title: Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs.
abstract: A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.
authors.affiliation: Threshold Pharmaceuticals, 1300 Seaport Boulevard, Suite 500, Redwood City, California 94063, USA. jduan@thresholdpharm.com
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: Hailong
authors.initials: H
authors.lastname: Jiao
authors.forename: Jacob
authors.initials: J
authors.lastname: Kaizerman
authors.forename: Timothy
authors.initials: T
authors.lastname: Stanton
authors.forename: James W
authors.initials: JW
authors.lastname: Evans
authors.forename: Leslie
authors.initials: L
authors.lastname: Lan
authors.forename: Gustavo
authors.initials: G
authors.lastname: Lorente
authors.forename: Monica
authors.initials: M
authors.lastname: Banica
authors.forename: Don
authors.initials: D
authors.lastname: Jung
authors.forename: Jinwei
authors.initials: J
authors.lastname: Wang
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Ma
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Yang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: W Steve
authors.initials: WS
authors.lastname: Ammons
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.forename: Mark
authors.initials: M
authors.lastname: Matteucci
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D010756:Phosphoric Acids / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D010756:Phosphoric Acids; C011067:phosphoramidic acid