RESUMO
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.
Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pirazóis/química , Piridinas/química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Nucleosídeos/química , Pirazóis/síntese química , Piridinas/síntese química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Nucleosídeos/síntese química , Pirazóis/química , Pirimidinas/química , Animais , Antivirais/farmacologia , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Testes de Sensibilidade Microbiana , Nucleosídeos/química , Pirazóis/farmacologia , Pirimidinas/farmacologia , Células Tumorais Cultivadas , Células VeroRESUMO
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.
Assuntos
Nucleosídeos/química , Nucleosídeos/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , HIV/metabolismo , Humanos , Modelos Químicos , Nucleosídeos/síntese química , Pirimidinas/síntese química , TemperaturaRESUMO
The synthesis of 1-[1-(4-hydroxybutyl)-1,2,3-triazol-(4 and 5)-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidines 11a,b, 12a,b and 13-17 as carboacyclic nucleosides is described. The compounds 8a,b were condensed, separately, with compound 7 via 1,3-dipolar cycloaddition reaction to afford, after separation and deprotection. 1,4-regioisomers 11a,b and 1,5-regioisomers 12a,b. The deprotected carboacyclic nucleosides 11a served as precursor for the preparation of 4-amino 13. 4-methylamino 14, 4-benzylamino 15, 4-methoxy 16 and 4-hydroxy 17 analogues. All deprotected carboacyclic nucleosides were evaluated for their inhibitory effects against the replication of HIV-1(III), HIV-2(ROD), various DNA viruses, a variety of tumor-cell lines and tuberculosis. No marked biological activity was found.
Assuntos
Nucleosídeos/química , Nucleosídeos/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , Fibroblastos/metabolismo , HIV/metabolismo , Células HeLa , Humanos , Modelos Químicos , Nucleosídeos/síntese química , Pirimidinas/síntese química , Temperatura , Células Tumorais CultivadasRESUMO
The synthesis of some acyclic alpha-(pyrazolo[3,4-d]pyrimidin-4-ylthio)alkylamide nucleosides is described.