RESUMEN
2-Amino-4,6-bis[(phosphonomethoxy)alkoxy]pyrimidines bearing two equal or different achiral or chiral phosphonoalkoxy chains have been prepared either by aromatic nucleophilic substitution of 2-amino-4,6-dichloropyrimidine or by alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine with appropriate phosphonate-bearing building block. Alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine proved to be the method of choice for efficient preparation of variety of bisphosphonates. The enantiomeric purity of selected compounds was determined by capillary electrophoresis. Antiviral activity of bisphosphonates is discussed.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Difosfonatos/síntesis química , Difosfonatos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Alquilación , Animales , Antivirales/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Difosfonatos/química , Ensayos de Selección de Medicamentos Antitumorales , Electroforesis Capilar , Células HL-60 , Células HeLa , Humanos , Ratones , Estructura Molecular , Nucleósidos/química , Pirimidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
2-Amino-3-(purin-9-yl)propanoic acids substituted at position 6 of the purine base moiety by dimethylamino, cyclopropylamino, pyrrolidin-1-yl, hydroxy, and sulfanyl group as well as their 2-aminopurine analogues were prepared from corresponding 9-(2,2-diethoxyethyl)purines and 2-aminopurines, respectively, by the Strecker synthesis. 2-Aminopropanoic acid derivatives were tested for their immunostimulatory and immunomodulatory potency. Some of these compounds significantly enhanced secretion of chemokines RANTES and MIP-1alpha, the most potent was 2-amino-6-sulfanylpurine derivative. Most of these compounds also augmented NO biosynthesis triggered primarily by IFN-gamma.
Asunto(s)
Propionatos/síntesis química , Propionatos/farmacología , Animales , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Femenino , Pruebas Inmunológicas , Interferón gamma/farmacología , Proteínas Inflamatorias de Macrófagos/inmunología , Proteínas Inflamatorias de Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Óxido Nítrico/biosíntesis , Propionatos/inmunología , Relación Estructura-ActividadRESUMEN
Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N6-substituted adenines (5a-5c) and 2,6-diaminopurines (5d-5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8-10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).
