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
-
Inhibitors of Lactate Dehydrogenase Isoforms and their Therapeutic Potentials
Current Medicinal Chemistry Benzimidazole Derivatives as Kinase Inhibitors
Current Medicinal Chemistry Chemical Intuition in Drug Design and Discovery
Current Topics in Medicinal Chemistry Chitinases: Biomarkers for Human Diseases
Protein & Peptide Letters Targeted Cancer Therapy: The Next Generation of Cancer Treatment
Current Drug Discovery Technologies Structure-Function Relationships and Clinical Applications of L-Asparaginases
Current Medicinal Chemistry Future Approaches for Treating Hematologic Disease
Current Pharmaceutical Biotechnology Modulation of Mast Cell and Basophil Functions by Benzene Metabolites
Current Pharmaceutical Design Chromosomal Translocations as Biomarkers in Leukemia Diagnosis and Pharmacogenomics
Recent Patents on Biomarkers Haploidentical Stem Cell Transplantation in Childhood
Current Cancer Therapy Reviews Single Nucleotide Polymorphisms as the Efficient Prognostic Markers in Breast Cancer
Current Cancer Drug Targets The Iron Requirement of Breastfeeding Infants
Current Pediatric Reviews Role of EGFR Monoclonal Antibodies in the Management of Non–small Cell Lung Cancer
Current Cancer Drug Targets Allogeneic Hematopoietic Stem Cell Transplant for Severe Aplastic Anemia: Current State and Future Directions
Current Stem Cell Research & Therapy Quinone-Based Drugs: An Important Class of Molecules in Medicinal Chemistry
Medicinal Chemistry An Overview of Nanoformulated Nutraceuticals and their Therapeutic Approaches
Current Nutrition & Food Science Factors that Control the Circulation Time of Nanoparticles in Blood: Challenges, Solutions and Future Prospects
Current Pharmaceutical Design Targeting Bcl-2 in CLL
Current Medicinal Chemistry Immunotoxins in the Treatment of Hematologic Malignancies
Current Drug Targets VEGF Inhibitors and Prostate Cancer Therapy
Current Molecular Pharmacology