RESUMO
Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.
Assuntos
Doenças Autoimunes , COVID-19 , Humanos , Inibidores de Interleucina-6 , Simulação de Acoplamento Molecular , Doenças Autoimunes/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Interleucina-6 , Relação Estrutura-AtividadeRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder that causes uncontrollable movements. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, and only trials to relieve symptoms have been evaluated. Recently, we reported the total synthesis of cudraisoflavone J and its chiral isomers [Lu et al., J. Nat. Prod. 2021, 84, 1359]. In this study, we designed and synthesized a series of novel cudraisoflavone J derivatives and evaluated their neuroprotective activities in neurotoxin-treated PC12 cells. Among these compounds, difluoro-substituted derivative (13m) and prenylated derivative (24) provided significant protection to PC12 cells against toxicity induced by 6-hydroxydopamine (6-OHDA) or rotenone. Both derivatives inhibited 6-OHDA- or rotenone-induced production of reactive oxygen species and partially attenuated lipid peroxidation in rat brain homogenates, indicating their antioxidant properties. They also increased the expression of the antioxidant enzyme, heme oxygenase (HO)-1, and enhanced the nuclear translocation of Nrf2, the transcription factor that regulates the expression of antioxidant proteins. The neuroprotective effects of 13m and 24 were eliminated by Zn(II)-protoporphyrin IX, an HO-1 inhibitor, demonstrating the critical role of HO-1 in their actions. Moreover, upregulation of HO-1 was abolished by nuclear factor erythroid 2-related factor (Nrf2) knockdown, verifying that Nrf2 is an upstream regulator of HO-1. Compounds 13m and 24 triggered phosphorylation of ERK1/2, JNK, and Akt. Most importantly, 13m- and 24-induced enhancement of Nrf2 translocation and HO-1 expression was reversed by U0126 (an ERK inhibitor), SP600125 (a JNK inhibitor), and LY294002 (an Akt inhibitor). Collectively, our results show that compounds 13m and 24 exert neuroprotective and antioxidant effects through the Nrf2/HO-1 pathway mediated by phosphorylation of ERK1/2, JNK, or Akt in PC12 cells. Based on our findings, both derivatives could serve as potential therapeutic candidates for the neuroprotective treatment of PD.
Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Animais , Ratos , Antioxidantes/farmacologia , Citocromo P-450 CYP2B1/metabolismo , Citocromo P-450 CYP2B1/farmacologia , Heme Oxigenase-1/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologiaRESUMO
Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.
Assuntos
Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 2/antagonistas & inibidores , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Sítios de Ligação , Biomarcadores Tumorais , Receptor com Domínio Discoidina 1/química , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 2/química , Receptor com Domínio Discoidina 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Cudraisoflavone J (1), isolated from Cudrania tricuspidata, is a potent neuroprotective compound with a chiral center. Herein, we report the first total synthesis of racemic cudraisoflavone J (1) using a Claisen rearrangement and a Suzuki coupling reaction as the key steps. Racemic secondary alcohol was kinetically resolved to give (+)- and (-)-cudraisoflavone J with up to 97 and 88% enantiomeric excess, respectively. The modified Mosher's method was used to elucidate the absolute configuration of naturally occurring cudraisoflavone J.
Assuntos
Isoflavonas/síntese química , Fármacos Neuroprotetores/síntese química , Estrutura Molecular , Moraceae/químicaRESUMO
1. Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. 2. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-gp were evaluated.3. The 7-day treatment with LC478 increased docetaxel absorption via intestinal P-gp inhibition in rats. Intestinal concentrations of LC478 were 8.31-10.3 µM in rats after 7-day treatment of LC478. These concentrations were close to 10 µM that reduced P-gp mediated docetaxel efflux and P-gp expression in MDCK-MDR1 cells. Considering that intestinal LC478 concentrations after 1-day treatment were 2.68-4.19 µM, higher LC478 concentrations after 7-day treatment might have driven P-gp inhibition and increased docetaxel absorption. LC478 might competitively inhibit P-gp considering its stimulated ATPase activity and its binding site with nucleotide binding domain of P-gp. 4. Therefore, repeated treatment with LC478 can determine its feasibility for P-gp inhibition and changing docetaxel bioavailability.
Assuntos
Adamantano/análogos & derivados , Adamantano/metabolismo , Antineoplásicos/farmacocinética , Docetaxel/farmacocinética , Inibidores Enzimáticos/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adamantano/farmacocinética , Animais , Disponibilidade Biológica , Transporte Biológico , Absorção Intestinal , RatosRESUMO
Norovirus (NV), is the most common cause of acute gastroenteritis worldwide. To date, there is no specific anti-NV drug or vaccine to treat NV infections. In this study, we evaluated the inhibitory effect of different stilbene-based analogs on RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23). Initial screening of our in-house chemical library against NV led to the identification of a hit containing stilbene scaffold 5 which on initial optimization gave us a vinyl stilbene compound 16c (EC50â¯=â¯4.4⯵M). Herein we report our structure-activity relationship study of the novel series of vinyl stilbene analogs that inhibits viral RNA genome replication in a human NV-specific manner. Among these newly synthesized compounds, several amide derivatives of vinyl stilbenes exhibited potent anti-NV activity with EC50 values ranging from 1 to 2⯵M. A trans-vinyl stilbenoid with an appended substituted piperazine amide (18k), exhibited potent anti-NV activity and also displayed favorable metabolic stability. Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral mechanism.
Assuntos
Antivirais/farmacologia , Norovirus/efeitos dos fármacos , Estilbenos/farmacologia , Compostos de Vinila/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos/efeitos dos fármacos , Microssomos/microbiologia , Estrutura Molecular , Células RAW 264.7 , RNA Viral/efeitos dos fármacos , RNA Viral/genética , Estilbenos/química , Relação Estrutura-Atividade , Compostos de Vinila/química , Replicação Viral/efeitos dos fármacos , Replicação Viral/genéticaRESUMO
Saturated oxygen heterocycles are widely found in a broad array of natural products and other biologically active molecules. In medicinal chemistry, small and medium rings are also important synthetic intermediates since they can undergo ring-opening and -expansion reactions. These applications have driven numerous studies on the synthesis of oxygen-containing heterocycles and considerable effort has been devoted toward the development of methods for the construction of saturated oxygen heterocycles. This paper provides an overview of the biological roles and synthetic strategies of saturated cyclic ethers, covering some of the most studied and newly discovered related natural products in recent years. This paper also reports several promising and newly developed synthetic methods, emphasizing 3-7 membered rings.
Assuntos
Produtos Biológicos/química , Éteres Cíclicos/síntese química , Animais , Produtos Biológicos/farmacologia , Química Farmacêutica , Avaliação Pré-Clínica de Medicamentos , Éteres Cíclicos/química , Éteres Cíclicos/farmacologia , Humanos , Estrutura Molecular , Oxigênio/químicaRESUMO
P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6â»20.5, from (LC478 concentration in intestine, 9.37â»12.3 µM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 µM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.
RESUMO
Benzofuran derivatives have wide range of biological activities as anti-oxidant, anti-inflammatory and anticonvulsant agent. In this study, we investigated whether the novel benzofuran derivative, DK-1014 has the anti-inflammatory effects on macrophage and lung epithelial cells and anti-asthmatic effects on ovalbumin-treated mice. A series of 2-arylbenzofuran analogues were synthesized and evaluated for NO and interleukin-6 (IL-6) inhibition in LPS-stimulated Raw264.7 cells. Of these analogues, compounds 8, 22a, 22d, and 22 f (DK-1014) exhibited notable inhibitory activity with respect to IL-6 and NO production. In particular, compound DK-1014 strongly reduced IL-6, IL-8, and MMP-9 mRNA expression and IL-6, IL-8, and MCP-1 production in phorbol myristate acetate stimulated A549 cells, reduced MAPKs phosphorylation and c-fos translocation, and attenuated AKT, p70S6K and GSK phosphorylation. In vivo experiments were also performed on ovalbumin-sensitized and challenged BALB/c mice. DK-1014 reduced the airway hyperresponsiveness, inflammatory cell counts and cytokine levels (IL-4, 5, 13) in bronchial alveolar lavage fluid (BALF) and immunoglobulin E in serum, and attenuated inflammatory cell infiltration and mucus hypersecretion in lung tissue. These findings indicate that DK-1014 can protect against allergic airway inflammation through the AP-1 and AKT/mTOR pathways and could be useful source for the development of a therapeutic agent for asthma.
Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Benzofuranos/química , Benzofuranos/uso terapêutico , Macrófagos/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Mucosa Respiratória/imunologia , Animais , Anti-Inflamatórios/química , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Transcrição AP-1/metabolismoRESUMO
Stilbenes are biologically active metabolites of plants that have the potential to attenuate a broad range of human diseases. Gramistilbenoids are a class of natural products with a stilbene skeleton, isolated from the bamboo orchid ( Arundina graminifolia), and with significant cytotoxicity against cancer cell lines (NB4, A549, SHSY5Y, PC3, and MCF7). These are the first identified naturally occurring diphenylethylenes to possess a hydroxyethyl unit. However, some of these compounds are not abundant in nature, and thus, their synthesis is advantageous. This paper reports the first synthesis of gramistilbenoids A (1), B (2), and C (3), with overall yields of 10, 2, and 8% respectively. These natural products were synthesized using key reactions, such as Horner-Wadsworth-Emmons olefination, Stille coupling, and hydroboration-oxidation.