RESUMO
The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.
Assuntos
Aurora Quinase A/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirimidinas/química , Animais , Aurora Quinase A/metabolismo , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Total synthesis of the proposed structure of (±)-nidemone has been accomplished either from 2-hydroxy-6-methoxybenzaldehyde (7) or 2-bromo-6-methoxybenzaldehyde (8) in 10 and 13 synthetic steps, respectively. Sonogashira coupling, regioselective hydrogenation, and an intramolecular Stetter reaction were the key steps in the synthesis.
RESUMO
Centella asiatica (CA) is a traditional herbal medicine that has been shown to exert pharmacological effects on wound healing. This study demonstrated that CA extract facilitates the wound-repair process by promoting fibroblast proliferation and collagen synthesis and exhibits antibacterial activity. Gelatin nanofibres containing C. asiatica extract were fabricated via electrospinning and were shown to exhibit dermal wound-healing activity in a rat model. The wound areas of rat skin treated with electrospun gelatin membranes containing C. asiatica (EGC) presented the highest recovery rate compared with those treated with gauze, neat gelatin membranes and commercial wound dressings. The results of the histopathological examination support the outcome of the wound models. Contact-angle and water-retention measurements confirmed that the addition of C. asiatica extract did not significantly affect the hydrophilicity of the EGC membranes. The measured weight loss revealed that the EGC membranes are biodegradable. The findings suggest that EGC membranes are a promising material for the treatment of skin wounds. Copyright © 2015 John Wiley & Sons, Ltd.
