title: Antitumor agents. 172. Synthesis and biological evaluation of novel deacetamidothiocolchicin-7-ols and ester analogs as antitubulin agents.
abstract: A series of novel 7-O-substituted deacetamidothiocolchicine derivatives has been synthesized and evaluated for their inhibitory activity against tubulin polymerization, the binding of [3H]-colchicine to tubulin, and the growth of human Burkitt lymphoma cells. Of these new derivatives, thiocolchicone (8), wherein an acetamido group in thiocolchicine is replaced by a carbonyl oxygen at C(7), was obtained from deacetythiocolchicine (6) by Schiffs base equilibration and acid hydrolysis. Reduction of thiocolchiocone with sodium borohydride yielded the racemic alcohol 9, the structure of which was verified by X-ray crystallographic analysis. Optically pure alcohols 9a,b were obtained by treatment of 9 with the optically pure reagent (1S)-(-)-camphanic chloride followed by chromatographic separation of the camphanate esters and hydrolysis of the diastereomers. X-ray crystallographic analysis established the aS,7S-configuration of 9a. Racemic and optically active esters 11-15, 11a,b, 12a, 14a, and 15a were obtained by esterification of the corresponding alcohols. The compounds showing activity equivalent to or greater than (-)-thiocolchicione (2a) in all the biological assays were three (-)-aS,7S optically pure enantiomers: the alcohol 9a, the acetate 11a (an oxygen isostere of thiocolchicine), and the isonicotinoate 15a. In addition, the ketone 8 and two (-)-aS,7S enantiomers (12a, 14a) had high activity in the biochemical assays with tubulin but reduced antiproliferative activity. In all cases, optically pure isomers with the (-)-aS,7S configuration exhibited greater biological activity than racemic mixtures or isomers or isomers with the (+)-aR,7R configuration.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Shi
authors.forename: P
authors.initials: P
authors.lastname: Verdier-Pinard
authors.forename: A
authors.initials: A
authors.lastname: Brossi
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: A T
authors.initials: AT
authors.lastname: McPhail
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D014404:Tubulin; D050257:Tubulin Modulators; C014856:thiocholchicine; D003078:Colchicine