5 発がんプロモーター・インドラクタムの活性コンフォメーション(口頭発表の部)

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Tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist as two stable conformers, the twist and the sofa form, in solution at room temperature (Fig. 2). To elucidate the common structural features among several TPA-type tumor promoters with different skeletons and quite similar biological activities (teleocidins, phorbol esters and aplysiatoxins), it is indispensable to know the active conformation of teleocidins. Synthesis of conformationally restricted analogues of 1 is one of the most promising approaches. We have synthesized novel twist-restricted analogues (6a and 7) via aza-Claisen rearrangement of (-)-N^<13>-desmethyl-N^<13>-allylindolactam-V (4) along with a sofa-restricted analogue, (-)-5-methylindolactam-V (2). The tumor-promoting activity of these compounds was examined by two in vitro bioassays closely related to in vivo tumor promotion: binding affinity to the protein kinase C (PKC) regulatory domain and the Epstein-Barr virus early antigen (EBV-EA) inducing ability. The binding affinity to the PKC regulatory domain was measured using peptide C (Fig. 5), a newly introduced and readily available peptide incorporating amino acids 101-151 of the second cysteine-rich repeat of rat brain PKC γ. Both 6a and 7, whose fixed conformation was the twist form, showed significant biological activities comparable to 1. By contrast, the sofa-restricted 2 did not show any biological activities related to tumor promotion. These results clearly showed that the active conformation of (-)-indolactam-V (1) is close to the twist form, not to the sofa form. Although a similar conclusion has been recently reported using newly designed benzolactams, indolactam analogues without the pyrrole moiety, this is the first time to demonstrate the active conformation using the intact indolactam skeleton. Bridge formation between position 5 and 13 of (-)-indolactam-V (1) is one of the most effective methods to fix the molecule to the active conformation and to develop new PKC activators with high isozyme selectivity.
天然有機化合物討論会の論文
1995-09-01

5 発がんプロモーター・インドラクタムの活性コンフォメーション(口頭発表の部)

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