interactions between the benzene ring of RA and hydrophobic residues of the Topo I-DNA complex were likely to be responsible for the stability of the docked complex, RA inhibiting the Topo I activity in an allosteric manner.…”

“…RA also possesses a significant antimalarial activity [ 12 ]. In our previous studies, RA displayed an obvious Topo I inhibition activity and cytotoxicity, which was probably mediated by an arrest of the tumor cells at the G1 phase and a suppressed cell proliferation via the induction of apoptosis [ 13 ]. Nevertheless, the anti-tumor mechanism of RA still remains unclear, so the biological activities of RA need further exploration.…”