Synthesis, Structure, and In Vitro Biological Evaluation of Semi-Synthetic Derivatives of Betulin

Betulin and alpha-lipoic acid are naturally occurring substances with different biological properties. Combining two phytochemical units into a conjugate is a frequently used method to obtain new compounds with better pharmacokinetic parameters. This research concerned the preparation of lipoate derivatives of betulin using the Steglich method. Experimental lipophilicity values were determined for target compounds 6-10 by reversed-phase thin-layer chromatography. In silico methods were used to calculate the physicochemical parameters and lipophilicity of new derivatives and to determine the probable directions of biological activity. alpha-Lipoic acid, betulin, and lipoate derivatives 6-10 were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, HCT116, MiaPaca-2, and Hs294T cancer cells. 3-(5-(1,2-Dithiolan-3-yl)pentanoyl))betulin 10 showed moderate anticancer activity against MV4-11, PC-3, and HCT116, with IC50 values in the range of 39.8-76.7 mu M. The introduction of a dithiolate substituent at the C3 position in 28-acetylbetulin gave compound 9 the highest activity (IC50 = 37.9 mu M), in the ratio of biphenotypic B myelomonocytic leukemia cells (MV4-11). All lipoate derivatives were inactive towards normal cells.