Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid

A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their invitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2b) methyl 2-bromobetulonate (3b), 2-bromooleanonic acid (5b), and 2-thiocyanooleanonic acid (5c) were best, with IC50 values less than 10m against CCRF-CEM cells (e.g., 3b: IC50=2.9m) as well as 2-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5f, IC50=9.7m) and 2-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5k, IC50=11.4m). Compound 5c leads to the accumulation of cells in the G(2) phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1xIC(50). The G(2)/M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycinD. Compound 5c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3b) and methyl 2-thiocyanometulonate (3c) were found to inhibit nucleic acid synthesis only at 5xIC(50). We assume that in 3b and 3c (unlike in 5c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1xIC(50) or lower concentration.