First total synthesis of phenylpyridine analogues of the antimitotic rhazinilam.
The first synthesis of phenylpyridine analogues of rhazinilam and evaluation of these new structures as inhibitors of microtubule disassembly by interaction with tubulin are described. The synthesis is based on such key steps as picolinic metalation, hetero-ring cross-coupling and reduction of an acetyl group to an ethyl group. Elaboration of a quaternary picolinic carbon is one of the challenges of the synthesis. Biological evaluation of compounds bearing a quaternary picolinic carbon showed interactions with tubulin similar to (-)-rhazinilam but at a lower level.
Pasquinet
E
E
Institut de Recherche en Chimie Organique Fine, UMR 6014, Institut National des Sciences Appliquées, B.P. 08, 76131 Mont Saint Aignan Cedex, France.
Rocca
P
P
Richalot
S
S
Guéritte
F
F
Guénard
D
D
Godard
A
A
Marsais
F
F
Quéguiner
G
G
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007212:Indolizines; D020128:Inhibitory Concentration 50; D007769:Lactams; D008870:Microtubules / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D050257:Tubulin Modulators
D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D007769:Lactams; D011725:Pyridines; D050257:Tubulin Modulators; C009170:rhazinilam