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1.
Biochem J ; 351 Pt 2: 319-26, 2000 Oct 15.
Article in English | MEDLINE | ID: mdl-11023816

ABSTRACT

The antiviral activity of several nucleoside analogues is often limited by their rapid degradation by pyrimidine nucleoside phosphorylases. In an attempt to avoid this degradation, several modified nucleosides have been synthesized. A series of 4'-thio-2'-deoxyuridines exhibits an anti-[herpes simplex virus (HSV)] activity significantly higher (20-600 times) than that shown by the corresponding 4'-oxy counterpart. We investigated the mode of action of these compounds and we found that: (i) several 4'-thio-2'-deoxyuridines are phosphorylated to the mono- and di-phosphates by HSV-1 thymidine kinase (TK) more efficiently than their corresponding 4'-oxy counterpart; (ii) both are inhibitors of cellular thymidylate synthase; (iii) 4'-thio-2'-deoxyuridines are resistant to phosphorolysis by human thymidine phosphorylase; (iv) both 4'-oxy- and 4'-thio-2'-deoxyuridines are phosphorylated to deoxyribonucleotide triphosphate in HSV-1-infected cells and are incorporated into viral DNA; (v) 4'-thio-2'-deoxyuridines are better inhibitors than their 4'-oxy counterparts of [(3)H]thymidine incorporation in HSV-1-infected cells; (vi) 4'-thio-2'-deoxyuridines are not recognized by HSV-1 and human uracil-DNA glycosylases. Our data suggest that 4'-thio-2'-deoxyuridines, resistant to pyrimidine phosphorylase, can be preferentially or selectively phosphorylated by viral TK in HSV-infected cells, where they are further converted into triphosphate by cellular nucleotide kinases. Once incorporated into viral DNA, they are better inhibitors of viral DNA synthesis than their corresponding 4'-oxy counterpart, either because they are not recognized, and thus not removed, by viral uracil-DNA glycosylase, or because they preferentially interfere with viral DNA polymerase.


Subject(s)
Antiviral Agents/pharmacology , Simplexvirus/metabolism , Thiouridine/analogs & derivatives , Thiouridine/pharmacology , Blood Platelets/metabolism , Cell Line , Chromatography, High Pressure Liquid , Cloning, Molecular , DNA/biosynthesis , DNA/drug effects , DNA, Complementary/metabolism , DNA-Directed DNA Polymerase/metabolism , HeLa Cells , Humans , Kinetics , Nucleosides/chemical synthesis , Phosphorylation , Thiouridine/chemical synthesis , Thymidine Kinase/metabolism , Thymidine Phosphorylase/genetics
3.
J Med Chem ; 39(3): 789-95, 1996 Feb 02.
Article in English | MEDLINE | ID: mdl-8576922

ABSTRACT

A series of 5-substituted 2'-deoxy-4'-thiopyrimidine nucleosides was synthesized and evaluated as potential antiviral agents. A number of analogues such as 2'-deoxy-5-propyl-4'-thiouridine (3ii), 2'-deoxy-5-isopropyl-4'-thiouridine (3iii), 5-cyclopropyl-2'-deoxy-4'-thiouridine (3iv), 2'-deoxy-4'-thio-5-vinyluridine (3viii), and 5-(2-chloroethyl)-2'-deoxy-4'-thiouridine (3xx) were found to be highly active against herpes simplex virus type-1 (HSV-1) and varicella zoster virus (VZV) in vitro with no significant cytotoxicity. The compound with the broadest spectrum of activity was 2'-deoxy-5-ethyl-4'-thiouridine (3i) which showed significant activity against HSV-1, HSV-2, and VZV.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Simplexvirus/drug effects , Animals , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Humans , Vero Cells , Viral Plaque Assay
4.
Nucleic Acids Symp Ser ; (34): 9-10, 1995.
Article in English | MEDLINE | ID: mdl-8841526

ABSTRACT

From readily available starting materials, the preparation and characterization of a variety of pyrimidine 2', 3'-dideoxyribo-, 2'-deoxyribo-, 3'-deoxyribo- and ribo- N-protected 4'-aza nucleosides is reported. None was found to possess any significant antiviral activity.


Subject(s)
Aza Compounds/chemical synthesis , Deoxyribonucleosides/chemical synthesis , Ribonucleosides/chemical synthesis , Aza Compounds/chemistry , Deoxyribonucleosides/chemistry , Molecular Structure , Pyrrolidonecarboxylic Acid/chemistry , Ribonucleosides/chemistry
5.
Nucleic Acids Symp Ser ; (27): 185-6, 1992.
Article in English | MEDLINE | ID: mdl-1289812

ABSTRACT

Pyrimidine nucleosides (or their 5'-aldehydes) when treated with DAST give O2,5'-(fluoro)-anhydronucleosides. If this is prevented by blocking N-3 or O4, the desired 5'-deoxy-5'-(di)-fluoronucleoside is accompanied by the production of a compound resulting from migration of the base following scission of the N-1-->C-1' bond and formation of O2-->C-5'. This is a particular example of a much more general phenomenon, seen when suitably substituted ribofuranoses are treated with DAST.


Subject(s)
Diethylamines/chemistry , Fluorine/chemistry , Pyrimidine Nucleosides/chemistry , Indicators and Reagents , Nucleic Acid Conformation
6.
J Med Chem ; 34(9): 2782-6, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1654428

ABSTRACT

Starting from benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro- pentofuranoside (4), the following 2'-deoxy nucleoside analogues have been synthesized: 4'-thiothymidine (8), 3'-azido-4'-thio- deoxythymidine (10), and (E)-5-(2-bromovinyl)-4'-thio-2'-deoxyuridine (22). The first compound is toxic, the second is not toxic nor has detectable biological activity, and the third is not toxic and has significant activity against some herpesviruses.


Subject(s)
Antiviral Agents , Thionucleosides/chemical synthesis , Antiviral Agents/chemical synthesis , Cytomegalovirus/drug effects , HIV/drug effects , Thionucleosides/pharmacology
7.
Nucleic Acids Symp Ser ; (24): 1-4, 1991.
Article in English | MEDLINE | ID: mdl-1668682

ABSTRACT

A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Deoxyribonucleosides/chemistry , Thionucleosides/chemical synthesis , Thionucleosides/pharmacology , Animals , Deoxyribonucleosides/pharmacology , HIV-1/drug effects , Simplexvirus/drug effects , Vero Cells , Vesicular stomatitis Indiana virus/drug effects
8.
J Med Chem ; 33(9): 2368-75, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2391680

ABSTRACT

(E)-5-(2-Bromovinyl)-2'-deoxy-5'-O-(3-methyl-2-oxo-5-formyl-1,3,2- oxazaphosphacyclopentan-2-yl)uridine has been synthesized and, under physiological conditions and without the necessity for enzyme activity, has been shown to yield the 5'-nucleotide in vitro. Unfortunately this compound is not sufficiently stable in solution for it to be tested in vivo. The biological properties of this and some related derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine and acyclovir have been evaluated in in vitro and in vivo systems designed to show the effects of any intracellular liberation of the nucleotide. Although some of the derivatives are probably acting as prodrugs of the active nucleosides, there is no evidence for the liberation of meaningful concentrations of the 5'-nucleotide by any of the compounds.


Subject(s)
Antiviral Agents/chemical synthesis , Prodrugs/chemical synthesis , Animals , Antiviral Agents/therapeutic use , Herpes Simplex/drug therapy , Humans , Mice , Mice, Nude , Prodrugs/therapeutic use , Rabbits , Tumor Cells, Cultured/drug effects
9.
J Med Chem ; 33(9): 2488-94, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2167980

ABSTRACT

The synthesis and antiviral activity of a number of 3'-C-difluoromethyl and 3'-deoxy-3'-C-fluoromethyl nucleosides are reported. The 3'-C-difluoromethyl nucleosides 26a and 26b were obtained by treatment of the corresponding 2',5'-di-O-protected-3'-C-formyl nucleosides 25a and 25b with (diethylamino)sulfur trifluoride (DAST). Removal of the 2'-O-protecting group from 26a and subsequent reaction with DAST furnished the 2'-deoxy-2'-fluoro-beta-D-ribo-pentofuranosyl nucleoside 29. Selective fluorination with DAST of the 5'-O-protected analogues 3'-deoxy-3'-C-hydroxymethyl derivatives 13a and 13b gave the 3'-deoxy-3'-C-fluoromethyl derivatives 30a and 30b, while nonselective fluorination afforded the 2',3'-dideoxy-2'-fluoro-3'-C-fluoromethyl analogues 31a and 31b. The deprotected uracil analogue 17a was iodinated to the 5-iodouracil derivative 18. The fully deprotected fluorinated 3'-C-branched nucleosides 14-18 and 32 were evaluated for their antiviral activity. None were active against human immunodeficiency virus type-1 (HIV-1) at concentrations up to 100 microM. However, 5-iodouracil analogue 18 showed activity, comparable to that of acyclovir, against varicella zoster virus without observed cytotoxicity.


Subject(s)
Antiviral Agents/chemical synthesis , Hydrocarbons, Fluorinated/chemical synthesis , Nucleosides/chemical synthesis , Antiviral Agents/pharmacology , Chemical Phenomena , Chemistry , HIV-1/drug effects , Herpesvirus 3, Human/drug effects , Structure-Activity Relationship , Trifluridine/analogs & derivatives
10.
J Med Chem ; 33(9): 2494-501, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2167981

ABSTRACT

A series of 3'-branched-chain sugar nucleosides, in particular 3'-deoxy-3'-C-hydroxmethyl nucleosides, have been synthesized and evaluated as antiviral agents. Reaction of 1-(2,3-epoxy-5-O-trityl-beta-D-lyxo-pentofuranosyl) derivatives 12 and 13, of uracil and thymine, respectively, with 5,6-dihydro-2-lithio-5-methyl-1,3,5-dithiazine 14 afforded the corresponding 3'-functionalized nucleosides 15 and 16, respectively. Replacement of the trityl group with tertbutyldiphenylsilyl allowed high yielding hydrolysis of the 3'-function to give the 3'-deoxy-3'-C-formyl-beta-D-arabino-pentofuranosyl nucleosides 21 and 22. Desilylation afforded the 1-(3-deoxy-3-C-formyl-beta- D-lyxo-pentofuranosyl) 3',5'-O-hemiacetal nucleosides 33 and 34, respectively. Reduction of the formyl group of 21 and 22, followed by desilylation, yielded the 3'-deoxy-3'-C-(hydroxymethyl)-beta-D-arabino- pentofuranosyl) analogues 7 and 8, respectively. The uracil base moiety of 7 was converted to 5-iodouracil and then to (E)-5-(2-bromovinyl)uracil to furnish an analogue 10 of BVaraU. The 1-(3-deoxy-3-C-(hydroxymethyl)-beta-D-lyxo-pentofuranosyl) and 1-(2,3-dideoxy-3-C-(hydroxymethyl)-beta-D-erythro-pentofuranosyl) derivatives of uracil (31 and 6, respectively) and 5-iodouracil (32 and 9, respectively) were also obtained. All novel, fully deprotected nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type-1, herpes simplex virus types-1 and -2, varicella zoster virus, human cytomegalovirus and influenza A. Of the compounds tested only (E)-5-(2-bromovinyl)-1-[3-deoxy- 3-C-(hydroxymethyl)-beta-D-arabino-pentofuranosyl]uracil (10) inhibited VZV (alone), but did so at concentrations well below the cytotoxicity threshold.


Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Animals , Antiviral Agents/pharmacology , Chemical Phenomena , Chemistry , Cytomegalovirus/drug effects , HIV-1/drug effects , Simplexvirus/drug effects , Structure-Activity Relationship
12.
Biomed Mass Spectrom ; 11(10): 512-21, 1984 Oct.
Article in English | MEDLINE | ID: mdl-6518271

ABSTRACT

Metabolism of 1,1,1,2,2-pentafluorohexane with liver microsomes from phenobarbital-treated rats gave only one metabolite, namely, the 5-hydroxy derivative. Under similar conditions 1,1-difluorocyclohexane was metabolized to give mainly the 3- and 4-hydroxy derivatives in the ratio 1: approximately 5.5. The structures of these metabolites were established by chemical ionization (CI) and/or electron impact (EI) mass spectrometry and confirmed by synthesis in the case of 1,1-difluorocyclohexan-4-ol. Oxidation of 1,1-difluorocyclohexane with lead tetrakis(trifluoroacetate) also gave, inter alia, the 3- and 4-hydroxy derivatives. In saturated hydrocarbons complete replacement of hydrogen by fluorine at one particular carbon will not only block microsomal hydroxylation thereat but will also inhibit hydroxylation at neighbouring hydrogen-bearing carbons, (alpha almost completely, beta markedly, gamma slightly).


Subject(s)
Hydrocarbons, Fluorinated/metabolism , Microsomes, Liver/metabolism , Animals , Enzyme Induction/drug effects , Hydroxylation , In Vitro Techniques , Male , Microsomes, Liver/drug effects , Oxygenases/biosynthesis , Phenobarbital/pharmacology , Rats , Rats, Inbred Strains
13.
J Med Chem ; 25(11): 1329-34, 1982 Nov.
Article in English | MEDLINE | ID: mdl-6292425

ABSTRACT

The following 5-substituted 2,4-dimethoxypyrimidines were synthesized: 5-(2,2,2-trichloro-1-hydroxyethyl), 5-(2,2,2-trichloro-1-fluoroethyl),5-(2,2-dichloro-1-fluorovinyl) (5), and 5-(perfluoropropen-1-yl) (a mixture of E and Z isomers, 6 and 7). Demethylation of 5 gave 5-(2,2-dichloro-1-fluorovinyl)uracil, and demethylation of the mixture of 6 and 7 gave some pure (E)-5-(perfluoropropen-1-yl)uracil. Compound 5 was converted into its 2'-deoxyribonucleoside (12) and its alpha-anomer by standard procedures. 2'-Deoxy-3,5-dilithio-3',5'-O-bis(trimethylsilyl)uridine was reacted with the appropriate fluoroalkene to give the following 5-substituted 2'-deoxyuridines in low yield (6-24%): 5-(2-chloro-1,2-difluorovinyl) (a mixture of E and Z isomers, 15 and 16, which were separated on a small scale), 5-(perfluoropropen-1-yl), 5-(perfluorocyclohexen-1-yl), and 5-(perfluorocyclopenten-1-yl). In these reactions, 2'-deoxy-5-(trimethylsilyl)uridine and 2'-deoxyuridine were also formed. The 5-substituted 2'-deoxyuridines were tested for activity against herpes simplex virus type 1. Compound 12 and the mixture of 15 and 16 had an ID50 of 20-26 micrograms/mL in Vero cells. The activity of the mixture resided in one isomer, which by analogY with the corresponding (Z)- and (E)-5-(2-bromovinyl)-2'-deoxyuridines was concluded to be the Z isomer (16).


Subject(s)
Antiviral Agents/chemical synthesis , Deoxyuridine/analogs & derivatives , Cells, Cultured , Chemical Phenomena , Chemistry, Physical , Deoxyuridine/chemical synthesis , Deoxyuridine/pharmacology , Humans , Simplexvirus/drug effects
14.
J Med Chem ; 23(11): 1226-9, 1980 Nov.
Article in English | MEDLINE | ID: mdl-7452672

ABSTRACT

In seeking to block and thereby determine the role of the rapid in vivo hydroxylation of the cyclohexyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in relation to antitumor activity and tissue distribution, the 3-(1H-decafluorocyclohexyl) analogue (FCCNU) was synthesized. FCCNU showed marked toxicity and little activity against the intracerebral L1210 leukemia in mice. At pH 7 in phosphate buffer at room temperature FCCNU rapidly decomposed to give 1-(1H-decafluorocyclohexyl)-3-nitrosoimidazolidin-2-one (3) and thence, by loss of HF, the 1-(nonafluorocyclohexenyl) derivative (4); CCNU did not follow this decomposition pathway to any significant extent. Both 3 and 4 were unstable in the buffer, but each was isolated crystalline and characterized. The formation of 3 and 4 account for the biological properties of FCCNU.


Subject(s)
Antineoplastic Agents/chemical synthesis , Lomustine/chemical synthesis , Nitrosourea Compounds/chemical synthesis , Animals , Antineoplastic Agents/metabolism , Female , Leukemia L1210/drug therapy , Lomustine/analogs & derivatives , Lomustine/metabolism , Lymphoma/drug therapy , Mice , Neoplasms, Experimental/drug therapy
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