P-68 海洋産抗腫瘍性マクロライドbryostatin 10のコンホメーション解析と生物活性(ポスター発表の部)

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Conformational analysis of the antineoplastic macrolide bryostatin 10 (1) was conducted by the spectroscopic and computational chemical methods. A combination of homonuclear two-dimensional NMR techniques at 600MHz (DQF-COSY and HOHAHA) have enabled us to performed complete assignment of the ^1H signals of bryostatin 10 (1) in CDCl_3. The solution form in CDCl_3 was elucidated by a phase senstive ROESY spectrum, temperature effect on OH proton and ^3J vicinal coupling constants. Distances deduced from ROE measurements were used for the refinements by the restrained molecular dynamics calculations using MM2^* force field (Macromodel 4.5). The dominant solution conformation of bryostatin 10 analyzed by high field NMR and MD calculations was homologous to that observed in the solid state of bryostatin 2. Biological activities of bryostatin 10 (1) and its derivatives (26-acetate 2,26-propionate 3,26-butyrate 4 and Δ^<19(20)>-olefin 5) as followed (A) cytotoxicity against P388 lumphocytic leukemia, (B) inhibition of cell division for fertilized sea urchin egg, (C) inhibition of fertilization for sea urchin egg and (D) effect on the movement of sea urchin sperm, were examined and the results were summarized in Table 1. It is interest that activities of Δ^<19(20)>-olefin derivative (5) were more stronger than those of bryostatin 10 (1) and also activities of 26-esters (2, 3 and 4) were decreased remarkablely. Interest strong effect of bryostatin 10 (1) for cell-to-cell infection in the HIV Molt-4 cells at concentration of 0.01〜3μg/ml was observed, as shown in Fig. 4, besides more mild exhibition of bryostatin 10 (1) against the HIV MT-4 cells than that of AZT was observed. Moreover, we have attempted an examination of the effect of bryostatin 10 (1) on steroidogenesis in the primary cultured bovine adrenocortical cells. Bryostatin 10 (1) increased about 1.8 times of ACTH-induced steroidogenesis. The macrolide itself induced steroidogenesis. The steroidogenic potency of the macrolide was not affected by extracellular Ca^<2+> concentration. Also, from the recent experimental result using phorbol 12-myristate 13-acetate (PMA), bryostatin 10-induced steroidogenesis was suggested to be caused by protein kinase C (PKC) activation similarly to PMA.
天然有機化合物討論会の論文
1995-09-01

P-68 海洋産抗腫瘍性マクロライドbryostatin 10のコンホメーション解析と生物活性(ポスター発表の部)

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