Aoyama T, Shioiri T
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Yakugaku Zasshi. 1995 Jun;115(6):446-59. doi: 10.1248/yakushi1947.115.6_446.
Tilivalline (1a), a metabolite isolated from Klebsiella pneumoniae var. oxytoca, belongs to a group of pyrrolo[2,1-c][1,4]benzodiazepines, a characteristic skeleton of anthramycin-type antitumor antibiotics. We have accomplished a completely stereoselective, efficient and convenient synthesis of 1a utilizing a new Mannich type intramolecular cyclization as a key step. Further, a computational chemical analysis clarified the effect of zinc chloride on the high stereoselectivity in the tilivalline synthesis. To aim both the extension of the scope of the new Mannich type intramolecular cyclization and the studies on the structure-biological activity relationship, we further extended the method to the synthesis of tilivalline derivatives and 2-(3'-indolyl)-1,4-benzodiazepines (50). Investigation on the cytotoxicity of 1a and its analogs has revealed that 1a shows the strong cytotoxicity toward mouse leukemia L 1210 cells and the replacement of the indole function of 1a with cyano one increases the cytotoxicity of 1a about 100 times (IC50 = 0.05 microgram/ml).
替利瓦林（1a）是从产酸克雷伯菌中分离出的一种代谢产物，属于吡咯并[2,1-c][1,4]苯并二氮杂卓类，是氨茴霉素型抗肿瘤抗生素的特征骨架。我们利用一种新的曼尼希型分子内环化反应作为关键步骤，完成了1a的完全立体选择性、高效且便捷的合成。此外，计算化学分析阐明了氯化锌在替利瓦林合成中对高立体选择性的影响。为了拓展新的曼尼希型分子内环化反应的适用范围以及研究结构-生物活性关系，我们进一步将该方法扩展至替利瓦林衍生物和2-(3'-吲哚基)-1,4-苯并二氮杂卓（50）的合成。对1a及其类似物的细胞毒性研究表明，1a对小鼠白血病L 1210细胞显示出强细胞毒性，并且将1a的吲哚官能团用氰基取代后，1a的细胞毒性增加约100倍（IC50 = 0.05微克/毫升）。
