Structure-activity relationships of (E)-5-(2-bromovinyl)uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses.
A series of (E)-5-(2-bromovinyl)uracil analogues and related nucleosides was synthesized, and their antiviral activities were evaluated. (E)-5-(2-Bromovinyl)-2'-deoxy-L-uridine (L-BVDU, 2), 1-(beta-L-arabinofuranosyl)-(E)-5-(2-bromovinyl)uracil (L-BVAU, 4), (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-ribofuranosyl)uracil (L-FBVRU, 8) and (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)urac il (L-FBVAU, 10) were synthesized via appropriate 5-iodouracil analogues from L-arabinose. D- and L-Oxathiolane and -dioxolane derivatives 13, 16, 20, 21, and 29-34 were prepared by glycosylation reaction of the oxathiolane and dioxolane intermediates with silylated uracil analogues using TMSI as the coupling agent. The synthesized compounds were evaluated in cell cultures infected with the following viruses: varicella zoster virus (VZV), Epstein Barr virus (EBV), and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Among the tested compounds, beta-L-CV-OddU (29), beta-L-BV-OddU (31), and beta-L-IV-OddU (33) exhibited potent in vitro antiviral activity against VZV with EC(50) values of 0.15, 0. 07, and 0.035 microM, respectively, and against EBV with EC(50) values of 0.49, 0.59, and 3.91 microM, respectively.
Choi
Y
Y
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens 30602-2352, USA.
Li
L
L
Grill
S
S
Gullen
E
E
Lee
C S
CS
Gumina
G
G
Tsujii
E
E
Cheng
Y C
YC
Chu
C K
CK
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C411152:1-(2-(hydroxymethyl)-1,3-dioxolan-5-yl)-5-(2-iodovinyl)uracil; C411151:5-(2-bromovinyl)-1-(2-(hydroxymethyl)-1,3-dioxolan-5-yl)uracil; C411150:5-(2-chlorovinyl)-1-(2-(hydroxymethyl)-1,3-dioxolan-5-yl)uracil; D000998:Antiviral Agents; D004148:Dioxolanes; D011741:Pyrimidine Nucleosides; D014753:Vinyl Compounds; D014498:Uracil