[A stereoselective synthesis of tilivalline and its analogs utilizing a new Mannich type intramolecular cyclization].
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).
Aoyama
T
T
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Shioiri
T
T
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000494:pharmacology; D003500:Cyclization; D051379:Mice; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; C093067:tilivalline