Toxicity of 5-methoxymethyl-2′-deoxyuridine in hamsters and evaluation of its mutagenicity by sister chromatid exchanges and hypoxanthine guanine phosphoribosyl transferase assays

Nucleosides, Nucleotides and Nucleic Acids

et al. 2012

Analogs of (E)-5-(2-bromovinyl)-2'-deoxycytidine (BrVdCyd) (1) by substitution at N(4) were synthesized to impart resistance against deamination. The anti-HSV-1 activity and solution conformation of these analogs were determined. N(4)-Acetyl-BrVdCyd (2) was a potent inhibitor of HSV-1 replication whereas N(4)-propanoyl-BrVdCyd (3) had good activity and N(4)-Butanoyl-BrVdCyd (4) had only low activity against HSV-1 replication. N(4)-Methyl-BrVdCyd (5) was devoid of activity against HSV-1.

Section: Antiviral Activitymentioning

confidence: 99%

Synthesis, Molecular Conformation and Activity Against Herpes Simplex Virus of (E)-5-(2-Bromovinyl)-2′-Deoxycytidine Analogs

Zoghaib

Mannala

Nucleosides, Nucleotides and Nucleic Acids

et al. 2012

“…The compounds 5-methoxymelthyl-2'-deoxyuridine (MMdUrd) and 5-methoxymethyl-2'-deoxycytidine (MMdCyd) are potent, selective antiherpesvirus agents with low cytotoxicity (Aduma et al, 1990;Ayisi et al, 1980Ayisi et al, ,1986Meldrum et al, 1980). Our hypothesis is that MMdCyd and MMdUrd would be anabolized by viral and cellular enzymes in HSV-infected cells to their triphosphate form, which is the 'active' form of the drugs responsible for antiviral activity.…”

Section: *Corresponding Authormentioning

confidence: 99%

Acute and Delayed Toxicity Studies on the Antiherpesvirus Agents 5-Methoxymethyl-2′-Deoxycytidine and 5-Methoxymethyl-2′-Deoxyuridine

Shi

Kukhanova

et al. 1997

Antivir Chem Chemother

Summary5-Methoxymethyl-2'-deoxycytidine (MMdCyd) and the corresponding deoxyuridine analogue, 5-methoxymethyl-2'-deoxyuridine (MMdUrd) are selective antiherpesvirus agents. MMdCyd (ED 50 1.5~lM) is a more potent inhibitor of herpes simplex virus replication than MMdUrd (ED 5o 30~lM) when maintained in the deoxycytidine form (deamination prevented). The 5'-triphosphates, MMdCTP and MMdUTP, were synthesized, and incorporation into DNA. by mitochondrial DNA polymerase y was investigated. MMdcTPand MMdUTP were incorporated into DNA in place of dCTP and dTTP, respectively. The effect of MMdCyd and MMdUrd on cell growth (acute toxicity) and proloriged exposure (delayed cytotoxicity) in CEM cells was investigated. The two analogues did not exhibit acute or delayed toxicity (2 weeks exposure) up to 1000~lM. In contrast, at a concentration as low as 0.125~lM of 2' )'-dideoxycytidine (ddC; control druq], the doubling time of the cells increased after 10 days. At higher concentrations, a very marked increase in doubling time was observed from 6 days onward with ddC treatment. The data suggest that in uninfected cells neitherMMdUrd nor MMdCyd are anabolized to the triphosphate Form in signiFicant amounts. As a result, little or no MMdCTP or MMdUTP builds up in the mitochondria and thus delayed toxicity is not observed.

Interaction of 5-Methoxymethyl-2′-Deoxyuridine Triphosphate with DNA Polymerases: Effects of the 5-Substituent and Comparison with the Deoxycytidine Derivative

Aduma

1992

Antivir Chem Chemother

Summary 5-Methoxymethyl-2'-deoxyuridine (MMdUrd) is a selective anti-herpes agent that is dependent upon initial phosphorylation by Herpes simplex virus-' induced deoxythymidine kinase. In order to determine its mechanism of action, MMdUrd was converted to the 5' -triphosphate (MMdUTP) and the nature of interaction of MMdUTP and dTTP with DNA polymerase of E. coli, HSV-1, and human a was investigated. The order of utilization of deoxyuridine analogues by bacterial and HSV-1 DNA polymerases for DNA synthesis was: dTTP > MMdUTP. In contrast, 5-methoxymethyl-2'-deoxycytidine-5'·triphosphate (MMdCTP) was a better substrate for HSV DNA polymerase compared to dCTP. MMdUTP is a competitive inhibitor of HSV-1 DNA polymerase with respect to dTTP incorporation (Kj = 2.9 x 10-6 M). The IC so values of MMdUTP for both HSV and human aDNA polymerases were 4.5 x 10-6 M . These data suggest that the selective activity of MMdUrd is due to its preferential phosphorylation by viral thymidine kinase and not at the DNA polymerase level. These results may also account for the difference in anti-HSV activity between MMdUrd and its deoxycytidine analogue.The first generation antivirals, such as iododeoxyuridine and triflurothymidine (Prusoff, 1979;King and Heidelberger, 1979), are useful drugs for treatment of herpes Received 2 December, 1991; revised 15 February, 1992 simplex virus (HSV) infections but lack selectivity. In contrast, more recently discovered 5-substituted deoxyuridine analogues, such as MMdUrd (Babiuk et et., 1975;Gupta, 1981), EtdUrd (Swierkowski and Shugar, 1969)and BrVdUrd (DeClercq et al., 1979)have a selective inhibitory effect on HSV replication. These compounds appear to owe their selectivity to preferential phosphorylation initially by viral-induced thymidine kinase (TK)* to the monophosphate, (Cheng et sl., 1981a(Cheng et sl., , 1981bLarder et al., 1983; Gupta et aI., 1987) followed by subsequent phosphorylation by cellular kinases to the triphosphate which is the active drug (Allaudeenet al., 1981(Allaudeenet al., ,1982Ruth and Cheng, 1981;Mancini et al., 1983;Otto and Prusoff, 1984;Reid et al., 1987). The lack of activity against HSV mutants (with a mutation in the TK gene) further lends credibility to the suggestion that viral TK is required for their activation.Deoxycytidine analogues are more selective inhibitors of HSV than their corresponding deoxyuridine derivatives (Doberson and Greer, 1978; De Clercq et aI., 1982). Our studies with BrVdCyd and MMdCyd (5-methoxymethyl-2'-deoxycytidine) in combination with deaminase inhibitors have shown that the selectivity of these compounds is most likely due to specific interaction with HSV TK and viral DNA polymerase (Aduma et al., 1990a(Aduma et al., , 1990b(Aduma et al., , 1991 Gupta et el., 1991).The substrate specificity towards viral-TK appears to be related to the chain length of the substituent at the C(5) position of the pyrimidine ring. This in turn seems to determine specificity and cytotoxicity of nucleoside analogues. For example, EtdUrd inhibits r...