Synthesis and antiviral activity of novel 5-(1-azido-2-haloethyl) and 5-(1-azido-, amino-, or methoxyethyl) analogs of 2'-deoxyuridine.
A new class of 5-(1-azido-2-haloethyl)-2'-deoxyuridines 3a-c was synthesized by the regiospecific addition of XN3 (X = I, Br, Cl) to the vinyl substituent of 5-vinyl-2'-deoxyuridine. Treatment of the 5-(1-azido-2-iodoethyl) compound (3a) with H2 and 10% Pd/C yielded the 5-(1-azidoethyl) (4) and 5-(1-aminoethyl) (5) derivatives of 2'-deoxyuridine. A similar hydrogenation of 5-(1-methoxy-2-iodoethyl)-2'-deoxyuridine (1f) afforded the 5-(1-methoxyethyl) analog 6. The 5-(1-azido-2-haloethyl)-2'-deoxyuridines 3a-c exhibited in vitro antiviral activity against HSV-1, HSV-2, VZV, and EBV, but they were inactive against HCMV. In this group of compounds, the activity order was Cl > or = I > Br against HSV-1 and Br > or = Cl > I against HSV-2. A halogen atom in the 5-(1-azido-2-haloethyl) moiety 3a-c is an essential requirement since the 5-(1-azidoethyl) analog 4 was inactive, except for weak antiviral activity against VZV. Although the 5-(1-aminoethyl)-2'-deoxyuridine.HI (5) was inactive against HSV-1 and HSV-2, the 5-(1-methoxyethyl) compound 6 was equiactive to 5-ethyl-2'-deoxyuridine (EDU) against both HSV-1 and HSV-2 and 7-fold and 12-fold less active against HCMV relative to EDU and ganciclovir, respectively. All compounds investigated (3-6) exhibited low host cell cytotoxicity (IC50 > 118 microM) and inhibited cell proliferation only at high concentrations (IC50 > 76 microM).
Kumar
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wiebe
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Knaus
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D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001386:Azides; C082816:5-(1-azido-2-chloroethyl)-2'-deoxyuridine; D003857:Deoxyuridine