|Budget Amount *help
¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1997 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1996 : ¥1,200,000 (Direct Cost : ¥1,200,000)
There are number of natural and synthetic compounds that interfere with microtubule function by binding to tubulim. Curacin A,isolated from a Caribbean cyanobacterium Lyngbya majuscula, was found to be a novel antimitotic agent. Asymmetric total synthesis of curacin A was performed in a highly stereo-controlled manner. The key steps were (1) an asymmetric allylation using a chiral allyltitanium reagent and a double-asymmetric Simmons-Smith cyclopropanation to introduce three chiral centers, (2) Wittig and Wittig-Horner reactions to construct the C(3-4) and C(7-10) alkenes, and (3) a direct conversion of the thiazolidine to thiazoline. The four stereoisomers of a partial structure at the thiazoline moiety were also synthesized to elucidate the absolute configurations of three chiral centers in curacin A.In addition, A series of side chain analogs of curacin A were synthesized and the effect to in vitro micritubule polymerization was examined. These side chain analogs showed weak or no anti-tubulin activity suggesting that the side chain of curacin A was restrictly recognized by microtubule proteins. Ustiloxin D,isolated as the minor component of ustiloxins from the water extract of false smut balls, exhibits potent anti-tubulin activity. The common structure found in these class of compounds is 13-membered core structure, which seems to be responsible substructure for anti-tubulin activity. Reductive removal of sulfoxide side chain of ustiloxin A gave ustiloxin D,an important intermediate for the symthesis of its analogs. Methylation of phenolic hydroxyl group or methylamino geoup resulted in disappearance of the antitubulin activity. The 13-membered cyclic peptides, novel analogs of phomopsin-ustiloxin class of antibiotics without glycine residue, were also synthesized.