RESUMO
Although the copolymerizations of l-lactide (LA) with seven- or six-membered ring lactones have been extensively studied, the copolymerizations of LA with four-membered ring lactones have scarcely been reported. In this work, we studied the copolymerization of LA with ß-propiolactone (PL) and the properties of the obtained copolymers. The copolymerization of LA with PL was carried out using trifluoromethanesulfonic acid as a catalyst and methanol as an initiator to produce poly(LA-co-PL) with Mn of ~50,000 and PL-content of 6-67 mol %. The Tg values of the copolymers were rapidly lowered with increasing PL-contents. The Tm and ΔHm of the copolymers gradually decreased with increasing PL-contents, indicating their decreased crystallinity. Biodegradation test of the copolymers in compost demonstrated their improved biodegradability in comparison with the homopolymer of LA.
Assuntos
Biodegradação Ambiental , Dioxanos/síntese química , Dioxanos/metabolismo , Polímeros/síntese química , Polímeros/metabolismo , Propiolactona/síntese química , Propiolactona/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Catálise , Lactonas/metabolismo , Teste de Materiais , Peso Molecular , Polimerização , Polímeros/química , TemperaturaRESUMO
Cycles of depalmitoylation and repalmitoylation critically control the steady-state localization and function of various peripheral membrane proteins, such as Ras proto-oncogene products. Interference with acylation using small molecules is a strategy to modulate cellular localization--and thereby unregulated signaling--caused by palmitoylated Ras proteins. We present the knowledge-based development and characterization of a potent inhibitor of acyl protein thioesterase 1 (APT1), a bona fide depalmitoylating enzyme that is, so far, poorly characterized in cells. The inhibitor, palmostatin B, perturbs the cellular acylation cycle at the level of depalmitoylation and thereby causes a loss of the precise steady-state localization of palmitoylated Ras. As a consequence, palmostatin B induces partial phenotypic reversion in oncogenic HRasG12V-transformed fibroblasts. We identify APT1 as one of the thioesterases in the acylation cycle and show that this protein is a cellular target of the inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Propiolactona/análogos & derivados , Tioléster Hidrolases/antagonistas & inibidores , Tioléster Hidrolases/química , Proteínas ras/fisiologia , Animais , Linhagem Celular , Cães , Regulação para Baixo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Rim/efeitos dos fármacos , Rim/fisiologia , Ligantes , Lipase/química , Lipase/metabolismo , Lipoilação/efeitos dos fármacos , Modelos Moleculares , Propiolactona/síntese química , Propiolactona/química , Propiolactona/farmacologia , Conformação Proteica , Proto-Oncogene Mas , Transdução de Sinais , Estômago/enzimologia , Tioléster Hidrolases/genética , Proteínas ras/efeitos dos fármacos , Proteínas ras/metabolismoRESUMO
Although inhibitors of the enzymatic hydrolysis of the endocannabinoid 2-arachidonoylglycerol are available, they are either rather weak in vitro (IC(50)>30 microM) or their selectivity towards other proteins of the endocannabinoid system has not been tested. Here we describe the synthesis and activity in vitro and in vivo of a tetrahydrolipstatin analogue, OMDM169, as a potent inhibitor of 2-AG hydrolysis, capable of enhancing 2-AG levels and of exerting analgesic activity via indirect activation of cannabinoid receptors. OMDM169 exhibited 0.13 microM
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Ácidos Araquidônicos/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Formamidas/síntese química , Formamidas/farmacologia , Glicerídeos/antagonistas & inibidores , Propiolactona/análogos & derivados , Animais , Ácidos Araquidônicos/metabolismo , Células COS , Chlorocebus aethiops , Endocanabinoides , Glicerídeos/metabolismo , Humanos , Hidrólise/efeitos dos fármacos , Concentração Inibidora 50 , Lipase Lipoproteica/metabolismo , Camundongos , Monoacilglicerol Lipases/metabolismo , Propiolactona/síntese química , Propiolactona/farmacologia , RatosRESUMO
Spray dried vaccine formulations might be an alternative to traditional lyophilized vaccines. Compared to lyophilization, spray drying is a fast and cheap process extensively used for drying biologicals. The current study provides an approach that utilizes Design of Experiments for spray drying process to stabilize whole inactivated influenza virus (WIV) vaccine. The approach included systematically screening and optimizing the spray drying process variables, determining the desired process parameters and predicting product quality parameters. The process parameters inlet air temperature, nozzle gas flow rate and feed flow rate and their effect on WIV vaccine powder characteristics such as particle size, residual moisture content (RMC) and powder yield were investigated. Vaccine powders with a broad range of physical characteristics (RMC 1.2-4.9%, particle size 2.4-8.5µm and powder yield 42-82%) were obtained. WIV showed no significant loss in antigenicity as revealed by hemagglutination test. Furthermore, descriptive models generated by DoE software could be used to determine and select (set) spray drying process parameter. This was used to generate a dried WIV powder with predefined (predicted) characteristics. Moreover, the spray dried vaccine powders retained their antigenic stability even after storage for 3 months at 60°C. The approach used here enabled the generation of a thermostable, antigenic WIV vaccine powder with desired physical characteristics that could be potentially used for pulmonary administration.
Assuntos
Química Farmacêutica/métodos , Vírus da Influenza A , Vacinas contra Influenza/síntese química , Propiolactona/síntese química , Previsões , Vacinas de Produtos Inativados/síntese químicaRESUMO
To mimic the folded side chain conformation of 1233A (1), which is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase inhibitor, 1233A analogs with aromatic rings in the side chain were synthesized. The 2-oxetanone moiety was kept intact. Among 1233A and its synthetic analogs, trans-3-hydroxymethyl-4-[2-(7-methoxycarbonyl-1-naphthyl)ethyl]-2-oxe tanone (23) showed the highest HMG-CoA synthase inhibitory activity in vitro. The structure-activity relationship at the side chain is discussed.
Assuntos
Ácidos Graxos Insaturados/síntese química , Hidroximetilglutaril-CoA Sintase/antagonistas & inibidores , Lactonas/síntese química , Propiolactona/análogos & derivados , Propiolactona/síntese química , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Ácidos Graxos Insaturados/farmacologia , Lactonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Propiolactona/farmacologia , Relação Estrutura-AtividadeRESUMO
Isosteric side chain analogs of 3a were synthesized and tested for inhibitory activities towards 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and upon cholesterol production in Hep G2 cells and in mouse liver. It became clear that the lipophilic substituent on the aromatic ring and the terminal hydrophilic group in the side chain were important in the enhancement of activity. 4-[2-(3-n-Hexyloxyphenyl)ethyl]-3-hydroxy-methyl-2-oxetanone (5a) showed equivalent inhibitory activity in vivo to that of 1233A.