RESUMEN
Lysine methyltransferases are important regulators of epigenetic signaling and are emerging as a novel drug target for drug discovery. This work demonstrates the positioning of novel 1,5-oxaza spiroquinone scaffold into selective SET and MYND domain-containing proteins 2 methyltransferases inhibitors. Selectivity of the scaffold was identified by epigenetic target screening followed by SAR study for the scaffold. The optimization was performed iteratively by two-step optimization consisting of iterative synthesis and computational studies (docking, metadynamics simulations). Computational binding studies guided the important interactions of the spiro[5.5]undeca scaffold in pocket 1 and Lysine channel and suggested extension of tail length for the improvement of potency (IC50: up to 399 nM). The effective performance of cell proliferation assay for chosen compounds (IC50: up to 11.9 nM) led to further evaluation in xenograft assay. The potent compound 24 demonstrated desirable in vivo efficacy with growth inhibition rate of 77.7% (4 fold decrease of tumor weight and 3 fold decrease of tumor volume). Moreover, mirosomal assay and pharmacokinetic profile suggested further developability of this scaffold through the identification of major metabolites (dealkylation at silyl group, reversible hydration product, the absence of toxic quinone fragments) and enough exposure of the testing compound 24 in plasma. Such spiro[5.5]undeca framework or ring system was neither been reported nor suggested as a modulator of methyltransferases. The chemo-centric target positioning and structural novelty can lead to potential pharmacological benefit.
Asunto(s)
Compuestos Aza/farmacología , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Quinonas/farmacología , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Aza/síntesis química , Compuestos Aza/química , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Epigénesis Genética/genética , Femenino , Células HEK293 , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinonas/síntesis química , Quinonas/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
The cycloisomerization of 1,8-enynes in the presence of platinum(II) chloride was developed to generate bicyclic nitrogen-containing heterocycle species via 6- endo-dig cyclization and [3,3]-sigmatropic rearrangement in acceptable to good yields. The related control experiments and preliminary mechanistic studies indicate a plausible mechanism involving 1,6- endo-dig aminoplatination of the alkyne and allylic [3,3]-sigmatropic rearrangement with total inversion of the allylic moiety.
RESUMEN
The 1:1 zwitterionic intermediates obtained from the reaction between isoquinoline, quinoline, pyridine, or N-methylimidazole with activated acetylenes are trapped by ethyl pyruvate to produce highly functionalized fused [1,3]oxazines in good yields.