113(P-62) 発がんプロモーター・インドラクタムVのコンホメーション固定によるプロテインキナーゼCアイソザイム選択的リガンドの分子設計(ポスター発表の部)

概要

論文の詳細を見る
Conventional and novel protein kinase C (PKC) isozymes are main targets of tumor promoters. These isozymes contain two C1 domains (C1A, C1B), both of which bind tumor promoters. Design of new ligands with high selectivity among the C1 domains of PKC isozymes is indispensable to elucidate the precise mechanism of tumor promotion. Indolactam-V (1) was selected as a lead compound for such ligands since 1 showed a binding preference for the C1B domains of novel PKC isozymes. Compound 1 exists as two stable conformers in solution at room temperature; the twist form with the cis amide and the sofa form with the trans amide. Highly improved selectivity for the C1B domains of novel PKC isozymes was observed in the sofa-restricted analogue (3), while the binding selectivity of the twist-restricted analogue (2) was similar to that of 1. This indicates that the conformation of 1 plays an important role on the binding selectivity for C1 domains of PKC isozymes. Based on this result, new conformationally-restricted analogues of 1, indolinelactam-Vs (4, 5), were synthesized. (3R)-Indolinelactam-V (4) adopted a conformation similar to the twist form of 1, while the conformation of (3S)-indolinelactam-V (5) was close to that of the sofa form. The binding selectivity of 4 and 5 for the C1B domains of novel PKCs was considerably higher than that of 1, and sofa-like 5 showed slightly higher binding selectivity than twist-like 4. These results suggest that conventional PKC isozymes (α, βI, βII, γ) strictly recognize the twist form of 1 and that the sofa-restricted analogues of 1 such as 3 and 5 would be lead compounds of new legands with high selectivity for the C1B domains of novel PKC isozymes.
天然有機化合物討論会の論文
2003-09-01

113(P-62) 発がんプロモーター・インドラクタムVのコンホメーション固定によるプロテインキナーゼCアイソザイム選択的リガンドの分子設計(ポスター発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク