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.

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

“…Not only taxanes, but a number of chemotherapeutic agents also induce neuropathy, including cisplatin, oxaliplatin, ifosfamide, vinca alkaloids, etoposide. 40 Given the fact that the cytotoxic effector of TH-302 is structurally very similar to that of ifosfamide, 18 we tested whether TH-302 might cause neuropathy as a monotherapy or add more neurotoxicity when combined with gemcitabine and nab-paclitaxel. We used immunocompetent CD-1 mice to conduct mechanical hyperalgesia tests by the von Frey Assay as a preclinical model of peripheral neuropathy.…”

“…17 TH-302 (1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N 0 -bis(2-bromoethyl)phosphorodiamidate) is a hypoxia-activated prodrug composed of 2-nitroimidazole linked to a brominated analog of isophosphoramide mustard (Br-IPM). 18 The 2-nitroimidazole moiety of TH-302 is a substrate for intracellular 1-electron reductases and, when TH-302 is reduced under hypoxic conditions, Br-IPM is released. TH-302 exhibits hypoxia-selective in vitro cytotoxicity cross a wide variety of human cancer cell lines 19 and in vivo anti-tumor efficacy in a panel of human tumor xenograft models.…”

Dual Targeting of Hypoxia and Homologous Recombination Repair Dysfunction in Triple-Negative Breast Cancer

“…There was no obvious relationship between BRCA1 mutational status and cytotoxic potency or hypoxia selectivity. Sensitivity to the active metabolites of PR-104A (i.e., PR-104H) and SN30548 (i.e., SN30550) again showed no clear relationship with BRCA1 genotype, as was also the case for HN2, which we used as a model for the aliphatic mustard active metabolite from TH-302, bromo-isophosphoramide mustard (41). Cisplatin showed a similar cell line dependence to HN2 (r ¼ 0.83; P ¼ 0.01).…”

Synthesis and Cytotoxicity Evaluation of Naphthalimide Derived N-Mustards

“…As the earliest agents used for chemotherapy, DNA alkylating nitrogen mustards have been widely utilized in oncology treatment, and many such agents are still in clinical use ( Figure 1) [1][2][3][4][5]. However, progress in developing new N-mustard agents is limited due to its drawbacks [6].…”