Synthesis and evaluation of 3‐halocyclophosphamides and analogous compounds as novel anticancer “pro‐prodrugs”

Gerald Zon, Susan Marie Ludeman, Günay Özkan, Srinivasan Chandrasegaran, Charles F. Hammer, Ruth Dickerson, Kazutaka Mizuta, William Egan

Research output: Contribution to journalArticlepeer-review

Abstract

3‐Fluoro‐, 3‐chloro‐, and 3‐bromocyclophosphamide were prepared from the reaction of trifluoromethylhypofluorite, sodium hypochlorite, and bromine with the anticancer drug cyclophosphamide. Treatment of cis‐ and trans‐4‐phenylcyclophosphamide and 5,6‐benzocyclophosphamide with sodium hypochlorite afforded cis‐ and trans‐3‐chloro‐4‐phenylcyclophosphamide and 3‐chloro‐5,6‐benzocyclophosphamide, respectively. 31P‐NMR spectroscopy was used to study the reactivity of these compounds: the fluoro derivative was reduced to cyclophosphamide on incubation with mouse liver slices, and the reactivity order for sulfhydryl‐induced reduction of the 3‐halocyclophosphamides was Br ≅ Cl ≫ F. Compared with the therapeutic efficacy of cyclophosphamide against L‐1210 and P‐388 cancers in mice, 3‐fluoro‐and 3‐chlorocyclophosphamide were less active, although the fluoro derivative was more efficacious than the 3‐chloro compound. The individual R and S enantiomers of 3‐chlorocyclophosphamide, prepared from (S)‐ and (R)‐cyclophosphamide, respectively, showed no significant difference in therapeutic activity in the P‐388 test system.

Original languageEnglish (US)
Pages (from-to)687-691
Number of pages5
JournalJournal of Pharmaceutical Sciences
Volume72
Issue number6
DOIs
StatePublished - Jun 1983
Externally publishedYes

Keywords

  • Antineoplastic agents—cyclophosphamide and N‐halogented derivatives, synthesis and NMR characterization, therapeutic efficacy in mouse cancers
  • Cyclophosphamide—synthesis of N‐halogenated derivatives, NMR spectroscopic characterization, therapeutic efficacy in mouse cancers
  • Synthesis—of N‐halogenated derivatives of cyclophosphamide, NMR spectroscopic characterizations, therapeutic efficacy in mouse cancers

ASJC Scopus subject areas

  • Pharmaceutical Science

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