Mechanism of action of 5-nitro-2'-deoxyuridine.

doi:10.1021/JM00352A033

Paper

Mechanism of action of 5-nitro-2'-deoxyuridine.

Published Oct 1, 1982 · W. Washtien, D. Santi

Journal of medicinal chemistry

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4

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0

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Abstract

Results are described that demonstrate that the mechanism of action of the potent cytotoxic agent 5-nitro-2'-deoxyuridine (NO2-dUrd) involves thymidine (dThd) kinase catalyzed formation of 5-nitro-2'-deoxyuridylate (NO2dUMP) and subsequent potent inhibition of thymidylate (dTMP) synthetase by this compound. The evidence for this is as follows: (a) cells lacking dThd kinase are not inhibited by high concentrations of NO2dUrd; (b) the drug has no effect on dThd or uridine (Urd) incorporation into nucleic acids but prevents incorporation of deoxyuridine (dUrd); (c) growth inhibition is reversed by dThd but not by dUrd; (d) NO2dUrd causes changes in deoxynucleoside triphosphate pool sizes which are characteristic of specific inhibition of dTMP synthetase; (e) cells treated with [3H]NO2dUrd possess macromolecular bound [3H]NO2dUMP, which has properties characteristic of the NO2dUMP-dTMP synthetase complex. Treatment of L1210 leukemic mice at 400 mg/kg daily for 6 days gave only a 33% increase in life span, probably because of its rapid degradation to the inactive nitrouracil.

In Vitro Study

Study Snapshot

The cytotoxic agent 5-nitro-2'-deoxyuridine (NO2-dUrd) acts by inhibiting thymidylate synthetase, causing cell death through thymidine kinase-catalyzed formation of NO2dUMP and its rapid degradation

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Mechanism of action of 5-nitro-2'-deoxyuridine.

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References

Citations

Synthesis of 1-(dihydroxypropyl)-5-substituted uracils

Novel 1-(dihydroxypropyl)-5-substituted uracils were synthesized under mild conditions, offering potential as new building blocks for oligonucleotide synthesis.

Synergistic Effect of 5-Nitro-2′-deoxyuridine with Ganciclovir Against Human Cytomegalovirus In Vitro

Combining 5-NO2-dU with ganciclovir effectively inhibits human cytomegalovirus-induced cell killing in vitro.

Thymidylate Synthetase Inhibitors: Experimental and Clinical Aspects

Thymidylate synthetase inhibitors, like FdUMP, play a crucial role in DNA synthesis and have shown antitumor activity, with recent studies exploring alternative cytotoxic events.