10 キチナーゼ阻害剤Argifinの固相全合成と分子設計、in situクリックケミストリーを駆使した新規キチナーゼ阻害剤の創製(口頭発表の部)

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Chitin, the second most abundant polysaccharide in nature, is a constituent of fungal cell walls, the exoskeletons of crustaceans and insects, and the microfilarial sheaths of parasitic nematodes. Accumulation of chitin by organisms is modulated by chitin synthase-mediated biosynthesis and by chitinases-mediated hydrolytic degradation. Consequently, chitinases have been expected to be specific target for antifungal, insecticidal and antiparasitic agents. Argifin (1) represents a family of peptide products, of natural microorganic origin, isolated from the cultured broth of a fungal strain, Gliocladium sp. FTD-0668, by our research group and characterized as a novel chitinase inhibitor, with strong inhibitory activity against Serratia marcescens chitinases (SmChi). Recently, X-ray crystallographic analysis of chitinases-argifin complexes has revealed that there are strong hydrogen-bond interactions between the N^ω-methylcarbamoyl-L-arginine moiety and the motif of the hydrolytic pocket of bacterial chitinases, resulting in nanomolar to micromolar range inhibition. We report the efficient solid phase total synthesis of arigifin, the molecular design of novel chitinase inhibitors derived from its structure, and application of in situ click chemistry, using an azide-bearing simplified analogue, to identify more potent chitinase inhibitors.
天然有機化合物討論会の論文
2008-09-01