Nguyen C H, Lhoste J M, Lavelle F, Bissery M C, Bisagni E
URA 1387 CNRS, U 219 INSERM, Institut Curie, Orsay, France.
J Med Chem. 1990 May;33(5):1519-28. doi: 10.1021/jm00167a037.
The thermal Fischer indolization of hydrazones resulting from 4-hydrazino-5-methyl-1H-pyridin-2-one and various beta- and alpha-tetralones led to 4-methyl-6,7-dihydro-2H,5H-pyrido[4,3- b]benzo[e]indol-1-ones and 4-methyl-11-dihydro-2H,5H-pyrido[4,3- b]benzo[g]indol-1-ones, respectively. After aromatization, these compounds were transformed by phosphorus oxychloride, giving 1-chloro-4-methyl-5H-pyrido[4,3- b]benzo[e]- and -benzo[g]indoles which were substituted by [(dialkylamino)alkyl]amines. The resulting 1-[[(dialkylamino)alkyl]amino]-4-methyl-5H-pyrido- [4,3-b]benzo[e]- and -benzo[g]indoles, as well as hydroxy derivatives obtained by demethylation of methoxylated compounds with hydrobromic acid, were tested for antitumor activity in vitro (leukemic and solid tumor cells) and in vivo on various experimental tumor models using the standard NCI protocols. 1-[[3-(Dialkylamino)propyl]-amino]-4-methyl-9-hydroxy-5H-pyrido[4,3- b]benzo[e]indoles appeared as a promising new class of antineoplastic agents.
由4-肼基-5-甲基-1H-吡啶-2-酮与各种β-和α-四氢萘酮生成的腙的热费歇尔吲哚合成反应分别得到4-甲基-6,7-二氢-2H,5H-吡啶并[4,3-b]苯并[e]吲哚-1-酮和4-甲基-11-二氢-2H,5H-吡啶并[4,3-b]苯并[g]吲哚-1-酮。芳构化后，这些化合物用三氯氧磷转化，得到1-氯-4-甲基-5H-吡啶并[4,3-b]苯并[e]-和-苯并[g]吲哚，它们被[(二烷基氨基)烷基]胺取代。所得的1-[[(二烷基氨基)烷基]氨基]-4-甲基-5H-吡啶并[4,3-b]苯并[e]-和-苯并[g]吲哚，以及用氢溴酸将甲氧基化化合物脱甲基得到的羟基衍生物，按照标准的美国国立癌症研究所方案在体外（白血病和实体瘤细胞）和体内各种实验性肿瘤模型上测试其抗肿瘤活性。1-[[3-(二烷基氨基)丙基]氨基]-4-甲基-9-羟基-5H-吡啶并[4,3-b]苯并[e]吲哚似乎是一类有前景的新型抗肿瘤药物。
