26 発癌プロモーター、ホルボール関連物質のコンピューター支援デザインと合成研究(ポスター発表の部)

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Protein kinase C (PKC), a serine and threonine phosphorylating enzyme, plays crucial roles in signal transduction. The enzyme is usually physiologically activated by diacylglycerol but it is also activated by structurally diverse tumor promoters like phorbol myristate acetate (PMA), ingenols, teleocidins, and bryostatins. The tumor promoting activities of these compounds were found incidentally so that the structures would not be necessarily the best ones to bind with PKC. Although, the precise structural requirements for the biological activities exhibited by these compounds have not been established, we have thought that computer assisted design of an advanced analog of PMA which is structurally simpler and has more potent activity can be possible. Taking synthetic route into consideration, compound 1 and 4 were selected as candidates for this purpose based on computer graphics by comparison with the stable conformer of PMA and a lot of its computationaly designed analogs. It is now clear that PKC is a family of more than ten subspecies with distinct structures and individual enzymological properties. So, the designed analogs 1 and 4 may specifically activate certain PKC subspecies and they may become useful tools for biochemical studies. Starting from the optically active (+)-3-carene, common synthetic intermediate 11 for 1 and 4 was synthesized highly stereoselectively using intramolecular nitrile oxide cycloaddition of 17 as a key step. Instead of the acyloxy group at C-12 position, PhMe_2Si group was introduced to 12 as a hydroxy group equivalent to avoid β-elimination. In order to confirm the effectivity of seven membered B-ring annulation to synthesis of 1, compound 10 was used as a model for the further transformation. After 10 being converted into the nitro derivative 21, 21 was treated with p-ClC_6H_4NCO and Et_3N to give desired 23 as a sole product in good yield. Although attempt to construct the A-ring moiety via McMurry coupling of 30 resulted in giving 4-epi derivative 31, nucleophilic addition of cerium trimethylsilylacetilide to 34 utilizing neighboring-group assistance gave a desired adduct 36 in 76% yield. Analogously, skeletal synthetic study of 4 is in progress via the functionalized derivative 43 as an intermediate.
天然有機化合物討論会の論文
1991-09-07

26 発癌プロモーター、ホルボール関連物質のコンピューター支援デザインと合成研究(ポスター発表の部)

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