Design, synthesis, and biological evaluation of betulinic acid derivatives as new antitumor agents

Abstract

Chronic myeloid leukemia (CML) is a cancer that is currently treated with imatinib, however, resistance to this drug usually develops over time. Triterpenes such as betulinic acid can be analogues of triptolide, a compound recently shown to be active against CML cells resistant to imatinib. The aim of this study was to perform modifications on betulinic acid based on the structure-activity relationship of triptolide to generate new analogues, and evaluate their cytotoxicity. The main modification performed was fluorination on C-28. A total of 5 analogues were synthesized, being 3 previously described and 2 novel compounds. The MTT assay was performed using HeLa, B16F10 and HaCaT cell lines. The results show that the presence of fluorine in the molecule has an important role in increasing the antitumor activity. However, fluorination also enhanced the cytotoxicity on non-tumor cells, being betulinic acid less toxic than its tested derivatives. Considering B16F10 cells, compound 3 was the most active and selective, with IC50 of 1.9 μM, being considered a promising agent for the treatment of melanoma. Further studies are needed to investigate the antitumor activity in CML cells, since the mechanism of death and activity may be different for different cell lines.