Synthesis and Promising Cytotoxic Activity of Betulonic Acid Modified Derivatives

In this paper, a series of betulonic acid N-methylpiperazinyl amide derivatives, especially holding C2-nicotinoylidene/furfurylidene/fluorobenzylidene fragments, have been synthesized and evaluated for their cytotoxic activity against the NCI-60 cancer cell line panel. N-Methylpiperazinyl amide of betulinic acid 11 (GI(50)=0.49 mu M for leukemia CCRF-CEM cell line), 2-(4-pyridinoylidene)-betulinic 9 and betulonic 14 acids (GI(50)=1.60 and 1.36 mu M for colon cancer HCT-116 cell line, respectively), as well as 2-(furfurylidene)-betulonic acid 16 (GI(50)=1.66 mu M for melanoma LOX IMVI cell line) were found to be the lead compounds. The activity displayed for these compounds was higher than for the standard drug doxorubicin against colon cancer HCT-15 and ovarian cancer NCI/ADR-RES cell lines. Cell cycle analysis indicates that compound 11 promotes cytotoxic activity through the apoptosis induction both in conditionally normal (HEK293) and in cancer (A549, MCF-7) cells, whereas compound 14 exhibits both cytostatic and cytotoxic activity, dependently on cell line evaluated. In particular, in HEK293 cells the compound 14 induces mainly apoptotic cell death, while in A549 and MCF-7 cells cytostatic effect is dependent on cell cycle arrest in the G(2)/M phase. Compounds 11 and 14 are promising molecules for future antitumor drug development.