RESUMEN
The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of O(6)-methylguanine and S(6)-methylthioguanine are described. The crystal structures and pK(a) values of these analogues are reported. In a standard substrate assay with the human repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.
Asunto(s)
Guanina/análogos & derivados , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Guanina/síntesis química , Guanina/química , Guanina/farmacología , Humanos , Técnicas In Vitro , Cinética , Estructura Molecular , O(6)-Metilguanina-ADN Metiltransferasa/antagonistas & inhibidoresRESUMEN
The stereospecific synthesis of (-)-neplanocin F was achieved in 15 steps from 2,3-O-isopropylidene-D-1,4-ribonolactone. The synthetic methodology can give an access through appropriate modifications to new series of carbanucleosides.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/química , Métodos , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , EstereoisomerismoRESUMEN
The syntheses of novel tricyclic pyrrolo[2,3-d]pyrimidine analogues of S6-methylthioguanine are described. The crystal structures and pKa values of these and related O6-methylguanine analogues are reported. All compounds display higher pKa values than O6-methylguanine with the sulfur-containing analogues being the more basic and exhibiting higher stability in aqueous solution. In a standard substrate assay with the human repair protein O6-methylguanine-DNA methyltransferase (MGMT) only the oxygen-containing analogue displayed activity.
Asunto(s)
Guanina/análogos & derivados , Pirimidinas/síntesis química , Pirroles/síntesis química , Tioguanina/análogos & derivados , Cristalografía por Rayos X , Guanina/síntesis química , Guanina/química , Guanina/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Estructura Molecular , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Especificidad por Sustrato , Tioguanina/síntesis química , Tioguanina/química , Tioguanina/metabolismoRESUMEN
The syntheses of the novel pyrrolo[2,3-d]pyrimidine-based heterocycles as tricyclic analogues of O6-methylguanine are described. Compound 5 is a weak inhibitor of human O6-alkylguanine DNA alkyltransferase.
