Abstract |
The (+)- and (-)-enantiomers of the carbocyclic analogues of (E)-5-(2-bromovinyl)-2'-deoxyuridine ( C-BVDU) and 5-iodo-2'-deoxyuridine ( C-IDU) were synthesized by separate routes. Both the (+)- and (-)-enantiomers of C-BVDU and C-IDU were markedly inhibitory to herpes simplex virus type 1 (HSV-1) replication. (+)- C-BVDU and (+)- C-IDU were as inhibitory to HSV-1 as the racemic (+/-)- C-BVDU and (+/-)- C-IDU, respectively, whereas the (-)-enantiomers were only 10-fold less active. Also, the (+)- and (-)-enantiomers of C-BVDU were equally inhibitory to the growth of murine mammary carcinoma cells transformed by the HSV-1 or HSV-2 thymidine kinase (TK) gene (designated FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The (+)- and (-)-enantiomers of C-BVDU and the (+)- and (-)-enantiomers of C-IDU had a remarkably similar affinity for HSV-1 TK [Ki, 0.09 and 0.19 microM for (+)- C-BVDU and (+)- C-IDU and 0.16 and 0.19 microM for (-)- C-BVDU and (-)- C-IDU, respectively]. The inhibition of HSV-1 TK by BVDU, IDU, (+)- C-BVDU, and (+)- C-IDU was purely competitive with regard to the natural substrate ( thymidine), whereas (-)- C-BVDU, (-)- C-IDU, (+/-)- C-BVDU, and (+/-) C-IDU showed a linear mixed-type inhibition of HSV-1 TK. C-BVDU and C-IDU are examples of chiral molecules of which both isomeric forms are markedly active at both the cellular and enzymatic level.
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Authors | J Balzarini, E De Clercq, H Baumgartner, M Bodenteich, H Griengl |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 37
Issue 3
Pg. 395-401
(Mar 1990)
ISSN: 0026-895X [Print] United States |
PMID | 2156153
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antiviral Agents
- Cyclopentanes
- carbocyclic 5-iodo-2'-deoxyuridine
- 1-(3-hydroxy-4-(hydroxymethyl)-cyclopentyl)-5-(2-bromovinyl)-2,4-(1H,3H)-pyrimidinedione
- Thymidine Kinase
- Bromodeoxyuridine
- Deoxyuridine
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Topics |
- Animals
- Antiviral Agents
(metabolism, pharmacology)
- Bromodeoxyuridine
(analogs & derivatives, metabolism, pharmacology)
- Cell Division
(drug effects)
- Cyclopentanes
(metabolism, pharmacology)
- Deoxyuridine
(analogs & derivatives, metabolism, pharmacology)
- Kinetics
- Mice
- Phosphorylation
- Simplexvirus
(enzymology)
- Stereoisomerism
- Structure-Activity Relationship
- Thymidine Kinase
(antagonists & inhibitors)
- Tumor Cells, Cultured
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