Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Bioorg Med Chem Lett. 2011 Jul 1;21(13):3986-91. doi: 10.1016/j.bmcl.2011.05.009. Epub 2011 May 7.
A series of nitrobenzyl phosphoramide mustards and their analogs was designed and synthesized to explore their structure-activity relationships as substrates of nitroreductases from Escherichia coli and trypanosomes and as potential antiproliferative and antiparasitic agents. The position of the nitro group on the phenyl ring was important with the 4-nitrobenzyl phosphoramide mustard (1) offering the best combination of enzyme activity and antiproliferative effect against both mammalian and trypanosomatid cells. A preference was observed for halogen substitutions ortho to benzyl phosphoramide mustard but distinct differences were found in their SAR of substituted 4-nitrobenzyl phosphoramide mustards in E. coli nitroreductase-expressing cells and in trypanosomatids expressing endogenous nitroreductases.
设计并合成了一系列硝基苄基磷酰胺芥及其类似物，以研究它们作为大肠杆菌和原生动物硝基还原酶的底物的结构-活性关系，以及作为潜在的抗增殖和抗寄生虫药物。苯环上硝基的位置很重要，4-硝基苄基磷酰胺芥（1）在对哺乳动物和原生动物细胞的酶活性和抗增殖作用方面提供了最佳的组合。人们观察到对苄基磷酰胺芥的邻位卤素取代有偏好，但在大肠杆菌硝基还原酶表达细胞和表达内源性硝基还原酶的原生动物中，取代的 4-硝基苄基磷酰胺芥的 SAR 存在明显差异。
