3 プロテインキナーゼC(PKC)の活性を制御する新規C1ドメインリガンドの創製(口頭発表の部)

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概要

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• Protein kinase C (PKC) is a family of enzymes which play important roles in intracellular signal transduction. We designed a series of novel PKC ligands having an isobenzofuranone template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol), a physiological PKC ligand, with the PKCδC1b ligand-binding domain. Since interaction of the hydrophobic alkyl chain of the isobenzofuranone derivatives with lipid membrane is expected to be critical for the PKC activation, we were interested in the synthesis of the isobenzofuranone derivatives having the hydrophobic alkyl chain at various positions of the benzene ring. All four regioisomers were synthesized, and their activities as PKC ligands were evaluated. The isobenzofuranone derivatives having a 7- or 6-alkyl group bound to PKCαC1b domain strongly, on the other hand, 5- or 4-substituted derivative showed lower affinity toward PKCαC1b domain. Effects of these synthetic ligands on the PKCα phosphorylation activity were also examined. While the 7- or 6-substituted derivative was found to be a strong activator of PKCα, 5-substituted derivative activated PKCα only weakly. Surprisingly, 4-substitued derivative showed no activation of PKCα even at high concentration at which significant binding to PKCα was observed. These results suggest that position of the hydrophobic chain is critical for the PKC activation. 7-Substituted isobenzofuranone derivatives which have straight alkyl chain or bulky alkyl group were also synthesized. The domain selectivity of synthetic ligands toward the C1a and C1b domain were evaluated using overlay plot method. The compound which have bulky alkyl group at the both acyl and phenolic substituent showed the strongest binding affinity toward the C1b domain. In contrast, the compounds which have straight alkyl chain at the acyl position might preferably bind toward C1a domain, because significant PKCα activation was observed at the low concentration at which binding toward the C1b domain was not observed. All of these compounds showed the synergistic effect with TPA. The compound which have acetyl group at acyl position showed moderate PKCα binding affinity. Surprisingly, at high concentration it showed inhibition of PKCα activity induced with 1μM TPA.

• 天然有機化合物討論会の論文
• 2005-09-15

著者

• 平井 剛

  理研

• 清水 忠

  理研

• 袖岡 幹子

  理化学研究所袖岡有機合成化学研究室

• 大窪 恵

  理研

• 渡邉 亨

  理研

• 生越 洋介

  東北大多元研

• 袖岡 幹子

  理研

• 袖岡 幹子

  理研:東北大多元研

• 大窪 恵

  理研:東北大多元研

• 渡邉 亨

  理研:東北大多元研

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