Assuntos
Carcinoma de Células Escamosas , Ácidos Graxos Ômega-3 , Neoplasias Cutâneas , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Humanos , Instabilidade de Microssatélites , Repetições de Microssatélites , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genéticaRESUMO
We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of (R)-azetidine-2-carboxamide analogues that have sub-micromolar potencies. 5a, 5o, and 8i have STAT3-inhibitory potencies (IC50) of 0.55, 0.38, and 0.34 µM, respectively, compared to potencies greater than 18 µM against STAT1 or STAT5 activity. Further modifications derived analogues, including 7e, 7f, 7g, and 9k, that addressed cell membrane permeability and other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with KD of 880 nM (7g) and 960 nM (9k). 7g and 9k inhibited constitutive STAT3 phosphorylation and DNA-binding activity in human breast cancer, MDA-MB-231 or MDA-MB-468 cells. Furthermore, treatment of breast cancer cells with 7e, 7f, 7g, or 9k inhibited viable cells, with an EC50 of 0.9-1.9 µM, cell growth, and colony survival, and induced apoptosis while having relatively weaker effects on normal breast epithelial, MCF-10A or breast cancer, MCF-7 cells that do not harbor constitutively active STAT3.
Assuntos
Azetidinas/química , Fator de Transcrição STAT3/antagonistas & inibidores , Amidas/química , Apoptose/efeitos dos fármacos , Azetidinas/metabolismo , Azetidinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Fosforilação/efeitos dos fármacos , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-AtividadeRESUMO
The volatility of an alarm pheromone in male rats. PHYSIOL BEHAV 00(0) 000-000, 2008. We previously reported that an alarm pheromone released from the perianal region of male rats is perceived by the vomeronasal organ and evokes stress-induced hyperthermia and defensive and risk assessment behavior. In addition, we recently reported that the alarm pheromone enhances the acoustic startle reflex (ASR). However, in contrast to our knowledge about such biological aspects of the pheromone, information concerning the physical character of the alarm pheromone is extremely limited. In this study, we investigated the volatility of the alarm pheromone using enhancement of the ASR as an index of the pheromone effect. The alarm pheromone enhanced the ASR when it was presented at a distance of 10 mm but not at 200 mm. In addition, the pheromone effect was observed even after the pheromone was trapped in the adsorbent (Tenax) and then extracted using purified water. These results suggest that the alarm pheromone is both volatile and water soluble.