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.
Brecht
R
R
Pharmazeutisch-Chemisches Institut der Philipps-Universität, Marburg, Germany.
Seitz
G
G
Guénard
D
D
Thoret
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D003078:Colchicine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D007769:Lactams; D014404:Tubulin; D050257:Tubulin Modulators; C014856:thiocholchicine; C032782:allocolchicine; D003078:Colchicine