ANTITUMOR AGENTS - 185 - SYNTHESIS AND BIOLOGICAL EVALUATION OF TRIDEMETHYLTHIOCOLCHICINE ANALOGS AS NOVEL TOPOISOMERASE-II INHIBITORS

Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomeras es in vitro. Exhaustive demethylation of thiocolchicine analogues comp letely changes their biological profiles. Instead of displaying antitu bulin activity, most target compounds inhibited topoisomerase II activ ity. Only compounds with a larger side chain, such as 15a, 23a, and 24 a, did not interfere with topoisomerase II enzymatic functions. The cy totoxicity of target compounds was reduced by 3 orders of magnitude co mpared to that of colchicine in most cell lines, The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxici ty. To test this hypothesis, 27-30 were prepared from 16a by protectin g all hydroxy groups with esters with an aim to facilitate drug transp ortation. In vitro cytotoxicity assays indicated that 27 was more pote nt than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect aga inst KB cells (IC50 = 2.7 mu g/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.