Studies on the Mechanism of Action of Benzamide Riboside: A Novel Inhibitor of IMP Dehydrogenase
Our studies have characterized the metabolites of BR, especially its NAD analogue, BAD, by synthesizing this active metabolite by enzymatic means, and identifying its structure by NMR and mass spectrometry. We have partially purified IMPDH from tumor cells and have examined the kinetics of inhibition of IMPDH by BAD. We have also compared biochemical and cytotoxic activities of BR with tiazofurin and selenazofurin, that share similar mechanisms of action with BR. Our studies demonstrated that 2-3-fold more BAD is formed compared to TAD and SAD, the active metabolites of tiazofurin and selenazofurin, respectively. BR has demonstrated potent cytotoxic activity in a diverse group of human tumor cells, specifically more active in sarcomas and CNS neoplasms compared to tiazofurin or selenazofurin. Future in vivo animal studies should set a stage for determining its effectiveness in clinical Phase I studies.
Keywords: benzamide adenine dinucleotide; benzamide riboside; cytotoxic activity; deoxyribonucleoside triphosphates; imp dehydrogenase; inhibitor; phosphodiesterase; tiazole-4-carboxamide adenine dinucleotide
Document Type: Review Article
Publication date: 01 April 2002
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