Oxime and dithiolane derivatives of 5-formyl-2'-deoxyuridine and their 5'-phosphates: antiviral effects and thymidylate synthetase inhibition.
5-Formyl-2'-deoxyuridine (2a), an effective inhibitor of herpes simplex virus type 1 or 2 (HSV-1, HSV-2) and vaccinia virus, was converted to the oxime (3a) and dithiolane (4a) derivatives. The oxime (3a) was equally as potent as the formyl compound against HSV-1, but one-fifth as active against HSV-2, 100 times less effective against vaccinia, and 25 times less toxic for the host cells. In addition, compound 3a was about 10 times less active than 2a in inhibiting thymidylate synthetase in vivo (as reflected by a differential inhibition of dThd and dUrd incorporation into host cell DNA). The dithiolane (4a) did not exert an appreciable effect on either virus multiplication or dThd or dUrd incorporation, nor was it cytotoxic. All these compounds as their 5'-phosphate derivatives were potent in vitro inhibitors of thymidylate synthetase (Lactobacillus casei). The inhibition was competitive with substrate with Ki/Km ratios of 0.05 for the formyl 2b, 0.5 for the oxime 3b, and 0.2 for the dithiolane 4b. Thus, 3b was 10 times less active than 2b as an in vitro inhibitor of thymidylate synthetase, which appears to corroborate the in vivo findings.
D000998:Antiviral Agents / Q000138:chemical synthesis*; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007780:Lacticaseibacillus casei / Q000201:enzymology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014616:Vaccinia virus / Q000187:drug effects
D000998:Antiviral Agents; D003856:Deoxyuracil Nucleotides; D004247:DNA; D008780:Methyltransferases; D013940:Thymidylate Synthase; D003857:Deoxyuridine