111328-06-4

Upstream product

• 106232-36-4 4-Nitroso-5-phenylimidazole 
• 120626-18-8 C₉H₇Cl₂N₃ 
• 670-95-1 4-Phenylimidazole 
• 14953-62-9 4⁽⁵⁾-nitro-5⁽⁴⁾-phenylimidazole 
• 98-80-6 phenylboronic acid 

Downstream Products

• 120626-16-6 5-acetamino-4-phenylimidazole 

Relevant academic research and scientific papers

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

IMIDAZOTETRAZINE COMPOUNDS

New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

Formation of Cyanide Ion or Cyanogen Chloride through the Cleavage of Aromatic Rings by Nitrous Acid or Chlorine. X. Pathway of Cyanogen Chloride Formation in the Reactions of 1-Naphthol and 4-Phenylimidazole with Chloramine

The pathway in the formation of cyanogen chloride from the reaction of 1-naphthol (1) and 4-phenylimidazole with chloramine was investigated.The intermediates isolated in the reaction of 1-naphthol (1) with chloramine were N-chloro-1,2-naphthoquinone 2-imine (2) and o-carboxycinnamonitrile (6), the latter of which, liberating cyanogen chloride, was finally converted to phthalide-3-carboxylic acid (8).The products obtained in the reaction of 4-phenylimidazole (10) with chloramine were benzonitrile (14), benzoylformic acid (22) and benzoic acid (23) besides cyanogen chloride.Cyanogen chloride formed by the reaction of 4-methylimidazole with 15N>-chloramine was C14NCl.From these results the pathway of cyanogen chloride formation was elucidated.Keywords - cyanogen chloride; 1-naphthol; 4-phenylimidazole; histidine; chloramine; hypochlorous acid