ABSTRACT
1-(2-Fluoro-2-deoxy-beta-D-drabinofuranosyl) uracil (5) and 1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)cytosine (6) were synthesized as reported earlier. Both of these compounds were converted into 2'-fluoro-2'-deoxy-3'-C-ethynyl and 3'-C-vinyl-beta-D-lyxofuranosyl nuclearsides (16-19) by a multistep sequence. All these new nucleosides were evaluated against seven human tumor cell lines in vitro.
Subject(s)
Arabinonucleotides/chemistry , Pyrimidine Nucleosides/chemistry , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Cytosine/chemistry , Drug Design , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Models, ChemicalABSTRACT
The chemical synthesis and biological evaluation of some acyclic alpha-[6-(1'-carbamoylalkylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylamide nucleosides are described.
Subject(s)
Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Pyrazoles/chemistry , Pyridines/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cell Survival/drug effects , Cytomegalovirus/drug effects , Herpesvirus 3, Human/drug effects , Humans , Indicators and Reagents , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/drug effects , Nucleosides/chemistry , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The chemical synthesis of some acyclic alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10-12)a-c is described. The treatment of IH-pyrazolo[3,4-d]pyrimidin-4-thione 1 with compounds 2a-c gave, regioselectively, ethyl alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylates 3a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 4, 5 and 6 to give, regioselectively, the N1-acyclic nucleosides (7-9)a-c which were deprotected to afford the desired products (10-12)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The products (10-12)a-c were evaluated for their inhibitory effects against the replication of HIV-1 (III(B)), HIV-2 (ROD), various DNA viruses, a variety of tumor-cell lines and M. tuberculosis. No marked biological activity was found.
Subject(s)
Nucleosides/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemistry , Animals , Antiviral Agents/pharmacology , Chlorocebus aethiops , Drug Screening Assays, Antitumor , Microbial Sensitivity Tests , Nucleosides/chemistry , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Tumor Cells, Cultured , Vero CellsABSTRACT
The chemical synthesis of some 4-substituted 1-[1-(2-hydroxyethoxy)-methyl-1,2.3-triazol-(4 and 5)-ylmethyl]-1-H-pyrazolo[3,4-d]pyrimidines 12a,b, 13a,b and 14-23 as acyclic nucleosides is described. Treatment of (2-acetoxyethoxy)methylbromide with sodium azide afforded (2-acetoxyethoxy)methylazide 9. The heterocycles 6a,b were alkylated, separately, with propargyl bromide to obtain. regioselectively, 4-(methyl and benzyl)thio-1-(prop-2-ynyl)-1H-pyrazolo[3,4-d]pyrimidines 7a,b. These N-alkylated products were condensed with compound 9 via a 1,3-dipolar cycloaddition reaction to obtain, after separation and deprotection, 1,4- and 1,5-regioisomers 12a,b and 13a,b. The deprotected acyclic nucleosides 12a and 13a served as precursors for the preparation of 4-amino (14 and 15), 4-methylamino (16 and 17). 4-benzylamino (18 and 19), 4-methoxy (20 and 21) and 4-hydroxy (22 and 23) analogues. Compounds 7a,b and all deprotected acyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-(IIIB) and HIV-2(ROD) in MT-4 cells and for their anti-tumor activity. No marked activity was found. However, initial evaluation of 6a,b, 7a,b. 12a,b, 13a,b and 14-23 showed that compound 7b has marked activity against M. tuberculosis.
Subject(s)
Nucleosides/chemistry , Nucleosides/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cell Line , HIV/metabolism , Humans , Models, Chemical , Nucleosides/chemical synthesis , Pyrimidines/chemical synthesis , TemperatureABSTRACT
The synthesis of some acyclic alpha-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides is described.
