Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs.
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.
Duan
Jian-Xin
JX
Threshold Pharmaceuticals, 1300 Seaport Boulevard, Suite 500, Redwood City, California 94063, USA. jduan@thresholdpharm.com
Jiao
Hailong
H
Kaizerman
Jacob
J
Stanton
Timothy
T
Evans
James W
JW
Lan
Leslie
L
Lorente
Gustavo
G
Banica
Monica
M
Jung
Don
D
Wang
Jinwei
J
Ma
Huaiyu
H
Li
Xiaoming
X
Yang
Zhijian
Z
Hoffman
Robert M
RM
Ammons
W Steve
WS
Hart
Charles P
CP
Matteucci
Mark
M
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
D000577:Amides; D000970:Antineoplastic Agents; D010756:Phosphoric Acids; C011067:phosphoramidic acid