Effect of modification of betulinic acid at the C3-carbon atom of homolupane triterpenoids on the antiproliferative activity in vitro

In search of new cytotoxic derivatives based on the lupane scaffold, methyl betulonate and methyl 20,29-dihydrobetulonate were conjugated with Reformatsky reagents to provide homolupanes extended at the C3-carbon atom. Further transformations of the functional groups afforded a series of derivatives with 2-hydroxyethyl and allyl alcohol moieties. Their varying antiproliferative activity in vitro was then investigated in four cancer cell lines and in normal human BJ fibroblasts. In cervical carcinoma HeLa cells, derivatives 5, 6 and 17 were the most promising with lower micromolar IC50s and no toxicity to fibroblasts, thus showing a high therapeutic index. In addition, induction of apoptosis was found in HeLa cells after 24 h treatment with compounds 5, 6, 13 and 29. This newly synthesized series is more interesting than the published lupane and homolupane triterpenes and saponins, due to their nontoxicity towards healthy human cells and stronger cytotoxicity to various cancer cell lines. This approach increases their potential as anticancer agents. [Display omitted] •Homolupanes extended at the C3-carbon atom were prepared by Reformatsky reaction.•A series of lupanes containing allyl alcohol and 2-hydroxyethyl groups was obtained.•Compounds 5, 6 and 17 showed a high therapeutic index and no toxicity to fibroblast.•Induction of apoptosis in HeLa cells with derivatives 5, 6, 13 and 29.•Nontoxicity towards healthy human cells and greater cytotoxicity in cancer cells.