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.
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.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
Baumgartner
H
H
Bodenteich
M
M
Griengl
H
H
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003517:Cyclopentanes / Q000378:metabolism / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D018139:Simplexvirus / Q000201:enzymology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D003517:Cyclopentanes; C063455:carbocyclic 5-iodo-2'-deoxyuridine; C045200:1-(3-hydroxy-4-(hydroxymethyl)-cyclopentyl)-5-(2-bromovinyl)-2,4-(1H,3H)-pyrimidinedione; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; D003857:Deoxyuridine