Inhibition of herpes simplex virus DNA replication by ara-tubercidin

Turk, Steven R.; Cook, P.D.; Reinke, C.Michael; Drach, John C.

doi:10.1016/0166-3542(87)90080-5

Cited by 1 publication

(1 citation statement)

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“…The most logical loci of inhibition are DNA polymerase and ribonucleotide reductase. Indeed, the 5 -triphosphate of the arabinosyl analog of tubercidin is an inhibitor of cellular and HSV-encoded DNA polymerases (Turk et al, 1987a) as well as HCMV-encoded DNA polymerase (our unpublished data). Furthermore, the need to keep compound 102 in contact with cells for it to express antiviral (Yang et al, 1990) and cytostatic activity (Nassiri et a1.,1990) plus the fact that these activities are reversed by drug removal, suggest the following: incorporation into DNA and blockage of chain elongation are not likely mechanisms of DNA synthesis inhibition or incorporated molecules are readily removed from DNA by repair mechanisms.…”

Section: Discussionmentioning

confidence: 81%

Activity of acyclic halogenated tubercidin analogs against human cytomegalovirus and in uninfected cells

et al. 1991

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Novel acyclic halogenated tubercidins (4-amino-5-halo-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidines) were examined for their ability to inhibit human cytomegalovirus (HCMV) in yield reduction assays. 5-Bromo acyclic tubercidin (compound 102) was a more potent inhibitor of virus replication than the chloro- and iodo-substituted analogs (compounds 100 and 104). At a 100 microM concentration, the bromo and chloro compounds were more potent than acyclovir but not ganciclovir. Virus titers were reduced more than 99% by compounds 102 and 104 whereas compound 100 and the equally potent acyclovir reduced titers by only 90%. Quantitation of viral DNA by DNA hybridization demonstrated strong inhibition of HCMV DNA synthesis by these compounds. The most potent inhibitor, compound 102, had a 50% inhibitory (I50) concentration (1.6 microM) comparable to that of ganciclovir (1.8 microM). Cytotoxicity in uninfected human cells was evaluated and revealed the following: cell growth rates slowed markedly in the presence of 10 microM compound 102 whereas the same concentration of compounds 100 and 104 led to only a slight prolongation of population doubling time; these compounds inhibited cellular DNA synthesis but not RNA or protein synthesis, as measured by incorporation of radiolabeled precursors into acid-precipitable macromolecules; flow cytometry indicated that compound 102 was a mid-S phase blocker, and adenosine antagonized the inhibition of [3H]dThd incorporation by compound 102. Together, these results demonstrate that compound 102 is a potent and selective inhibitor of viral and cellular DNA synthesis and that acyclic halogenated pyrrolo-pyrimidine nucleosides may have therapeutic potential.

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Section: Discussionmentioning

confidence: 81%