Design, synthesis and antitumor activity of pentacyclic triterpenoid Asiatic acid derivatives as Sp1 inhibitors

Abstract

Asiatic acid (AA) was used as the lead compound and 22 inhibitors of specificity protein 1 (Sp1) were designed and synthesized with modification at A ring and C-28 position of AA, whose structures were confirmed by HRMS, ¹H NMR and ¹³C NMR. The growth inhibitory effects of Asiatic acid derivatives on human breast cancer cells (MCF-7) and cervical cancer cells (Hela) were determined by tetramethyl azole salt (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) colorimetric assay. The results showed that all of these compounds inhibited the proliferation of HeLa and MCF-7 cells, and all the derivatives showed stronger tumor cytotoxicity than AA, among which compounds I₈, II₆, and III₃ were comparable to the positive control drug cisplatin. Western blot (WB) and Cellular thermal shift assay (CETSA) assay analyses revealed that compound I₈ could directly bind to Sp1 and dose-dependently reduce Sp1 protein levels, suggesting that compound I₈ may exert its antitumor effects through binding to Sp1. This provides an experimental basis for the natural pentacyclic triterpenoid Asiatic acid to become a novel anti-tumor new drug candidate.