918633-87-1

Usage

Uses

Used in Oncology:
TH-302 is used as a hypoxia-activated prodrug for the treatment of various types of cancer, including non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, prostate cancer, and pancreatic cancer. It exhibits hypoxia-selective cytotoxicity and DNA damage in human cancer cells, leading to reduced survival and tumor growth inhibition.
Used in Cancer Research:
TH-302 is used as a research tool to study the effects of hypoxia on cancer cell growth and the mechanisms of hypoxia-activated prodrugs in cancer therapy. It helps researchers understand the role of hypoxia in cancer progression and develop new strategies for cancer treatment.

Upstream product

• 39070-13-8 ethyl 1-N-methyl-2-nitro-1H-imidazole-5-carboxylate 
• 40361-77-1 2-amino-1-methyl-1H-imidazole-5-carboxylic acid methyl ester 
• 2576-47-8 2-bromoethylamine hydrobromide 
• 39070-14-9 1-methyl-2-nitro-5-hydroxymethylimidazole 
• 141025-16-3 N,N'-bis(2-bromoethyl)phosphorodiamidic acid 

Relevant academic research and scientific papers

Preparation method of evofosfamide

The invention relates to a synthetic method for preparing evofosfamide, namely N,N'-bis(2-bromoethyl)diaminophosphonic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester (I), and belongs to the field of organic synthesis. The synthetic method has the advantages of safe and stable route, convenient operation, easy purification, high yield and the like.

Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions. Radiolabeling of 2-NIPAM with 125I was accomplished through a Cu(I)-mediated azide-alkyne cycloaddition reaction. The 125I-conjugate demonstrated 13.6 and 17.8% lower efflux rates for DU145 and PC-3 cells, correspondingly, under hypoxic conditions, suggesting that the increased retention is likely due to the known intracellular trapping mechanism. In conclusion, these studies demonstrate the potential of 2-NIPAM in serving as a trapping agent for radiopharmaceutical development.

TH-302 SOLID FORMS AND METHODS RELATED THERETO

The present invention provides a new method for making TH-302 and solid forms thereof. The compound in its solid form is an effective anti-cancer agent and may be used in various pharmaceutical compositions, and are particularly effective for the treatment of cancer. The invention also provides a method for preparing such compounds and forms and for treating cancer in a mammal comprising the step of administering a therapeutically effective amount of a solid form of TH-302 thereof.

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 us a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.

PHOSPHORAMIDATE ALKYLATOR PRODRUGS

Phosphoramidate alkylator prodrugs can be used to treat cancer when administered alone or in combination with one or more anti-neoplastic agents.