Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives.

A series of 27 cinchona alkaloid derivatives (1f-w, 2a-e and 3a-d) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF-7, A-549, Hep-G2, U-87 and HL-60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds (1u, 1w, 2e and 3d) were identified with promising cytotoxic activity with 50% growth inhibition (GI50 ) values below 10 μM. Two (2e and 3d) of the four compounds also exhibited potent anti-trypanosomal activity with GI50 values of 0.3-0.4 μM. All four active compounds represented derivatives modified at their C-9 hydroxy group. With respect to anti-proliferative activity and selectivity, 2e (epi-N-quinidyl-N'-bis(3,5-trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u, 1w, 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti-cancer and anti-trypanosome drug candidates.