title: Antitumor agents. 185. Synthesis and biological evaluation of tridemethylthiocolchicine analogues as novel topoisomerase II inhibitors.
abstract: 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 topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared 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 cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 microg/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.
authors.affiliation: Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: J
authors.initials: J
authors.lastname: Guan
authors.forename: X K
authors.initials: XK
authors.lastname: Zhu
authors.forename: Y
authors.initials: Y
authors.lastname: Tachibana
authors.forename: K F
authors.initials: KF
authors.lastname: Bastow
authors.forename: A
authors.initials: A
authors.lastname: Brossi
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D059005:Topoisomerase II Inhibitors; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: C112431:1,2,3-O-acetyl-1,2,3-demethyl-N-(4'-nitrobenzoyl)deacetylthiocolchicine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; C112430:tridemethyl-N-(4'-nitrobenzoyl)deacetylthiocolchicine; D004247:DNA; D003078:Colchicine