title: Synthesis and structure-activity relationships of nitrobenzyl phosphoramide mustards as nitroreductase-activated prodrugs.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. longhu@rutgers.edu
authors.forename: Longqin
authors.initials: L
authors.lastname: Hu
authors.forename: Xinghua
authors.initials: X
authors.lastname: Wu
authors.forename: Jiye
authors.initials: J
authors.lastname: Han
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Simon O
authors.initials: SO
authors.lastname: Vass
authors.forename: Patrick
authors.initials: P
authors.lastname: Browne
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Hall
authors.forename: Christopher
authors.initials: C
authors.lastname: Bot
authors.forename: Vithurshaa
authors.initials: V
authors.lastname: Gobalakrishnapillai
authors.forename: Peter F
authors.initials: PF
authors.lastname: Searle
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Knox
authors.forename: Shane R
authors.initials: SR
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009601:Nitroreductases / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D009588:Nitrogen Mustard Compounds; D009943:Organophosphorus Compounds; D011355:Prodrugs; D009601:Nitroreductases