Activity of acyclic halogenated tubercidin analogs against human cytomegalovirus and in uninfected cells.
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.
Nassiri
M R
MR
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor 48109-1078.
Turk
S R
SR
Birch
G M
GM
Coleman
L A
LA
Hudson
J L
JL
Pudlo
J S
JS
Townsend
L B
LB
Drach
J C
JC
D000241:Adenosine / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000276:immunology; D004279:DNA, Viral / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007624:KB Cells; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D004279:DNA, Viral; D011743:Pyrimidines; D011758:Pyrroles; D012367:RNA, Viral; C061594:4-amino-5-bromo-7-(2-hydroxyethoxymethyl)pyrrolo(2,3-d)pyrimidine; D000241:Adenosine; D014372:Tubercidin