Bioorganic & Medicinal Chemistry 1997-12-01

Antitumor agents--CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis.

Q Shi, P Verdier-Pinard, A Brossi, E Hamel, K H Lee

Index: Bioorg. Med. Chem. 5(12) , 2277-82, (1997)

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Abstract

(+)-Thiocolchicine (2b) was prepared from (+/-)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (-)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (-)-camphanylated diastereomer, had potent activity in all assays comparable to that of (-)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action.