Cytotoxicity of a new IMP dehydrogenase inhibitor, benzamide riboside, to human myelogenous leukemia K562 cells

COMPARE computer program suggested that benzamide riboside, BR, 3-(1-deoxy-β-D-ribofuranosyl)benzamide, should have a similar mechanism of action as that of tiazofurin, an inhibitor of IMP dehydrogenase (IMPDH). This hypothesis was tested in K562 cells in culture. BR was cytotoxic to K562 cells with...

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Bibliographic Details
Published inBiochemical and biophysical research communications Vol. 186; no. 3; pp. 1600 - 1606
Main Authors Jayaram, Hiremagalur N., Gharehbaghi, Kamran, Jayaram, Nagesh H., Rieser, Jason, Krohn, Karsten, Paull, Kenneth D.
Format Journal Article
LanguageEnglish
Published San Diego, CA Elsevier Inc 14.08.1992
Elsevier
Subjects
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line
Cell Survival - drug effects
Dose-Response Relationship, Drug
General aspects
Humans
IMP Dehydrogenase - antagonists & inhibitors
Kinetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Medical sciences
Molecular Structure
Nucleosides - pharmacology
Pharmacology. Drug treatments
Ribavirin - analogs & derivatives
Ribavirin - pharmacology
Ribonucleotides - metabolism
PBS
IC 50
TCA
TAD
HPLC
TOA
Human
Cell line
Enzyme
IMP dehydrogenase
Computerized processing
Enzyme inhibitor
Cytotoxicity
Hemopathy
Acute lymphocytic leukemia
Computer aid
Tumor cell
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Summary:COMPARE computer program suggested that benzamide riboside, BR, 3-(1-deoxy-β-D-ribofuranosyl)benzamide, should have a similar mechanism of action as that of tiazofurin, an inhibitor of IMP dehydrogenase (IMPDH). This hypothesis was tested in K562 cells in culture. BR was cytotoxic to K562 cells with an IC 50 of 2 μM. Incubation of K562 cells with BR resulted in a significant decrease in GMP and GTP levels with a concurrent increase in IMP pools, and with a significant inhibition of IMPDH activity. However, 290-fold higher BR concentration was needed to demonstrate in vitro inhibition of IMPDH activity, suggesting that the agent may require metabolism to exert its action. These results provide evidence that BR is a new inhibitor of IMPDH. This investigation should be helpful to design new analogues having activity against IMPDH.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(05)81591-8