Biologically active acyclonucleoside analogues. II. The synthesis of 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (BIOLF-62)

Abstract

Can. J . Chem. 60, 3005 (1982). The chemical synthesis of 9-[[2-hydroxy-l-(hydroxymethyl)ethoxy]methyl]guanine is described. This compound, known a s BIOLF-62, is active against herpesviruses. This compound is a member of a novel class of nucleoside analogues which lacka rigid carbohydrate ring, but which possess all of the functional groups of naturally occurring deoxynucleosides. I The search for biologically active molecules has ' focused a great deal of attention on modified nucleosides (1-3). For several years we have been i developing a nucleoside analogue structure intended to interfere with viral and bacterial systems. The I structure was designed to lack the rigid conformal tional feature (syn-anti) of natural nucleosides but i at the same time retain the essential chemical features of natural nucleosides (e.g., purine or I pyrimidine ring, 03', 0 4 ' , and Os'oxygen functionalities). In a preliminary report (4) we described the synthesis of the adenine analogue 9[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]adenine. This compound was neither a substrate nor an inhibitor for adenosine deaminase, a key enzyme in animal systems that inactivates in vivo most adenine derivatives that show promising biological activity in vitro. In this report we wish to describe the synthesis of another member of this series, the potent antiviral compound 9[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (5) which is known as BIOLF-62. Results and discussionThe first route fully explored for the synthesis of BIOLF-62 involved the condensation of 6-chloro-I

Synthesis of Certain New 1,2,3-Triazole Acyclonucleosides via 1,3-Dipolar Cycloaddition

“…In the 1 H NMR spectra of each 7 and 8 appeared a signal of acetyl groups and disappeared that of tosyl groups. Acylation of 7 at room temperature with acetyl bromide leads to the mixture of 9 and 10 in ratio 1/3 as shown by 1 H NMR. And the minor synthon 9 was equally obtained by acylation of 8 in 97% yield.…”

“…The discovery of the two structural isomers acycloguanosines [1][2][3][4][5][6] : 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG, 1) and 9-(2,3-dihydroxy-1-propoxymethyl) guanine (iso-NDG, 2) ( Figure 1) as the effective and highly selective antiviral drugs for the treatment of herpes simplex virus (HSV) infections has stimulated an extensive search for acyclic nucleosides that are more potent antiviral agents. So far, the structure-activity studies have shown that the side chain of acyclic nucleosides plays a main role in the antiviral activity (phosphorylation).…”

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

“…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.…”

N1‐allyl‐3‐substituted‐6,7‐dimethyl‐1,2‐dihydro‐2‐quinoxalinone as key intermediate for new acyclonucleosides and their regioisomer O‐analogues

“…The successful development of acyclovir I (ACV) [1,2], 9-[(2-hydroxyethoxy)-methyl]guanine, and ganciclovir II (DHPG) [3,4] as excellent antiviral agents have stimulated the synthesis and biological evaluation of a wide variety of acyclic nucleosides modified either in the base moiety or the acyclic part.…”

“…Conventional and common synthetic methods for the preparation of acyclic nucleosides and nucleotides involve the coupling reaction of heterocyclic bases with ␣-halo [5][6][7] or acetoxymethyl ethers catalyzed by various Lewis acids or bases [7,8], e.g., HMDS [5,6], SnCl 4 , Hg(CN) 2 , (CH 3 ) 3 SiClO 4 , (CH 3 ) 3 SiSO 3 C 4 F 9 [9,10], and natural phosphates (NP) [6] to afford the regioselective N-alkylation of the nucleobases, i.e., acyclonucleoside.…”