Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. 2008

Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
Threshold Pharmaceuticals, 1300 Seaport Boulevard, Suite 500, Redwood City, California 94063, USA. jduan@thresholdpharm.com

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.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D010756 Phosphoric Acids Inorganic derivatives of phosphoric acid (H3PO4). Note that organic derivatives of phosphoric acids are listed under ORGANOPHOSPHATES. Pyrophosphoric Acids,Acids, Phosphoric,Acids, Pyrophosphoric
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000577 Amides Organic compounds containing the -CO-NH2 radical. Amides are derived from acids by replacement of -OH by -NH2 or from ammonia by the replacement of H by an acyl group. (From Grant & Hackh's Chemical Dictionary, 5th ed) Amide
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D012995 Solubility The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Solubilities
D013058 Mass Spectrometry An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers. Mass Spectroscopy,Spectrometry, Mass,Spectroscopy, Mass,Spectrum Analysis, Mass,Analysis, Mass Spectrum,Mass Spectrum Analysis,Analyses, Mass Spectrum,Mass Spectrum Analyses,Spectrum Analyses, Mass

Related Publications

Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
July 1996, Anti-cancer drug design,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
January 2001, Oncology reports,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
September 2004, Current medicinal chemistry. Anti-cancer agents,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
August 2017, European journal of medicinal chemistry,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
October 2017, Chimia,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
February 2017, European journal of medicinal chemistry,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
June 2020, Chemical communications (Cambridge, England),
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
August 2017, Bioorganic & medicinal chemistry letters,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
October 2004, Discovery medicine,
Jian-Xin Duan, and Hailong Jiao, and Jacob Kaizerman, and Timothy Stanton, and James W Evans, and Leslie Lan, and Gustavo Lorente, and Monica Banica, and Don Jung, and Jinwei Wang, and Huaiyu Ma, and Xiaoming Li, and Zhijian Yang, and Robert M Hoffman, and W Steve Ammons, and Charles P Hart, and Mark Matteucci
January 2023, Frontiers in pharmacology,
Copied contents to your clipboard!