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

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.