RESUMO
Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.
Assuntos
Desenho de Fármacos , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Psoríase/tratamento farmacológico , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Células CACO-2 , Domínio Catalítico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/farmacocinética , Tetra-Hidroisoquinolinas/uso terapêutico , Distribuição TecidualRESUMO
A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[1,2-b]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa, 4bq, and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60-85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db/db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC50 > 10 µM).
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Ativadores de Enzimas/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Ativadores de Enzimas/farmacocinética , Hipoglicemiantes/síntese química , Isoquinolinas/farmacocinética , Camundongos , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells.