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

Abstract

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.

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

“…132 Acyclic analogues of 7-deazapurine nucleosides and nucleotides were also screened for antiviral activities but generally these compounds showed only poor activities, especially when compared with the corresponding purine analogues. [153][154][155][156] Nevertheless, some acyclic analogues of 7-bromo-7-deazaadenosine (81a-b) [157][158][159] and thiosangivamycin (82a-b) [160][161][162][163] possess selective activity against human cytomegalovirus that is comparable or better than that of ganciclovir.…”

Improved synthesis and biological evaluation of an acyclic thiosangivamycin active against human cytomegalovirus

“…For example, we have synthesized a number of acyclic pyrrolo[2,3-d]pyrimidine derivatives containing either the acyclovir or ganciclovir side chain as potential HCMV agents (Saxena et al, 1988;Pudlo et al, 1988;Gupta et al, 1989a;Gupta et al, 1989b;Pudlo et al, 1990). These studies identified a series of acyclic bromotubercidins with potent activity against HCMV both in vitro and in vivo (Pudlo et al, 1988(Pudlo et al, , 1990Nassiri et al, 1990Nassiri et al, , 1991b. The initial antiviral evaluation of other compounds also identified a thiosangivamycin analog (4amino-7-[(2-hydroxyethoxymethyl)]pyrrolo[2,3-d]pyrimidine-5-thiocarboxamide, compound 229*) as active against HCMV (ICs0= 11 #M) without the severe cytotoxicity observed with toyocamycin and sangivamycin (Gupta et al, 1989a).…”

Synthesis Strategies and Biological Value of Pyrrole and Pyrrolopyrimidine

“…Some pyrrolo[2,3-d]pyrimidine derivatives 168-170 are found to have a significant anti-viral activity[153][154][155][156][157] against human cytomegalovirus (CMV).Pyrrole derivatives 171-173 possess a significantanti-viral activity against human immunodeficiency virus (HIV)158-160 . Pyrrolo[2,3-d]pyrimidine derivatives 174-176 can inhibit the viral replication of herps simplex virus 161-ISSN: 2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Sayed et al, 2017, 1 (1), 1-24 Pyrrolo[2,3-d]pyrimidine derivatives 177, carbocyclic analogs Toyocamycin and sangivamycin, are proven to have anti-viral activity against hepatitis B virus (HBV) 164 .…”