Betulinic Acid-Nitrogen Heterocyclic Derivatives: Design, Synthesis, and Antitumor Evaluation in Vitro

Abstract

Betulinic acid (<b>BA</b>) is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 <b>BA</b>-nitrogen heterocyclic derivatives were synthetized, in addition to four intermediates, 23 of which were first reported. Moreover, they were screened for in-vitro cytotoxicity against four tumor cell lines (Hela, HepG-2, BGC-823 and SK-SY5Y) by a standard methylthiazol tetrazolium (MTT) assay. The majority of these derivatives showed much stronger cytotoxic activity than <b>BA</b>. Remarkably, the most potent compound <b>7e</b> (the half maximal inhibitory concentration (IC₅₀) of which was 2.05 ± 0.66 μM) was 12-fold more toxic in vitro than <b>BA</b>-treated Hela. Furthermore, multiple fluorescent staining techniques and flow cytometry collectively revealed that compound <b>7e</b> could induce the early apoptosis of Hela cells. Structure-activity relationships were also briefly discussed. The present study highlighted the importance of introducing nitrogen heterocyclic rings into betulinic acid in the discovery and development of novel antitumor agents.