The synthesis and some properties of some 5-substituted pyrimidine 4'-thio-2'-deoxynucleosides and oligodeoxynucleotides containing 4'-thiothymidine.
A series of 5-substituted pyrimidine 4'-thio-2'-deoxynucleosides has been synthesized and their antiviral properties determined. It seems likely that once an analogue is a kinase substrate, then that analogue is toxic for that organism. Thus 4'-thiothymidine is phosphorylated by both viral and host kinases and shows toxicity to viruses and the host. Unlike its oxygen-containing counterpart (5-vinyl-2'-deoxyuridine, which is extremely toxic in vitro and causes chromosome damage), 5-vinyl-4'-thio-2'-deoxyuridine is not toxic and shows a similar antiviral activity spectrum to 5-cyclopropyl- and 5-isopropyl-4'-thio-2'-deoxyuridines which also show no toxicity. Although a good leaving group at the 5'-position of a 4'-thionucleoside appears to be easily displaced (possibly involving intramolecular episulphide formation), when incorporated into an oligodeoxynucleotide, 4'-thiothymidine appears not to cause any gross distortion of the helix as shown by CD or Tm measurements and the phosphodiester backbone is stable to hydrolysis. Thus it is not yet clear whether the toxicity of 4'-thiothymidine is due to its presence in DNA or to the perturbation of the metabolic processes involved in its incorporation.
Basnak
I
I
School of Chemistry, University of Birmingham, UK.
Hancox
E L
EL
Connolly
B A
BA
Walker
R T
RT
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry; D001483:Base Sequence; D003587:Cytomegalovirus / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects; D013379:Substrate Specificity; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry
D000998:Antiviral Agents; D009838:Oligodeoxyribonucleotides; D013872:Thionucleosides; C070456:4'-thiothymidine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine