RESUMO
The objective of this research study is to develop novel composite nanofibers based on methacrylamide chitosan (ChMA)/poly(ε-caprolactone) (PCL) materials by the dual crosslinking and coaxial-electrospinning strategies. The prepared ChMA/PCL composite nanofibers can sequentially deliver tannic acid and curcumin drugs to synergistically inhibit bacterial reproduction and accelerate wound healing. The rapid delivery of tannic acid is expected to inhibit pathogenic microorganisms and accelerate epithelialization in the early stage, while the slow and sustained release of curcumin is with the aim of relieving chronic inflammatory response and inducing dermal tissue maturation in the late stage. Meanwhile, dual-drugs sequentially released from the membrane exhibited a DPPH free radical scavenging rate of ca. 95 % and an antibacterial rate of above 85 %. Moreover, the membrane possessed great biocompatibility in vitro and significantly inhibited the release of pro-inflammatory factors (IL-1ß and TNF-α) in vivo. Animal experiments showed that the composite membrane by means of the synergistic effect of polyphenol drugs and ChMA nanofibers, could significantly alleviate macrophage infiltration and accelerate the healing process of wounds. From the above, the as-prepared ChMA-based membrane with a stage-wise release pattern of drugs could be a promising bioengineered construct for wound healing application.
Assuntos
Quitosana , Curcumina , Nanofibras , Animais , Quitosana/química , Nanofibras/química , Curcumina/farmacologia , Curcumina/química , Preparações Farmacêuticas , Cicatrização , Poliésteres/química , Antibacterianos/farmacologiaRESUMO
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirróis/síntese química , Quinases Ativadas por p21/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cristalografia por Raios X , Cães , Humanos , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Conformação Molecular , Permeabilidade , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pteridinas/química , Pteridinas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Humanos , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/administração & dosagem , Pteridinas/farmacologia , Solubilidade , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismoRESUMO
Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43-50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1' group in the S1' and S3' sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1' group as IK682. Using this TACE-selective P1' group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Modelos Moleculares , Proteínas ADAM/química , Proteína ADAM17 , Sítios de Ligação , Humanos , Hidantoínas/química , Hidantoínas/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Lactamas/química , Lactamas/farmacologia , Conformação Molecular , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Zinco/químicaRESUMO
A series of novel hydantoins was designed and synthesized as structural alternatives to hydroxamate inhibitors of TACE. 5-Mono- and di-substituted hydantoins exhibited activity with IC50 values of 11-60 nM against porcine TACE in vitro and excellent selectivity against other MMPs.