RESUMEN
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Asunto(s)
Antineoplásicos/química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Pirimidinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/toxicidad , Línea Celular , Farmacorresistencia Viral , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , Mutación , Pirimidinas/farmacología , Pirimidinas/toxicidad , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/toxicidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HeLa , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Pirimidinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
R207910 is an enantiomeric compound from a new class of antimycobacterial agents, the diarylquinolines [Science; 307:223 (2005)]. As enantiospecific interaction is required for biologic activity, we have undertaken a combined nuclear magnetic resonance and molecular modeling study to gain new insights into its conformation in solution and its absolute configuration. A conformational analysis using a Monte-Carlo method has been performed on each of the four possible stereomers of this compound leading to the identification of their most stable conformation. Additional ab initio calculation was performed with emphasis on the strength of the observed intramolecular hydrogen bond. Simultaneously, a complete structural identification has been carried out by a set of monodimensional and bidimensional (1)H-(13)C-NMR experiments. Determination of inter-proton distances has been achieved by a series of (1)H-(1)H ROESY NMR experiments with different mixing times followed by a volume quantification of the correlations peaks. These experimental data were compared with the theoretical distances obtained from the conformational analysis. The remarkable match shows that R207910 adopts one of the low-energy conformations predicted by molecular modeling and belongs to the (RS, SR) couple of diastereoisomers. A posteriori validation of our approach has been performed by X-ray structure determination that concluded for the RS configuration.