RESUMEN
The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23⯰C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.
Asunto(s)
Antioxidantes/farmacología , Ciclobutanos/farmacología , Descubrimiento de Drogas , Isotiocianatos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacocinética , Línea Celular , Ciclobutanos/síntesis química , Ciclobutanos/farmacocinética , Expresión Génica , Hemo-Oxigenasa 1/genética , Humanos , Isotiocianatos/síntesis química , Isotiocianatos/farmacocinética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones Endogámicos C57BL , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Ratas , Solubilidad , Relación Estructura-Actividad , Sulfóxidos , Tiocarbamatos/síntesis química , Tiocarbamatos/farmacocinética , Tiocarbamatos/farmacologíaRESUMEN
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Asunto(s)
Acetatos/farmacología , Oxazoles/química , PPAR alfa/agonistas , PPAR gamma/agonistas , Acetatos/administración & dosificación , Acetatos/síntesis química , Administración Oral , Animales , Glucemia/efectos de los fármacos , HDL-Colesterol/sangre , HDL-Colesterol/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ligandos , Ratones , Ratones Mutantes , Ratones Obesos , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Relación Estructura-Actividad , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
[reaction: see text] Halogenation of achiral trans-2-pyridone photodimers results in 1,3-migration of an amide nitrogen and formation of a chiral structure with six stereogenic centers and well-differentiated functionality. The reactivity of this product toward nucleophiles, including the allylic halide, is dominated by participation by the amide nitrogen.
Asunto(s)
Amidas/química , Hidrocarburos Clorados/química , Piridonas/química , Estructura Molecular , Fotoquímica , EstereoisomerismoRESUMEN
A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.
