Acyclic Nucleosides. Synthesis and Antiherpetic Activity of 9-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Guanine and 1-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Cytosine

Abstract The synthesis and antiherpetic activity of 9-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy1]guanine (4) and 1-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy]cytosine (6), the side-chain thio analogues of ganciclovir (3) and BW A1117U (5), are described. The sidechain synthon 1,3-bis(benzyloxy)-2-[(chloromethyl)thio]propane (11) was prepared in four steps from 1,3-bis(benzyloxy)-2-propanol (7). Alkylation of 2-amino-6-chloro-9H-purine with 11 provided the intermediate 9-substituted-2-amino-6-chloropurine 12, which was conveniently converted to 4 in two steps. Reaction of a fivefold excess of cytosine with 11 provided the desired 1-isomer 14, which was debenzylated to give 6. In contrast with ganciclovir (3) and BW A1117U (5), neither 4 nor 6 had significant in vitro activity against human cytomegalovirus.

[1]  J. E. Kelsey,et al.  Effect of acyclic pyrimidines related to 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine on herpesviruses. , 1988, Journal of medicinal chemistry.

[2]  C. K. Chu,et al.  Chemistry and antiviral activities of acyclonucleosides , 1986 .

[3]  L. Corey,et al.  Antiviral chemotherapy: New directions for clinical application and research , 1989 .

[4]  J. C. Martin,et al.  Synthesis and antiherpes simplex virus activity of 9-[(1,3-dihydroxy-2-propylthio)methyl]guanine. , 1985, Journal of medicinal chemistry.

[5]  D. Smee,et al.  Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human, monkey, and rodent cytomegaloviruses , 1985, Antimicrobial Agents and Chemotherapy.

[6]  D. Nelson,et al.  Metabolic activation of the nucleoside analog 9-[( 2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N. Nguyen-ba,et al.  A trihydroxy acyclonucleoside series , 1984 .

[8]  E. Rollinson,et al.  Relative activities of acyclovir and BW759 against Aujeszky's disease and equine rhinopneumonitis viruses. , 1983, Antimicrobial Agents and Chemotherapy.

[9]  J. C. Martin,et al.  9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. , 1983, Journal of medicinal chemistry.

[10]  E. Huang,et al.  Unique spectrum of activity of 9-[(1,3-dihydroxy-2-propoxy)methyl]-guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. C. Martin,et al.  Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine , 1983, Antimicrobial Agents and Chemotherapy.

[12]  K. K. Ogilvie,et al.  Synthesis of 5-Substituted-1-[[2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl]cytosines , 1983 .

[13]  L. Beauchamp,et al.  Chapter 15. Antiviral Agents , 1983 .

[14]  K. K. Ogilvie,et al.  Biologically active acyclonucleoside analogues. II. The synthesis of 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (BIOLF-62) , 1982 .

[15]  J. D. Karkas,et al.  Activation by thymidine kinase and potent antiherpetic activity of 2'-nor-2'-deoxyguanosine (2'NDG). , 1982, Biochemical and biophysical research communications.

[16]  G. Appleyard,et al.  Sensitivity of herpes virus isolates from acyclovir clinical trials. , 1982, The American journal of medicine.

[17]  K. K. Ogilvie,et al.  A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2 , 1982, Antimicrobial Agents and Chemotherapy.

[18]  H. Schaeffer,et al.  Enzymatic phosphorylation of acyclic nucleoside analogs and correlations with antiherpetic activities. , 1981, Biochemical pharmacology.

[19]  J. E. Kelsey,et al.  Pyrimidine acyclic nucleosides, 1-[(2-Hydroxyethoxy)methyl]pyrimidines as candidate antivirals. , 1981, Journal of medicinal chemistry.

[20]  H. Schaeffer,et al.  Pyrimidine acyclic nucleosides. 5-Substituted 1-[(2-aminoethoxy)methyl]uracils as candidate antivirals. , 1981, Journal of medicinal chemistry.

[21]  W. C. Still,et al.  Rapid chromatographic technique for preparative separations with moderate resolution , 1978 .

[22]  D. J. Bauer,et al.  9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group , 1978, Nature.

[23]  H. Schaeffer,et al.  Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B. Ganem,et al.  Ferric chloride in acetic anhydide. Mild and versatile reagent for the cleavage of ethers , 1974 .

[25]  K. Miura,et al.  Nucleosides and nucleotides. VI. Preparation of diribonucleoside monophosphates containing 4-thiouridine. , 1973, Journal of biochemistry.

[26]  Louis Fieser,et al.  Reagents for Organic Synthesis , 1967 .

[27]  I. Iwai,et al.  Studies on synthetic nucleosides. I. Trimethylsilyl derivatives of pyrimidines and purines. , 1964, Chemical & pharmaceutical bulletin.

[28]  C. L. Butler,et al.  The Preparation of Benzyloxyalkyl p-Toluenesulfonates , 1938 .