title: Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents.
abstract: A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assays against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 cells under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cells and were also selectively toxic to HT-29 cells under hypoxic conditions (selectivity ratios 1.7 to >20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under aerobic conditions and thereby decreased hypoxic selectivity. In contrast, an electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the nitro group resulted in rapid expulsion of the cytotoxic phosphoramide mustard. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.
authors.affiliation: Department of Chemistry and Pharmacology and the Cancer Center, University of Rochester, New York 14642, USA. rickb@pharmacy.purdue.edu
authors.forename: R F
authors.initials: RF
authors.lastname: Borch
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: J P
authors.initials: JP
authors.lastname: Schmidt
authors.forename: J T
authors.initials: JT
authors.lastname: Marakovits
authors.forename: C
authors.initials: C
authors.lastname: Joswig
authors.forename: J J
authors.initials: JJ
authors.lastname: Gipp
authors.forename: R T
authors.initials: RT
authors.lastname: Mulcahy
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009943:Organophosphorus Compounds; D010100:Oxygen