Nitrobenzocyclophosphamides as potential prodrugs for bioreductive activation: Synthesis, stability, enzymatic reduction, and antiproliferative activity in cell culture

Zhuorong Li, Jiye Han, Yongying Jiang, Patrick Browne, Richard J. Knox, Longqin Hu

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

In efforts to obtain potential anticancer prodrugs for gene-directed enzyme prodrug therapy using Eschericia coli nitroreductase, a series of four benzocyclophosphamide analogues were designed and synthesized incorporating a strategically placed nitro group in a position para to the benzylic carbon for reductive activation. All four analogues were found to be stable in phosphate buffer at pH 7.4 and 37 °C and were good substrates of E. coli nitroreductase with half lives between 7 and 24 min at pH 7.0 and 37 °C. However, only two analogues 6a and 6c, both with a benzylic oxygen in the phosphorinane ring para to the nitro group, showed a modest 33-36-fold enhanced cytotoxicity in E. coli nitroreductase-expressing cells. These results suggest that good substrate activity and the para benzylic oxygen are required for activation by E. coli nitroreductase. Compounds 6a and 6c represent a new structure type for reductive activation and a lead for further modification in the development of better analogues with improved selective toxicity to be used in gene-directed enzyme prodrug therapy.

Original languageEnglish (US)
Pages (from-to)4171-4178
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number19
DOIs
StatePublished - Sep 15 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Nitrobenzocyclophosphamides as potential prodrugs for bioreductive activation: Synthesis, stability, enzymatic reduction, and antiproliferative activity in cell culture'. Together they form a unique fingerprint.

Cite this