Abstract
The ribonucleoside analogues (E)-5-(2-bromovinyl)uridine (5-BV-Urd) and 3'-spiro-(4'-amino-1',2'-oxathiole-2',2'-dioxide)-5-methyluridine (3'-AOD-5-MeUrd) emerged as potent and selective competitive inhibitors of mitochondrial thymidine kinase (TK)-2 with respect to thymidine (K(i)/K(m) values of 9.0 and 1.2 respectively). Cytosolic TK-1 did not show measurable affinity for these compounds. [(32)P]Phosphate transfer studies from [gamma-(32)P]ATP to 5-BV-Urd and 3'-AOD-5-MeUrd revealed extremely poor substrate activity but potent inhibitory potential of the compounds. It was concluded that the ribonucleosides 5-BV-Urd and 3'-AOD-5-MeUrd represent two new lead compounds for potent and selective inhibitors of mitochondrial TK-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Binding, Competitive
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Kinetics
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Mitochondria / enzymology
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Phosphorylation / drug effects
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Substrate Specificity
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Thymidine Kinase / antagonists & inhibitors*
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Thymidine Kinase / metabolism
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Uridine / analogs & derivatives*
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Uridine / chemistry*
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Uridine / pharmacology*
Substances
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3'-spiro-(4'-amino-1',2'-oxathiole-2',2'-dioxide)-5-methyluridine
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Antineoplastic Agents
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Enzyme Inhibitors
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5-(2-bromovinyl)uridine
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Adenosine Triphosphate
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thymidine kinase 2
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Thymidine Kinase
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thymidine kinase 1
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Uridine