Carbocyclic 5-iodo-2'-deoxyuridine (C-IDU) and carbocyclic (E)-5-(2-bromovinyl)-2'-deoxyuridine (C-BVDU) as unique examples of chiral molecules where the two enantiomeric forms are biologically active: interaction of the (+)- and (-)-enantiomers of C-IDU and C-BVDU with the thymidine kinase of herpes simplex virus type 1.

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.

• 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)

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

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