9-(1,3-Dihydroxy-2-propoxymethyl)guanine: a new potent and selective antiherpes agent

Abstract

The synthesis of a new acyclic analogue of deoxyguanosine, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1), is described starting from epichlorohydrin via condensation of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (5) with N2,9-diacetylguanine (6). In vitro studies indicate that DHPG is a potent and broad-acting (herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein-Barr virus) antiherpetic agent. In vivo studies indicate its lack of toxicity [LD50 (mice) = 1-2 g/kg, ip] and its superiority over acyclovir [oral ED50 = 7 (mg/kg)/day vs. 550 (mg/kg)/day in HSV-2 infected mice].

Allograft rejection-related gene expression in the endothelial cells of renal transplantation recipients after cytomegalovirus infection

“…An in vitro study demonstrates that synergistic action of IE expression product can activate the promoter region of ICAM-1 gene, which might be the mechanism of up-regulated ICAM-1 mRNA expression in ECs (Knight et al, 2000). Ganciclovir, a nucleoside analogue of guanosine, is effective in the treatment of CMV disease in humans (Martin et al, 1983), which is a homologue of acyclovir and the first-generation antiviral drug. In vivo, ganciclovir is transformed into ganciclovir triphosphate, which can inhibit viral DNA polymerases by competitively inhibiting the synthesis of deoxyguanosine triphosphate.…”

The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro.

“…Although inoculation of C6 or 9L glioma tumors with fibroblasts producing retroviral vectors results in transduction of no more than 10% of tumor cells (1,2), curative gene therapy has been demonstrated in some animal models after retroviral transfer of the herpes simplex virus thymidine kinase gene (HSV-tk) to tumor cells (3)(4)(5)(6)(7). Transduced cells become sensitive to ganciclovir (GCV), a guanine analog that causes premature chain termination when incorporated into replicating DNA, thereby disrupting cellular proliferation (8,9). The death of tumor cells not transduced with the HSV-tk transgene is called the "bystander effect" (3).…”

A facile synthesis of potent antiherpes drug substance, ganciclovir, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine, using a new masked glycerol derivative

“…In the reported processes for the introduction of acetoxymethyl moiety onto the secondary hydroxyl function of appropriate terminal protected glycerol derivatives, a two step protocol involving chloromethylation and subsequent nucleophilic displacement with acetoxy was practiced. 8,12 We have developed a relatively simple and convenient one step process for functionalizing the secondary hydroxyl to furnish the desired intermediate 4.…”

“…The formation of 1 (16% when calculated from 3) was confirmed by comparison of analytical data with that of authentic compound reported in literature. 8 …”

“…1,2 In view of its substantial commercial importance, several synthetic routes were developed for ganciclovir using guanine, 3,4 acetylguanine, 3 2-amino-6-chloropurine, 3,5 tetraacetylguanosine, 6,7 and diacetylguanine 2 (Figure 1), [8][9][10][11] as the source of guanine moiety. Coupling of one of such guanine derivatives with an appropriately protected, activated glycerol derivative such as 1,3-diacetoxy-2-acetoxymethoxy propane or 1,3-dibenzyloxy-2-acetoxymethoxy propane is the commonly employed strategy to access ganciclovir.…”