Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide (NSC-227114) and related compounds.
作者:AKIRA TAKAMIZAWA、SAICHI MATSUMOTO、TSUYOSHI IWATA、ITSUO MAKINO
DOI:10.1248/cpb.25.1877
日期:——
4-Hydroperoxyisophosphamide and its analogues were simply synthesized by ozonolysis reactions of O-(3-butenyl)-N, N'-bis (2-chloroethyl) phosphorodiamidate and related O-(3-butenyl) phosphoramidates. An acid-catalyzed isomerization of 4-hydroperoxyisophosphamide proceeded with inversion of its phosphorus configuration giving 2-epi-4-hydroperoxyisophosphamide. Both isomers readily afforded C4-substituted isophosphamide derivatives by reactions with nucleophilic agents and acid. L1210 antileukemic activities were tested for the isomers and some analogues revealing that the C4-hydroperoxylation of isophosphamide resulted in a marked enhancement of its activity and that the inverted stereochemistry of an alkylating functionality at the phosphorus atom is also effective in promoting the antitumor action as an alternative activated species of isophosphamide.
4-羟基过氧化异磷酰胺及其类似物通过O-(3-丁烯基)-N,N'-双(2-氯乙基)磷酸二酰胺及相关O-(3-丁烯基)磷酰胺的臭氧化反应简单合成。4-羟基过氧化异磷酰胺在酸性催化下发生异构化,其磷构型反转生成2-表-4-羟基过氧化异磷酰胺。两种异构体均能通过与亲核试剂及酸反应生成C4取代的异磷酰胺衍生物。对这些异构体及其某些类似物进行了L1210抗白血病活性测试,结果显示,异磷酰胺的C4羟基过氧化改性显著增强了其活性,且磷原子上烷基化功能的立体构型反转同样有效促进了其抗肿瘤作用,作为异磷酰胺的替代激活形式。