New Analogs of Acyclovir Substituted at the Side Chain

Abstract

A series of novel analogs of acyclovir, substituted with an alkyl (methyl, ethyl, n-butyl) or phenyl group at the positions 1', 4', and/or 5', has been obtained in a direct one-pot coupling reaction of guanosine and the respective 1,3-dioxolanes. The new acyclonucleosides were essentially inactive in antiviral (HSV, VV, VSV, HBV) evaluation in vitro.

7‐(β‐D‐Ribofuranosyl)guanine and its Analogues Modified in the Sugar Portion: Synthesis and Antiglioma Properties

“…In the 2’‐deoxynucleoside series, 7‐(2‐deoxy‐β‐ D ‐erythro‐pentofuranosyl)guanine ( 20 ) and its 7‐(2‐deoxy‐α‐ D ‐erythro‐pentofuranosyl) anomer ( 21 ) (Figure 2) were isolated as triacetyl derivatives from the reaction mixture obtained after isomerization of 9‐(3,5‐di‐O‐acetyl‐2‐deoxy‐β‐ D ‐erythro‐pentofuranosyl)‐N 2 ‐acetylguanine, as described previously, [9] and subsequently deprotected to free nucleosides. Similarly, synthesis of the branched guanine 7‐acyclonucleosides ( 22 – 24 ) (Figure 3) in the reaction of guanosine with 4‐substituted 1,3‐dioxolanes in acetic anhydride was reported previously, but their spectral characteristics were not published [2] . The latter were used in the cytotoxicity assay as enantiomeric mixtures.…”

“…Similarly, synthesis of the branched guanine 7acyclonucleosides (22)(23)(24) (Figure 3) in the reaction of guanosine with 4-substituted 1,3-dioxolanes in acetic anhydride was reported previously, but their spectral characteristics were not published. [2] The latter were used in the cytotoxicity assay as enantiomeric mixtures.…”

“…It also happened in our research, in which, for instance, antiviral activity of "natural" 9-substituted derivatives of acyclovir (i. e. 9-[(2-hydroxyethoxy)methyl]guanine) have been tested, while the simultaneously obtained 7-isomers have been totally neglected. [2] Therefore, our knowledge of biological activity of that class of compounds is very limited. In the case of 7-purine nucleosides, the only literature reference has reported a moderate cytostatic activity of some substituted 7-isomers of acyclovir in murine leukemia (L1210) cell line, and 2-aminopurin-6-thione derivative has appeared to be the most active compound (IC 50 28 μM).…”

“…Recently we have discovered that 7-regioisomer of naturally occurring guanosine (Figure 1; compound 1), i. e. 7-(β-Dribofuranosyl)guanine (2), demonstrated high (IC 50 1.6 μM) and selective anticancer activity in vitro against glioma cell lines T98G (Glioblastoma multiforme). [1] Glioblastomas are exceptionally malignant brain neoplasms, practically incurable at the present state of medicine.…”

Reactions of Transglycosylation in the Nucleoside Chemistry

“…In this synthetic variant, the reaction is carried out directly in acetic anhydride, in the presence of p-toluenesulfonic acid, and carefully selected thermodynamic conditions result in a highly efficient formation of the 9-isomer (73) (R 1 =R 2 =H). The application of 2-and/or 4-substituted derivatives of dioxolane opens a convenient synthetic route to a variety of 1'-and/or 4'-modified congeners of acyclovir [general structure (73)] [110,111].…”