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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

J Balzarini, E De Clercq, H Baumgartner, M Bodenteich and H Griengl

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

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.

Volume 37, Issue 3, pp. 395-401, 03/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




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L. L. Bennett Jr., P. W. Allan, G. Arnett, Y. F. Shealy, D. S. Shewach, W. S. Mason, I. Fourel, and W. B. Parker
Metabolism in Human Cells of the D and L Enantiomers of the Carbocyclic Analog of 2'-Deoxyguanosine: Substrate Activity with Deoxycytidine Kinase, Mitochondrial Deoxyguanosine Kinase, and 5'-Nucleotidase
Antimicrob. Agents Chemother., May 1, 1998; 42(5): 1045 - 1051.
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