A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2

Abstract

A novel nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-guanine (BIOLF-62), was found to have potent antiviral activity against herpes simplex virus types 1 and 2 at concentrations well below cytotoxic levels. For example, the Patton strain of herpes simplex virus type 1 was susceptible at concentrations 140-to 2,900-fold below that which inhibited cell division by 50%, depending upon the cell line used for assay. Different herpesvirus strains varied considerably in their susceptibility to the drug, as did results obtained with the same virus strain in different cell lines. BIOLF-62 compared favorably with 5-iodo-2'-deoxyuridine and acyclovir with respect to ratios of viral to cell inhibitory drug concentrations. Patterns of drug resistance in herpesvirus mutants suggested that the primary mode of action of BIOLF-62 is different from that of known antiviral compounds. Human adenovirus type 2, varicella-zoster virus, and Epstein-Barr virus were inhibited by this drug but at concentrations within the cell inhibitory range. Vaccinia virus and human cytomegalovirus were not inhibited at high drug concentrations.

Uracil analogues of the acyclonucleoside 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]- methyl]guanine (BIOLF-62)

“…We have introduced a novel ring-open nucleoside structure 1 (5 -7) which possesses all of the chemical functionality of deoxyribonucleosides but which lacks the rigid furanose ring structure. The purine derivatives of structure 1 have shown remarkable activity against herpesviruses (8)(9)(10). In this report we wish to describe the synthesis of a series of pyrimidine analogues of structure 1.…”

Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities

“…1 H NMR spectra of these two methoxy derivatives showed only one singlet signal (δ 4.38) attributable to the 7-O-methyl protons, which was consistent with the other 7-O-methyl derivatives (δ 4.37-4.40 for 4a-g). Besides, the physical and spectral data of 3-(2-hydroxyethyl)-7-methoxy 4f and 3-(3-hydroxypropyl)-7-methoxy-5-phenyl-3H- [1,2,3]triazolo- [4,5-d]pyrimidine 4g obtained by methylation of 2f and 2g were different from that of 8 and 9, respectively. Hence, it is obvious that the replacement of chlorine by methoxy group took place selectively at the 7-position without at the side chain of 6 and 7.…”

“…[1][2][3][4][5] Particular interests are the structural modification of purine bases as well as introduction of different functional groups into these bases in the view of searching potential antineoplastic and antiviral agents. Introduction of different functional groups, e.g., amino, oxo, thioxo, alkylthio, alkyl/aryl groups, into purine bases at different positions has been assessed for potency and selectivity for the biological system.…”

“…The absence of the alcoholic absorption band in the IR spectra as well as the broad singlet signal attributable to the alcoholic OH proton in the 1 H NMR spectra of these two derivatives 6 and 7 showed the substitution of hydroxyl group to chlorine. When the dichlorinated derivatives 6 and 7 were treated with sodium methoxide in methanol at room temperature, the nucleophilic substitution took place only at the 7-position to give the corresponding 3-(2-chloroethyl)-7-methoxy-8 and 3-(3-chloropropyl)-7-methoxy-5-phenyl-3H- [1,2,3]triazolo [4,5-d]pyrimidine 9 in 81% and 88% yields, respectively. 1 H NMR spectra of these two methoxy derivatives showed only one singlet signal (δ 4.38) attributable to the 7-O-methyl protons, which was consistent with the other 7-O-methyl derivatives (δ 4.37-4.40 for 4a-g).…”

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Abstract ---3-Alkyl-5-phenyl-3H- [1,2,3]triazolo [4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature. Simultaneous 6-N-and 7-O-alkylations were observed and the regioselectivity varied remarkably with size and shape of the alkylating agents as well as with the reaction temperature.

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