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1.
Acta Pharmacol Sin ; 43(1): 76-85, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34480112

RESUMO

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients. Myeloid differentiation 2 (MD2), a co-receptor of toll like receptor 4 (TLR4), plays an important role in LPS-induced ALI in mice. Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models, MD2 has become an attractive target for the treatment of ALI. In this study we identified two chalcone-derived compounds, 7w and 7x, as new MD2 inhibitors, and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model. In molecular docking analysis we found that 7w and 7x, formed pi-pi stacking interactions with Phe151 residue of the MD2 protein. The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 µM, respectively) and by bis-ANS displacement assay. 7w and 7x (2.5, 10 µM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation. In mouse peritoneal macrophages, 7w and 7x (1.25-10 µM) dose-dependently inhibited LPS-induced inflammatory responses, MAPKs (JNK, ERK and P38) phosphorylation as well as NF-κB activation. Finally, oral administration of 7w or 7x (10 mg ·kg-1 per day, for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury, pulmonary edema, lung permeability, inflammatory cells infiltration, inflammatory cytokines expression and MD2/TLR4 complex formation. In summary, we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo, proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Chalconas/farmacologia , Inflamação/tratamento farmacológico , Antígeno 96 de Linfócito/antagonistas & inibidores , Lesão Pulmonar Aguda/induzido quimicamente , Administração Oral , Animais , Células Cultivadas , Chalconas/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Antígeno 96 de Linfócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo
2.
Org Biomol Chem ; 9(10): 3817-24, 2011 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-21445440

RESUMO

A concise enantioselective synthesis of malyngamide W (1) and its 2'-epimer was described. The strategy was based on three key steps: (1) ozonolysis of compound 11 which was derived from (R)-(-)-carvone 8, followed by copper-iron-catalyzed rearrangement to give the key cyclohex-2-enone intermediate 5, (2) Nozaki-Hiyama-Kishi coupling reaction between aldehyde 4 and iodide 14 to afford alcohol 3, and (3) asymmetric (R)-CBS reduction of the ketone functionality in compound 21 to establish the C-2' chiral center in the target compound 1. The absolute configuration of malyngamide W (1) was thus confirmed via the synthesis of 1 and 2'-epi-1.


Assuntos
Cicloexanonas/química , Cicloexanonas/síntese química , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/síntese química , Oxirredução , Estereoisomerismo , Especificidade por Substrato
3.
Neuropeptides ; 43(4): 259-65, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19573913

RESUMO

Our previous study has pointed that arginine vasopressin (AVP) and norepinephrine (NA) are two most important bioactive substances that play a role in hypothalamic paraventricular nucleus (PVN) regulating pain process. The communication was designed to investigate the interaction between AVP and NA in the rat PVN during the pain process. We used the potassium iontophoresis inducing tail-flick to test the pain threshold, PVN push-pull perfusion to collect the samples, high performance chromatography (HPLC) to determine the NA concentration and radioimmunoassay (RIA) to measure the AVP concentration. The results showed that (1) pain stimulation increased both NA and AVP concentrations in the PVN perfusion liquid; (2) PVN administration of l-glutamate sodium increased AVP, not NA concentration in the PVN perfusion liquid; (3) AVP or d(CH(2))(5)Tyr(Et)DAVP (AVP-receptor antagonist) neither changed pain threshold, nor influenced NA concentration in the PVN perfusion liquid; (4) Microinjection of NA into PVN could increase pain threshold in a dose-dependent manner, while PVN administration with phentolamine (alpha-receptor antagonist), not propranolol (beta-receptor antagonist) decreased pain threshold; (5) Administration of NA increased AVP concentration, while phentolamine, not propranolol decreased AVP concentration in the PVN perfusion liquid. These data suggested that it is through alpha-receptor rather than beta-receptor, NA induced PVN secretion of AVP that was delivered to the related brain regions to participate in pain modulation.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Arginina Vasopressina/metabolismo , Norepinefrina/farmacologia , Limiar da Dor/efeitos dos fármacos , Dor/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Antagonistas Adrenérgicos/farmacologia , Animais , Iontoforese , Masculino , Medição da Dor , Núcleo Hipotalâmico Paraventricular/citologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley
4.
J Org Chem ; 73(17): 6873-6, 2008 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-18656980

RESUMO

An accelerated and improved asymmetric synthesis of malyngamide U (1) and its 2'-epimer (2'-epi-1) was accomplished from readily available n-hexanal, ethanolamine and (R)-(-)-carvone. The key steps involved a Johnson-Claisen rearrangement in the synthesis of an unsaturated carboxylic acid 4 and an aldol reaction in the construction of the skeleton of 1 and 2'-epi-1. There are 13 steps in the synthesis, with a 2.7% overall yield for 1 and a 0.4% yield for 2'-epi-1.


Assuntos
Aldeídos/química , Ácidos Carboxílicos/química , Cicloexanonas/síntese química , Etanolamina/química , Ácidos Graxos Monoinsaturados/síntese química , Monoterpenos/química , Álcoois/química , Monoterpenos Cicloexânicos , Modelos Químicos
5.
J Org Chem ; 72(7): 2344-50, 2007 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-17346080

RESUMO

The enantioselective synthesis of the previously proposed structure of malyngamide U (1) was accomplished in 18 steps from (S)-(+)-carvone. The key steps involved a hydroxymethylation of (S)-(+)-carvone and an asymmetric Henry reaction of aldehyde (+)-5, as well as condensation with the acid 3. The 1H and 13C NMR data of the synthetic compound 1 were not consistent with the data of the reported malyngamide U. The C-2' epimer of compound 1 was therefore synthesized by a similar reaction sequence. While the NMR data of C-2' epimer 23 were in full agreement with those of the reported product, the discrepancy in the specific rotation data suggested the correct structure of malyngamide U should be structure 2, in which the absolute configuration of the amine part was enantiomeric with that in compound 23. Then the correct absolute configuration of revised malyngamide U (2) was confirmed by the similar synthesis from (R)-(-)-carvone.


Assuntos
Cicloexanonas/síntese química , Ácidos Graxos Monoinsaturados/síntese química , Álcoois/química , Aldeídos/química , Cicloexanonas/química , Ácidos Graxos Monoinsaturados/química , Estrutura Molecular
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