title: NLP-1: a DNA intercalating hypoxic cell radiosensitizer and cytotoxin.
abstract: The 2-nitroimidazole linked phenanthridine, NLP-1 (5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide), was synthesized with the rationale of targeting the nitroimidazole to DNA via the phenanthridine ring. The drug is soluble in aqueous solution (greater than 25 mM) and stable at room temperature. It binds to DNA with a binding constant 1/30 that of ethidium bromide. At a concentration of 0.5 mM, NLP-1 is 8 times more toxic to hypoxic than aerobic cells at 37 degrees C. This concentration is 40 times less than the concentration of misonidazole, a non-intercalating 2-nitroimidazole, required for the same degree of hypoxic cell toxicity. The toxicity of NLP-1 is reduced at least 10-fold at 0 degrees C. Its ability to radiosensitize hypoxic cells is similar to misonidazole at 0 degrees C. Thus the putative targeting of the 2-nitroimidazole, NLP-1, to DNA, via its phenanthridine group, enhances its hypoxic toxicity, but not its radiosensitizing ability under the present test conditions. NLP-1 represents a lead compound for intercalating 2-nitroimidazoles with selective toxicity for hypoxic cells.
authors.affiliation: Department of Chemistry, University of Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Panicucci
authors.forename: R
authors.initials: R
authors.lastname: Heal
authors.forename: K
authors.initials: K
authors.lastname: Laderoute
authors.forename: D
authors.initials: D
authors.lastname: Cowan
authors.forename: R A
authors.initials: RA
authors.lastname: McClelland
authors.forename: A M
authors.initials: AM
authors.lastname: Rauth
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009593:Nitroimidazoles; D010100:Oxygen / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D007364:Intercalating Agents; D009593:Nitroimidazoles; D010617:Phenanthridines; D011838:Radiation-Sensitizing Agents; C059179:NLP 1; D010100:Oxygen