Design, synthesis, and biological evaluation of cyclic and acyclic nitrobenzylphosphoramide mustards for E. coli nitroreductase activation

Yongying Jiang, Jiye Han, Chengzhi Yu, Simon O. Vass, Peter F. Searle, Patrick Browne, Richard J. Knox, Longqin Hu

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

In efforts to obtain anticancer prodrugs for antibody-directed or gene-directed enzyme prodrug therapy using E. coli nitroreductase, a series of nitrobenzylphosphoramide mustards were designed and synthesized incorporating a strategically placed nitro group in a position para to the benzylic carbon for reductive activation. All analogues were good substrates of E. coli nitroreductase with half-lives between 2.9 and 11.9 min at pH 7.0 and 37 °C. Isomers of the 4-nitrophenylcyclophosphamide analogues 3 and 5 with a benzylic oxygen para to the nitro group showed potent selective cytotoxicity in nitroreductase (NTR) expressing cells, while analogues 4 and 6 with a benzylic nitrogen para to the nitro group showed little selective cytotoxicity despite their good substrate activity. These results suggest that good substrate activity and the benzylic oxygen are both required for reductive activation of 4-nitrophenylcyclophosphamide analogues by E. coli nitroreductase. Isomers of analogue 3 showed 23000-29000x selective cytotoxicity toward NTR-expressing V79 cells with an IC5o as low as 27 nM. They are about as active as and 3-4x more selective than 5-aziridinyl-2,4-dinitrobenzamide (CB 1954). The acyclic 4-nitrobenzylphosphoramide mustard ((±)-7) was found to be the most active and most selective compound for activation by NTR with 170000x selective cytotoxicity toward NTR-expressing V79 cells and an IC50 of 0.4 nM. Compound (±)-7 also exhibited good bystander effect compared to 5-aziridinyl-2,4-dinitrobenzamide. The low IC50, high selectivity, and good bystander effects of nitrobenzylphosphoramide mustards in NTR-expressing cells suggest that they could be used in combination with E. coli nitroreductase in enzyme prodrug therapy.

Original languageEnglish (US)
Pages (from-to)4333-4343
Number of pages11
JournalJournal of medicinal chemistry
Volume49
Issue number14
DOIs
StatePublished - Jul 13 2006

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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