RESUMO
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.
Assuntos
Antioxidantes/farmacologia , Ciclobutanos/farmacologia , Descoberta de Drogas , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Linhagem Celular , Ciclobutanos/síntese química , Ciclobutanos/farmacocinética , Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Isotiocianatos/síntese química , Isotiocianatos/farmacocinética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos Endogâmicos C57BL , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfóxidos , Tiocarbamatos/síntese química , Tiocarbamatos/farmacocinética , Tiocarbamatos/farmacologiaRESUMO
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Assuntos
Acetatos/farmacologia , Oxazóis/química , PPAR alfa/agonistas , PPAR gama/agonistas , Acetatos/administração & dosagem , Acetatos/síntese química , Administração Oral , Animais , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ligantes , Camundongos , Camundongos Mutantes , Camundongos Obesos , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Relação Estrutura-Atividade , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
[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.
Assuntos
Amidas/química , Hidrocarbonetos Clorados/química , Piridonas/química , Estrutura Molecular , Fotoquímica , EstereoisomerismoRESUMO
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.
