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 accessible from (-)-(M,7S)-colchicine via photooxygenation and subsequent endoperoxide-transformation, were synthesized and evaluated for their inhibitory effects on tubulin assembly in vitro. The amino-allocolchicinoid (9), a key compound 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 rearrangement. Surprisingly both do not notably affect tubulin assembly, despite obvious structural similarities with active analogues of the thiocolchicine- and azasteganacin-series.