Antitumor Agents. 185.† Synthesis and Biological Evaluation of Tridemethylthiocolchicine Analogues as Novel Topoisomerase II Inhibitors

摘要: Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes biological profiles. Instead displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only with a larger side chain, such as 15a, 23a, 24a, did not interfere enzymatic functions. The cytotoxicity was reduced by 3 orders magnitude compared to that colchicine lines. hydrophilicity phenolic might prevent drug passage through the plasma membrane and, thus, be responsible relatively weak cytotoxicity. To test this hypothesis, 27−30 were prepared from 16a protecting all hydroxy groups esters an aim facilitate transportation. In vitro assays i...