37 新規機能性ホルボールエステルの設計・合成および生物活性評価(口頭発表の部)

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The phorbol esters, such as phorbol 12-myristate 13-acetate (PMA), are known to be powerful tumor promoters and activators of protein kinase C (PKC). First discovered by Nishizuka et al., PKC is a phospholipid- and calcium-dependent serine/threonine kinase, physiologically activated by 1,2-diacyl-sn-glycerol (DAG). PKC is also known to be an important target for other structurally diverse tumor promoters such as the ingenols, teleocidins, and aplysiatoxins. Structure-activity analyses of a variety of analogs of DAG and these tumor promoters have been carried out. Although many pharmacophore models have been proposed from molecular modeling, no information about the specific amino acid residues that interact with these ligands is available. Moreover it has been shown that the biological activity of 11-demethyl-13-deoxyphorbol esters, which were synthesized by our group, was not fully consistent with the pharmacophore models so far. Thus we are now interested in determing the importance of the 13-acetoxy group in phorbol ester-PKC complexes. This has led us to design a new photoaffinity probe 3, and to carry out previously unprecedented photoaffinity labeling of PKC. We have also designed a new phorbol ester-phosphatidylserine hybrid molecule 19. Because phosphatidylserins in phospho lipid membranes are known to have specific interactions with phorbol ester-PKC complexes, such a hybrid molecule can be expected to act as a specific inhibitor of PKC by preventing PKC from interacting with phospholipid membranes. The hybrid molecule was synthesized and preliminary biological activities were examined.
天然有機化合物討論会の論文
1996-09-02

37 新規機能性ホルボールエステルの設計・合成および生物活性評価(口頭発表の部)

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