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 2 ENANTIOMERIC FORMS ARE BIOLOGICALLY-ACTIVE - INTERACTION OF THE (+)-ENANTIOMERS AND (-)-ENANTIOMERS OF C-IDU AND C-BVDU WITH THE THYMIDINE KINASE OF HERPES-SIMPLEX VIRUS TYPE-1

  • 1 March 1990
    • journal article
    • research article
    • Vol. 37  (3) , 395-401
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-ID U 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 .mu.M for (+)-C-BVDU and (+)-C-IDU and 0.16 and 0.19 .mu.M for (-)-C-BVDU and (-)-C-BVDU, 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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