Novel allocolchicinoids with an eight membered B-ring: Design, synthesis and inhibition of tubulin assembly

Several B-ring variations of O-methyl androbiphenyline (8), newly accessibl e from (-)-(M,7S)-colchicine via photooxygenation and subsequent endoperoxi de-transformation, were synthesized and evaluated for their inhibitory effe cts on tubulin assembly in vitro. The amino-allocolchicinoid (9), a key com pound in this study, was transformed to the highly potent ketone 10 and by oxidation with H2O2/Na2WO4 to a mixture of syn/anti-oximes, like 11 and 12. These could easily be transformed to hitherto unknown allocolchicinoids 13 and 14 with an eight membered B-ring lactam obtained via a Beckmann rearra ngement. Surprisingly both do not notably affect tubulin assembly, despite obvious structural similarities with active analogues of the thiocolchicine - and azasteganacin-series. (C) 2000 Elsevier Science Ltd. All rights reser ved.