RESUMO
A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD50 = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Fenantrenos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/toxicidade , Desenho de Fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/uso terapêutico , Compostos de Epóxi/toxicidade , Feminino , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/toxicidade , Fenantrenos/síntese química , Fenantrenos/toxicidade , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment. Here, we test a newly developed selective S1P1 modulator, Syl930, in four different psoriasis animal models. Our data reveals that oral administration of Syl930 can induce strong anti-proliferative and anti-inflammatory effects. Specifically, Syl930 decreases the pathological thickening of back skin induced by sodium lauryl sulfate (SLS), inhibits the proliferation of basal cells in a vaginal epithelium model and increases the granular layer scales in a mouse tail assay. Moreover, Syl930 can ameliorate the parakeratosis and acanthosis as well as improve granular layer composition and decrease the thickening of epidermis in a propranolol-induced guinea pig psoriasis model. Therefore, we demonstrate that Syl930 is a promising candidate for psoriasis therapy in clinical.