(Z)- and (E)-2-(1,2-Dihydroxyethyl)methylenecyclopropane Analogues of 2′-Deoxyadenosine and 2′-Deoxyguanosine. Synthesis of All Stereoisomers, Absolute Configuration, and Antiviral Activity

Abstract

Chiral Z and E-stereoisomers of (1,2-dihydroxyethyl)methylenecyclopropane analogues of 2'-deoxyadenosine and 2'-deoxyguanosine were synthesized and their antiviral activity investigated. (S)-Methylenecyclopropylcarbinol (16) was converted in seven steps to reagents 26 and 27 which were used for alkylation-elimination of adenine and 2-amino-6-chloropurine to get ultimately analogues 12a, 12b, 13a, 13b, 14a, 14b, 15a and 15b. The enantiomeric series ent-12a, ent-12b, ent-13a, ent-13b, ent-14a, ent-14b, ent-15a and ent-15b was obtained by similar procedures starting from (R)-methylenecyclopropylcarbinol (ent-16). The Z-isomer ent-12b was an inhibitor of two strains of human cytomegalovirus (HCMV) with EC 50 6.8 and 7.5 µM and murine cytomegalovirus (MCMV) with EC 50 11.3 µM. It was less active against HCMV with mutated gene UL97. It inhibited Epstein-Barr virus (EBV) with EC 50 8 µM. The E-isomers ent-15a, ent-13a and 15b were less effective. All adenine analogues with the exception of the Z-isomers ent-12a and ent-14a were moderate substrates for adenosine deaminase.

Synthesis and Antiviral Activities of Methylenecyclopropane Analogs with 6-Alkoxy and 6-Alkylthio Substitutions That Exhibit Broad-Spectrum Antiviral Activity against Human Herpesviruses

“…Additionally, some (Z)-and (E)-9-([(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl) adenine and -guanine analogs were modestly effective against CMV (29,30). These results were extended to include (Z)-and (E)-2-(1,2-dihydroxyethyl)methylenecyclopropane analogues of 2=-deoxyadenosine and 2=-deoxyguanosine, some of which were active against CMV, MCMV, and EBV (31).…”

Cyclopropavir Inhibits the Normal Function of the Human Cytomegalovirus UL97 Kinase

“…Additionally, some (Z)-and (E)-9-([(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl)adenine and -guanine analogs were modestly effective against CMV (20). These results were extended to include (Z)-and (E)-2-(1,2-dihydroxyethyl)methylenecyclopropane analogues of 2Ј-deoxyadenosine and 2Ј-deoxyguanosine, some of which were active against CMV, murine CMV, and EBV (40). The lead compound cyclopropavir (CPV; ZSM-I-62) was evaluated against all of the HHVs, and we reported previously that it was active in vitro against CMV, HHV-6A, HHV-6B, and HHV-8 (17).…”

Cytomegalovirus UL97 Mutations Affecting Cyclopropavir and Ganciclovir Susceptibility

“…Because the currently marketed drugs ganciclovir (GCV) (or its oral prodrug valganciclovir), foscarnet, and cidofovir can be limited by issues of tolerability and cross-resistance (10), there are ongoing efforts to develop new antiviral options. Several Z-isomer methylenecyclopropane nucleoside analogs have shown potent in vitro anti-CMV activity (12), particularly the compound cyclopropavir (CPV) (or ZSM-I-62, 5b [11]), which had low cytotoxicity (8) and showed in vivo efficacy in an immunodeficient mouse model of human CMV infection (7). CPV is an attractive candidate for clinical trials.…”

“…This is comparable to information in Table 1, where different mutations at codon 603 confer various levels of CPV resistance. The M460I-C603Y double mutant apparently showed 13-fold and 11-fold increases in EC 50 for CPV and GCV, respectively (12). Another conference abstract (1) reported that CPV selected for a frameshift mutation in UL97 that truncated the expressed protein at residue 168, far upstream of residues composing critical kinase domains.…”