Synthesis of pironetin and related analogs: studies on structure-activity relationships as tubulin assembly inhibitors.
Pironetin (1) and demethylpironetin (2) are potent inhibitors of tubulin assembly. They arrested the mammalian cell cycle in M-phase and showed antitumor activity against a murine tumor cell line, P388 leukemia, transplanted in mice. To investigate the chemical and biological properties of 1, we synthesized several derivatives and investigated the structure-activity relationships. All synthesized derivatives decreased biological activities, such as inhibition of cell cycle progression, and disruption of the microtubule network in situ. The most drastic decrease was observed in 6, 8 and 10. These results suggested that alpha,beta-unsaturated lactone, chirality at the 7-position bearing a hydroxyl group and the terminal portion of the alkyl chain are important for microtubule inhibitory activity of pironetins.
Watanabe
H
H
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan.
Watanabe
H
H
Usui
T
T
Kondoh
M
M
Osada
H
H
Kitahara
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002460:Cell Line; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D051379:Mice; D010937:Plant Growth Regulators / Q000138:chemical synthesis / Q000737:chemistry; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D010937:Plant Growth Regulators; D011753:Pyrones; C088446:pironetin