20 固相合成法を利用したオーリライドおよび環状デプシペプチドライブラリーの合成(口頭発表の部)

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Aurilide (1), 26-membered cyclic depsipeptide, was isolated from the Japanese sea hare Dolabella auricularia by Yamada and co-workers in 1996. This compound has very strong cytotoxicity against HeLa S_3 cells with an IC_<50> of 0.017μg/mL. To elucidate the mechanism of this cytotoxicity with conformation analysis, we started a library synthesis of aurilide derivatives. Herein we wish to report an approach to synthesize aurilide (1) and their derivatives using solid-support. The peptide moiety of aurilide, 3 was synthesized by Fmoc method using diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) on trityl linked solid-support. Optimization of elongation conditions of the tetrapeptide part including N-methyl amino acids was carried out all at once utilizing Mulipin methods followed by LC/MS analyses. The aliphatic moiety 4 was prepared in solution phase by the esterification of hydroxy acid, unsaturated carboxylic acid, and N-methylalanine. The coupling reaction of the solid-supported 3 and diester 4 was carried out by DIC-HOBt method. After deprotection of Fmoc group and cleavage of seco acid 11 from solid-support, macrocyclization was achieved under high dilution conditions using EDCI and HOAt as coupling reagents. Deprotection of a methylthiomethyl group provided aurilide (1) in 11% overall yield. In the synthesis of a combinatorial library, further optimization of coupling reaction of peptide moiety including N-methyl amino acids was performed. It was found that PyBroP was the best reagent for coupling of sterically hindered amino acids. Synthesis of a combinatorial library of 25 aurilide derivatives 2 was accomplished with a similar protocol using TranSort^<TM> technique. Progress toward the elucidation of the mechanism of cytotoxicity with conformation analysis is underway in our laboratory.
天然有機化合物討論会の論文
2002-09-01

20 固相合成法を利用したオーリライドおよび環状デプシペプチドライブラリーの合成(口頭発表の部)

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