Abstract
Benzamide riboside (BR) is a novel anticancer agent exhibiting pronounced activity against several human tumor cell lines via the inhibition of inosine 5- monophosphate dehydrogenase (IMPDH) that catalyzes the formation of xanthine 5- monophosphate from inosine 5-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. Phosphorylation of BR to its 5- monophosphate derivative appears to be ubiquitous in most cells catalyzed by the enzymes, adenosine kinase, nicotinam ide nucleoside kinase and 5 nucleotidase. BR 5- monophosphate is then converted to the active metabolite benzamide adenine dinucleotide (BAD) by NMN adenylyltransferase, the rate-limiting enzyme in the biosynthesis of NAD. As BAD is more potent in the inhibition of IMPDH than BR and BR 5-monophosphate, cytotoxicity of BR is closely connected with intercellular metabolism to BAD. However, intracellular BAD level is also affected by BADase activity, a phosphodiesterase which hydrolyzes BAD to BR-5-monophosphate and AMP. A recent study demonstrates enzymatic deamination of BR to noncytotoxic benzene carboxylic acid (BR-COOH) as the main hepatic BR biotransformation product in rat liver. As the IMPDH inhibitors tiazofurin and ribavirin exhibit predominant accumulation and biotransformation in liver, hepatic metabolism may be an important factor also for BR activation and inactivation and should be considered in human liver during cancer therapy when BR is used as a single drug or in combination with other anticancer agents.
Keywords: imp dehydrogenase inhibitor benzamide riboside, benzamide riboside
Current Medicinal Chemistry
Title: Metabolism of the Novel IMP Dehydrogenase Inhibitor Benzamide Riboside
Volume: 9 Issue: 7
Author(s): Walter Jager, Alexandra Salamon and Thomas Szekeres
Affiliation:
Keywords: imp dehydrogenase inhibitor benzamide riboside, benzamide riboside
Abstract: Benzamide riboside (BR) is a novel anticancer agent exhibiting pronounced activity against several human tumor cell lines via the inhibition of inosine 5- monophosphate dehydrogenase (IMPDH) that catalyzes the formation of xanthine 5- monophosphate from inosine 5-monophosphate and nicotinamide adenine dinucleotide, thereby restricting the biosynthesis of guanylates. Phosphorylation of BR to its 5- monophosphate derivative appears to be ubiquitous in most cells catalyzed by the enzymes, adenosine kinase, nicotinam ide nucleoside kinase and 5 nucleotidase. BR 5- monophosphate is then converted to the active metabolite benzamide adenine dinucleotide (BAD) by NMN adenylyltransferase, the rate-limiting enzyme in the biosynthesis of NAD. As BAD is more potent in the inhibition of IMPDH than BR and BR 5-monophosphate, cytotoxicity of BR is closely connected with intercellular metabolism to BAD. However, intracellular BAD level is also affected by BADase activity, a phosphodiesterase which hydrolyzes BAD to BR-5-monophosphate and AMP. A recent study demonstrates enzymatic deamination of BR to noncytotoxic benzene carboxylic acid (BR-COOH) as the main hepatic BR biotransformation product in rat liver. As the IMPDH inhibitors tiazofurin and ribavirin exhibit predominant accumulation and biotransformation in liver, hepatic metabolism may be an important factor also for BR activation and inactivation and should be considered in human liver during cancer therapy when BR is used as a single drug or in combination with other anticancer agents.
Export Options
About this article
Cite this article as:
Jager Walter, Salamon Alexandra and Szekeres Thomas, Metabolism of the Novel IMP Dehydrogenase Inhibitor Benzamide Riboside, Current Medicinal Chemistry 2002; 9 (7) . https://dx.doi.org/10.2174/0929867024606830
DOI https://dx.doi.org/10.2174/0929867024606830 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
TRAIL Agonists on Clinical Trials for Cancer Therapy: The Promises and the Challenges
Reviews on Recent Clinical Trials Transport of Nucleoside Analogs Across the Plasma Membrane: A Clue to Understanding Drug-Induced Cytotoxicity
Current Drug Metabolism Mesenchymal Stem Cells in Veterinary Regenerative Therapy: Basic Physiology and Clinical Applications
Current Stem Cell Research & Therapy A Review on Noscapine, and its Impact on Heme Metabolism
Current Drug Metabolism Histone Deacetylase Inhibitors: An Attractive Strategy for Cancer Therapy
Current Medicinal Chemistry Sirtuin Modulators: Mechanisms and Potential Clinical Implications
Current Medicinal Chemistry Mesenchymal Stromal Cells; Role in Tissue Repair, Drug Discovery and Immune Modulation
Current Drug Delivery DNA Demethylation: Where Genetics Meets Epigenetics
Current Pharmaceutical Design Neurocysticercosis: The Enigmatic Disease
Central Nervous System Agents in Medicinal Chemistry Pharmacological Profile and Pharmacogenomics of Anti-Cancer Drugs Used for Targeted Therapy
Current Cancer Drug Targets Targeting Telomerase for Cancer Therapy
Current Cancer Therapy Reviews KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions
Current Genomics Cancer Therapy Based on a Mechanism of Action for Controlling the Immune System and the Resulting Patent Portfolio
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Experimental Animal Models of Myocardial Damage in Regenerative Medicine Studies Involving Adult Bone Marrow Derived Stem Cells: Ethical and Methodological Implications
Cardiovascular & Hematological Disorders-Drug Targets Applications of Induced Pluripotent Stem Cells in the Modeling of Human Inflammatory Bowel Diseases
Current Stem Cell Research & Therapy Evaluating Treatment Response of Chronic Myeloid Leukemia: Emerging Science and Technology
Current Cancer Drug Targets Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation
Current Cancer Drug Targets Synthesis, Docking and Anti-Tumor Activity of β-L-1,3-Thiazolidine Pyrimidine Nucleoside Analogues
Medicinal Chemistry Current Status and Perspectives in Ceramide-Targeting Molecular Medicine
Current Pharmaceutical Design Protein Kinase B/AKT and Focal Adhesion Kinase: Two Close Signaling Partners in Cancer
Anti-Cancer Agents in Medicinal Chemistry