2. Academic Validation
  3. Nitroaryl phosphoramides as novel prodrugs for E. coli nitroreductase activation in enzyme prodrug therapy

Nitroaryl phosphoramides as novel prodrugs for E. coli nitroreductase activation in enzyme prodrug therapy

  • J Med Chem. 2003 Nov 6;46(23):4818-21. doi: 10.1021/jm034133h.
Longqin Hu 1,  Chengzhi Yu,  Yongying Jiang,  Jiye Han,  Zhuorong Li,  Patrick Browne,  Paul R Race,  Richard J Knox,  Peter F Searle,  Eva I Hyde
Affiliations

Affiliation

  • 1 Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, USA.
PMID: 14584930 DOI: 10.1021/jm034133h
Abstract

Cyclic and acyclic nitroaryl phosphoramide mustard analogues were activated by E. coli nitroreductase, an Enzyme explored in GDEPT. The more active acyclic 4-nitrobenzyl phosphoramide mustard (7) showed 167 500x selective cytotoxicity toward nitroreductase-expressing V79 cells with an IC(50) as low as 0.4 nM. This is about 100x more active and 27x more selective than CB1954 (1). The superior activity was attributed to its better substrate activity (k(cat)/K(m) 19x better than 1) and/or excellent cytotoxicity of phosphoramide mustard released.

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