New adenosine kinase inhibitors with oral antiinflammatory activity: synthesis and biological evaluation
Autor: | H. Shih, Dennis A. Carson, Raychaudhuri A, Howard B. Cottam, Di Pasquale G, D B Wasson |
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Rok vydání: | 1993 |
Předmět: |
Pyrimidine
Stereochemistry Pyridines Drug Evaluation Preclinical Administration Oral Adenosine kinase Carrageenan Tubercidin Rats Sprague-Dawley chemistry.chemical_compound Drug Discovery medicine Animals Humans Lymphocytes Adenosine kinase activity Adenosine Kinase Pleurisy Cells Cultured chemistry.chemical_classification biology Anti-Inflammatory Agents Non-Steroidal Biological activity Riboside Adenosine Rats Kinetics Enzyme chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Pyrazoles medicine.drug |
Zdroj: | Journal of medicinal chemistry. 36(22) |
ISSN: | 0022-2623 |
Popis: | Several 5-iodotubercidin analogues in the pyrazolo[3,4-d]pyrimidine ring system were synthesized as potential inhibitors of adenosine kinase by a direct Lewis acid-catalyzed glycosylation procedure using both the preformed carbohydrate and the heterocyclic base as starting materials. The 5'-hydroxyl, -chloro, -azido, -deoxy, -amino, and -fluoro derivatives were prepared and evaluated in three systems for biological activity relative to adenosine, the true substrate, and 5-iodotubercidin, a known inhibitor. First, each compound was studied kinetically for inhibition of purified human placental adenosine kinase activity. The order of potency was: iodotubercidin > hydroxyl > amino > or = deoxy > fluoro > chloro >> azido. The Ki values for the 5'-hydroxyl and 5'-amino compounds, the two most potent inhibitors, were 80 and 150 nM, respectively. The inhibition appeared to be essentially competitive in nature, although a noncompetitive component of significance for the more potent inhibitors cannot be ruled out. Second, a bioassay was conducted in which the toxicity of 6-methylmercaptopurine riboside toward human CEM lymphoblasts was reversed by varying concentrations of the compounds. The order of effectiveness of the compounds in this system, representing a functional inhibition of adenosine kinase in cultured cells, was about the same as that with the purified enzyme, except that the 5'-chloro and 5'-fluoro compounds were ineffective. Third, the 5'-hydroxyl derivative was evaluated in vivo in a rat pleurisy inflammation model and displayed biological activity at a dose of 30 mg/kg given orally. Finally, the in vitro toxicity of each compound was assessed in CEM lymphoblasts. Results indicated that the two most potent inhibitors in the pyrazolo[3,4-d]pyrimidine ring system, the 5'-hydroxyl (7) and the 5'-amino (20), were 15-fold and 75-fold, respectively, less growth inhibitory than 5-iodotubercidin. |
Databáze: | OpenAIRE |
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