Regioselective Synthesis and Antiviral Activity of Purine Nucleoside Analogues with Acyclic Substituents at N7

Jähne, Gerhard; Kroha, Herbert; Müller, A.; Helsberg, Matthias; Winkler, Irvin; Groß, Gerhard; Scholl, Thomas

doi:10.1002/anie.199405621

Cited by 30 publications

(22 citation statements)

References 17 publications

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“…The present results provide at least a good lead to the possible binding mode of these agonists to the A3 receptors. Furthermore, it is worth noting that N(7)-acyclonucleosides of guanine exhibit significant antiherpes activities [38], the mechanisms of which remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Calf spleen purine nucleoside phosphorylase: purification, sequence and crystal structure of its complex with an N(7)‐acycloguanosine inhibitor

et al. 1995

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Calf spleen pnrine nucleoside phosphorylase was purified to homogeneity and its amino acid sequence was determined. The complex of the enzyme with an N(7)-acycloguanosine inhibitor crystallized in the cubic space group P213, with unit cell dimension a = 94.02 A and one monomer in the asymmetric crystal unit. The biologically active trimer is formed by the crystallographic three-fold axis. The structure was solved by molecular replacement methods, using the model of the human erythrocyte enzyme, and refined at a resolution of 2.9 A to an R-factor of 0.21. The orientation of the inhibitor at the active site is examined in relation to the catalytic activity of the enzyme in the phosphorolysis of N(7)-fl-o-purine nucleosides.

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Section: Discussionmentioning

confidence: 99%

Calf spleen purine nucleoside phosphorylase: purification, sequence and crystal structure of its complex with an N(7)‐acycloguanosine inhibitor

et al. 1995

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“…Compound S2242 and its diacetate ester prodrug H961 ( Fig. 1) were kindly provided by I. Winkler (Hoechst, Frankfurt am Main, Germany) and were synthesized as reported previously (13). Cidofovir was a kind gift from Gilead Sciences (Foster City, Calif.).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of 2-Amino-7-(1,3-Dihydroxy-2-Propoxymethyl)Purine for Treatment of Vaccinia Virus (Orthopoxvirus) Infections in Mice

Neyts

Clercq

2001

Antimicrob Agents Chemother

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We have previously shown that the N-7 substituted acyclic nucleoside analog 2-amino-7-[1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) is, both in vitro and in animal models, a potent inhibitor of the replication of several herpesviruses (Neyts et al., Antimicrob. Agents Chemother. 39:56-60, 1995). Here we report on the potent and selective antiviral activity of S2242 against vaccinia virus (VV), an orthopoxvirus. The 50% effective concentrations for inhibition of VV-induced cytopathic effect and viral DNA synthesis in cell culture were 2.4 and 0.2 g/ml, respectively. We next studied the efficacy of S2242 in VV-infected mice. Immunocompetent NMRI mice that had been inoculated intravenously with VV developed tail lesions. Mice that had been treated for 5 consecutive days via the subcutaneous (s.c.) route with 100 mg of the diacetate ester prodrug of S2242 (compound H961) per kg of body weight did not develop any lesions and demonstrated no adverse effects. Severe combined immunodeficient (SCID) mice that had been inoculated intraperitoneally with VV became sick and died within 1 month after infection. Following treatment with H961 at 100 mg/kg for 10 consecutive days (either via oral gavage or s.c. injection) VV-inoculated SCID mice were completely protected, for at least 3 months, against virus-induced morbidity and mortality. At that time, no virus could be recovered from the organs of these mice (as assessed by titration for infectious virus, a DNA hybridization assay, and a PCR for VV-specific sequences). Compound S2242 and its oral prodrug H961 could be useful in treatment of orthopoxvirus infections.

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“…The synthesis of compound S2242 has been reported previously (11). The structural formula of the compound is depicted in Fig.…”

Section: Matermils and Methodsmentioning

confidence: 99%

“…Jahne et al (11) reported the synthesis of a series of N-7-substituted acyclic nucleoside analogs. In this report we describe the antiviral activity of 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242).…”

mentioning

confidence: 99%

The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication

Neyts

Andrei

Snoeck

et al. 1994

Antimicrob Agents Chemother

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2-Amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (compound S2242) represents the first antivirally active nucleoside analog with the side chain attached to the N-7 position of the purine ring. Compound S2242 strongly inhibits the in vitro replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (50% effective concentration [EC50], 0.1 to 0.2 ,ug/ml), varicella-zoster virus (EC50, 0.01 to 0.02 ,ug/ml) and thymidine kinase (TK)-deficient strains of HSV (EC50, 0.4 ,Lg/ml) and varicella-zoster virus (EC50, 0.2 to 0.5 ,ug/ml). Potent activity was also observed against murine cytomegalovirus (EC50, 1 gig/ml), human cytomegalovirus (HCMV) (EC50, 0.04 to 0.1 ,ug/ml), and human herpesvirus 6 (EC50, 0.0005 ,ug/ml). Compound S2242 (i) was not cytotoxic to confluent Vero, HeLa, or human fibroblast cells at concentrations of > 100 ,ug/ml, (ii) proved somewhat more cytostatic to Vero, HEL, HeLa, and C127I cells than ganciclovir, and (iii) was markedly more cytostatic than ganciclovir to the growth of the human lymphocytic cell lines HSB-2 and CEM°. In contrast to ganciclovir, (i) compound S2242 proved not to be cytocidal to murine mammary carcinoma (FM3A) cells transfected with the HSV-1 or HSV-2 TK gene, (ii) exogenously added thymidine had only a limited effect on its anti-HSV-1 activity, and (iii) the compound was not phosphorylated by HSV-1-encoded TK derived from HSV-1 TK-transfected FM3A cells, indicating that the compound is not activated by a virally encoded TK.Compound S2242 inhibited (i) the expression of late HCMV antigens at an EC50 of 0.07 ,ug/ml (0.6 ,ug/ml for ganciclovir) and (ii) HCMV DNA synthesis at an EC50 of 0.1 ,ug/ml (0.32 ,ug/ml for ganciclovir), i.e., values that are close to the EC50s for inhibition of HCMV-induced cytopathogenicity. Neither ganciclovir nor S2242 had any effect on the expression of immediate-early HCMV antigens, which occurs before viral DNA synthesis. In time-of-addition experiments, S2242 behaved like ganciclovir and acyclovir; i.e., the addition of the drugs could be delayed until the onset of viral DNA synthesis.Agents approved in one or more countries to treat herpesvirus infection include idoxuridine, trifluridine, vidarabine, and acyclovir for the topical treatment of herpetic eye infection; vidarabine and acyclovir for the systemic treatment of herpes encephalitis, acyclovir for the topical and systemic (oral or intravenous) treatment of genital herpes; acyclovir for the systemic (intravenous, oral) treatment of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infections in immunosuppressed patients; and ganciclovir and foscarnet for the systemic (intravenous) treatment of human cytomegalovirus (HCMV) retinitis in patients with AIDS. Foscarnet is effective in the treatment of infections with acyclovir-resistant thymidine kinase-deficient (TK-) HSV or VZV mutants and ganciclovir-resistant HCMV infections (5,16,18,25). However, double resistant viruses (i.e., ganciclovir-and foscarnet-resistant HCMV and acyclovir-and foscarnet-resistant HSV) have b...

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Regioselective Synthesis and Antiviral Activity of Purine Nucleoside Analogues with Acyclic Substituents at N7

Cited by 30 publications

References 17 publications

Calf spleen purine nucleoside phosphorylase: purification, sequence and crystal structure of its complex with an N(7)‐acycloguanosine inhibitor

Calf spleen purine nucleoside phosphorylase: purification, sequence and crystal structure of its complex with an N(7)‐acycloguanosine inhibitor

Efficacy of 2-Amino-7-(1,3-Dihydroxy-2-Propoxymethyl)Purine for Treatment of Vaccinia Virus (Orthopoxvirus) Infections in Mice

The N-7-substituted acyclic nucleoside analog 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine is a potent and selective inhibitor of herpesvirus replication

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