Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 582
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Chem Pharm Bull (Tokyo) ; 67(9): 966-976, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257308

RESUMO

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4'-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4'-alkylated derivative.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Bifenilo/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Alquilação , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Inflamação/metabolismo , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Estereoisomerismo
2.
Chem Commun (Camb) ; 55(61): 8975-8978, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290492
3.
Carbohydr Polym ; 222: 115029, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320097

RESUMO

This study reports (i) preparation and characterization of palladium nanoparticles (Pd NPs) stabilized on magnetically separable chitosan/agar microcapsules (Pd NPs@Fe3O4/CS-AG microcapsules) and (ii) investigation of catalytic behaviors of the prepared nanoparticles in Suzuki-Miyaura C-C cross-coupling reactions and reduction of p-nitrophenol (p-NP). Fourier transforms infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), elemental mapping, inductively coupled plasma-optical emission spectrometry (ICP-OES) and thermogravimetry/derivative thermogravimetry (TG/DTG) techniques were used for analyzing the Pd NPs@Fe3O4/CS-AG microcapsules. Characterization studies showed that Pd NPs@Fe3O4/CS-AG microcapsules were successfully synthesized and the size of the particles was in the range of 28-39 nm. Pd NPs@Fe3O4/CS-AG microcapsules displayed highly effective catalytic performance in the conversion of various aryl halides into the corresponding biaryl derivatives by Suzuki-Miyaura reaction under solvent-free conditions in 5 min. Pd NPs@Fe3O4/CS-AG microcapsules were also successfully employed in p-NP reduction to p-aminophenol (p-AP) in water at room temperature in 180 s. Moreover, reproducibility studies showed that Pd NPs@Fe3O4/CS-AG microcapsules were highly efficient and could be used many times in both catalytic reactions due to their magnetically separable nature. According to the results of this work, Pd NPs@Fe3O4/CS-AG microcapsules are highly efficient, economical, practical and environmentally superb catalysts for Suzuki-Miyaura reaction and p-NP reduction.


Assuntos
Ágar/química , Quitosana/química , Nanopartículas de Magnetita/química , Microesferas , Nitrofenóis/química , Paládio/química , Anisóis/química , Compostos de Bifenilo/síntese química , Ácidos Borônicos/química , Catálise , Reutilização de Equipamento , Fenômenos Magnéticos , Oxirredução
4.
Eur J Med Chem ; 172: 109-130, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959322

RESUMO

Fluoroquinolones substituted with N-1 biphenyl and napthyl groups were discovered to act as catalytically inhibitors of human topoisomerases I and II, and to possess anti-proliferative activity in vivo. Structural requirements for these novel quinolones to inhibit catalytic activity of human topoisomerase I have not been explored. In this work novel derivatives of the N-1 biphenyl fluoroquinolone were designed, synthesized and evaluated to understand structural requirements of the C-3 carboxylic acid, C-6 fluorine, C-7 aminomethylpyrrolidine, C-8 methoxy, and the N-1 biphenyl functional groups for hTopoI inhibition. Characterization of each analog for inhibition of hTopoI catalytic inhibition reveals critical insight into structural requirements of these novel quinolones for activity. Additionally, results of DNA binding and modeling studies suggest that N-1 biphenyl fluoroquinolones intercalate between the DNA base pairs with the N-1 biphenyl functional group, rather than the quinolone core, and that this mode of DNA intercalation contributes to inhibition of hTopoI by these novel structures. The results presented here support further development and evaluation of N-1 biphenyl fluoroquinolone analogs as a novel class of anti-cancer agents that act through catalytic inhibition of hTopoI.


Assuntos
Compostos de Bifenilo/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Fluoroquinolonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Fluoroquinolonas/síntese química , Fluoroquinolonas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
5.
Mater Sci Eng C Mater Biol Appl ; 98: 584-593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30813061

RESUMO

This work describes (i) an eco-friendly approach for in situ immobilization of Pd nanoparticles on the surface of Fe3O4 nanoparticles, with help of green tea extract and ultrasound irradiations, without using any toxic reducing agents and (ii) development of ultrasound assisted simple protocol for synthesis of biphenyl compounds. The structural, morphological and physicochemical characteristics of the catalyst were determined by different analytical methods including inductively coupled plasma (ICP) analysis, Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and vibrating sample magnetometry (VSM). Catalytic performance of Pd/Fe3O4 NPs as magnetic and heterogeneous catalyst was evaluated in synthesis of various biphenyl compounds throughout Suzuki coupling reactions by using the ultrasound-assisted method that was developed in this study. The Pd/Fe3O4 NPs demonstrated a noticeable catalytic activity by giving high product yields. Furthermore, the heterogeneous nanocatalyst was successfully recovered up to six times without significant activity loss. Additionally, with respect to conventional coupling reactions, the ultrasound-assisted synthesis reactions presented the advantages of green conditions, short reaction times, high yields and easier work-up.


Assuntos
Compostos de Bifenilo/síntese química , Magnetismo , Nanopartículas Metálicas/química , Nanopartículas/química , Paládio/química , Extratos Vegetais/química , Chá/química , Ondas Ultrassônicas , Catálise , Compostos Férricos/química , Cinética , Espectroscopia Fotoeletrônica , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura Ambiente , Difração de Raios X
6.
Acta Crystallogr C Struct Chem ; 75(Pt 2): 97-106, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30720447

RESUMO

Two novel Schiff bases derived from indole and biphenyl have been designed and synthesized, namely 3-((E)-{(E)-[1-(biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1-methyl-1H-indole (3-BEHMI) acetonitrile monosolvate, C24H21N3·CH3CN, and 3-((E)-{(E)-[1-(biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1-methyl-1H-indole (3-BEHEI) acetonitrile monosolvate, C24H21N3·CH3CN. Their structures were characterized by elemental analysis, quadrupole time-of-flight MS, NMR and UV-Vis spectroscopy. The single-crystal packing structure of 3-BEHMI is largely dominated by C-H...π interactions and weak van der Waals interactions. The in vitro cytotoxicity of the two title compounds have been evaluated against two tumour cell lines (A549 human lung cancer and 4T1 mouse breast cancer) and two normal cell lines (MRC-5 normal lung cells and NIH 3T3 fibroblasts) by MTT assay. The results indicate that 3-BEHEI exhibits a slightly weaker antiproliferative capability (IC50 = ∼50 µM) than the previously reported similar Schiff base 3-BEHI (IC50 = ∼20 µM). This is in line with docking results. 3-BEHMI demonstrates a weak cytotoxic activity, with IC50 values around 110 µM, which disagrees with its docking results. Overall, the tested compounds manifest relevant cytotoxicities on the selected cancer cell lines and normal cell lines. The UV-Vis and fluorescence spectra were recorded and reproduced through the TD-DFT method with four types of hybrid density functionals, including B3LYP, M062X, PBE1PBE and WB97XD.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Proliferação de Células/efeitos dos fármacos , Bases de Schiff/química , Bases de Schiff/farmacologia , Animais , Compostos de Bifenilo/síntese química , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Bases de Schiff/síntese química , Análise Espectral/métodos
7.
Bioorg Chem ; 85: 82-96, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30605887

RESUMO

A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2 ±â€¯0.01 µM) compared to standard donepezil (AChE, IC50: 0.1 ±â€¯0.002 µM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ±â€¯1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93 ±â€¯0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.


Assuntos
Inibidores da Colinesterase/farmacologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Piperazinas/farmacologia , Triazinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Desenho de Drogas , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nootrópicos/síntese química , Nootrópicos/metabolismo , Piperazinas/síntese química , Piperazinas/metabolismo , Ligação Proteica , Torpedo , Triazinas/síntese química , Triazinas/metabolismo
8.
Nat Prod Res ; 33(8): 1191-1195, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29683350

RESUMO

Cultivation of the marine-derived Aspergillus versicolor MCCC 3A00080 with the addition of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), significantly enhanced the diversity of secondary metabolites. From the culture treated, a new biphenyl derivative, named versiperol A (1), along with two known compounds, 2,4-dimethoxyphenol (2) and diorcinol (3) were isolated. The structures of 1-3 were established based on spectroscopic analysis and comparison with literature data. Among the isolates, versiperol A (1) exhibited modest inhibition of Staphylococcus aureus growth with MIC value of 8 µg/mL.


Assuntos
Antibacterianos/farmacologia , Aspergillus/química , Compostos de Bifenilo/síntese química , Antibacterianos/síntese química , Antibacterianos/isolamento & purificação , Aspergillus/genética , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacologia , Técnicas de Cultura de Células , Epigenômica , Fungos/genética , Inibidores de Histona Desacetilases/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Vorinostat/farmacologia
9.
Bioorg Med Chem Lett ; 29(2): 329-333, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472026

RESUMO

Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 µM, respectively, than honokiol.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Compostos de Bifenilo/farmacologia , Compostos Heterocíclicos/farmacologia , Lignanas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Linhagem Celular , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Lignanas/síntese química , Lignanas/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
10.
Cancer Lett ; 445: 1-10, 2019 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-30583077

RESUMO

We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives, namely PTA34, PTA73 and RS35 for experimentation in solid tumor cell lines, classical Hodgkin Lymphoma (cHL) cell lines and bona fide normal cell lines. Almost all tumor cells were sensitive to compounds in the nanomolar range whereas, they were not cytotoxic to normal ones. Interestingly the compounds caused a strong G2/M phase arrest in cHL cell lines, thus, here we investigated whether they affected the integrity of microtubules in such cells. We found that they induced a long prometaphase arrest, followed by induction of apoptosis which involved mitochondria. PTA73 and RS35 induced the mitotic arrest through the fragmentation of microtubules which prevented the kinethocore-mitotic spindle interaction and the exit from mitosis. PTA34 is instead a tubulin-targeting agent because it inhibited the tubulin polymerization as vinblastine. As such, PTA34 maintained the Cyclin B1-CDK1 regulatory complex activated during the G2/M arrest while inducing the inactivation of Bcl-2 through phosphorylation in Ser70, the degradation of Mcl-1 and a strong activation of BIML and BIMS proapoptotic isoforms. In addition PTA34 exerted an antiangiogenic effect by suppressing microvascular formation.


Assuntos
Antimitóticos/síntese química , Compostos de Bifenilo/síntese química , Doença de Hodgkin/metabolismo , Nicotina/química , Antimitóticos/química , Antimitóticos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Doença de Hodgkin/tratamento farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estrutura Molecular , Prometáfase/efeitos dos fármacos
11.
Bioorg Med Chem Lett ; 29(2): 138-142, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30551904

RESUMO

By further optimizing compound A [2'-fluoro-N-methyl-[1,1'-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2'-fluoro-[1,1'-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.


Assuntos
Acetamidas/uso terapêutico , Tonsila do Cerebelo/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Epilepsia/tratamento farmacológico , Excitação Neurológica/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Tonsila do Cerebelo/patologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Epilepsia/patologia , Excitação Neurológica/patologia , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 162: 59-69, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30408749

RESUMO

Oxidative stress plays a significant role in the pathogenesis of various human diseases. In this study, a series of bifendate derivatives bearing acrylamide moiety were synthesized and evaluated as anti-oxidant agents. Biological evaluation indicated that compounds 6a and 6e displayed more potent cytoprotective effect against H2O2-induced HBZY-1 mesangial cells death than lead compound bifendate and positive control resveratrol and sulforaphane. Preliminary anti-oxidant mechanism studies showed that compound 6e could diminish the ROS accumulation by dose- and time-dependently activating Nrf2 and increasing the expression of downstream detoxification enzymes NQO-1, HO-1, GCLM and GCLC at protein and mRNA levels, thus displaying potent anti-oxidant activity. Interestingly, the Nrf2 activating effect of 6e is achieved, at least partly, in Michael acceptor and Keap1-dependent manners. These results, together with the low intrinsic cytotoxicity, suggested that compound 6e might be a promising lead for the development of novel anti-oxidant agents to prevent diseases induced by oxidative stress.


Assuntos
Acrilamida/química , Antioxidantes/farmacologia , Compostos de Bifenilo/farmacologia , Células Mesangiais/efeitos dos fármacos , Antioxidantes/química , Compostos de Bifenilo/síntese química , Humanos , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade
13.
Bioorg Med Chem ; 26(23-24): 6146-6152, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30446437

RESUMO

Non-secosteroidal VDR ligands without any assymmetric carbon were designed and synthesized based on the structure of the previously reported non-secosteroidal VDR agonist LG190178. The VDR-agonistic activity of all synthesized compounds was evaluated, and 7b emerged as a potent agonist activity with an EC50 value of 9.26 nM. Moreover, a docking simulation analysis was also performed to determine the binding mode of 7b with VDR-LBD.


Assuntos
Compostos de Bifenilo/farmacologia , Receptores de Calcitriol/agonistas , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
14.
Org Biomol Chem ; 16(38): 7019-7028, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30232493

RESUMO

Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand-target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Lignanas/química , Lignanas/farmacologia , PPAR gama/metabolismo , Compostos de Bifenilo/síntese química , Cristalografia por Raios X , Dimerização , Descoberta de Drogas , Células HEK293 , Humanos , Ligantes , Lignanas/síntese química , Simulação de Acoplamento Molecular , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Ligação Proteica , Receptor X Retinoide alfa/metabolismo
15.
J Am Chem Soc ; 140(39): 12415-12423, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30185030

RESUMO

A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important building blocks in drug discovery, is described. In this method, KN(SiMe3)2 in combination with a (NIXANTPHOS)Pd catalyst accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization. This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction, which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of toluene derivatives by the K+-cation- π interaction, which may prove pertinent in the development of other, new reaction systems.


Assuntos
Compostos de Bifenilo/síntese química , Tolueno/química , Compostos de Bifenilo/química , Catálise , Cátions/química , Potássio/química
16.
Structure ; 26(11): 1431-1439.e6, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30146169

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are pharmacological targets for the treatment of metabolic disorders. Previously, we demonstrated the anti-diabetic effects of SR1664, a PPARγ modulator lacking classical transcriptional agonism, despite its poor pharmacokinetic properties. Here, we report identification of the antagonist SR11023 as a potent insulin sensitizer with significant plasma exposure following oral administration. To determine the structural mechanism of ligand-dependent antagonism of PPARγ, we employed an integrated approach combining solution-phase biophysical techniques to monitor activation helix (helix 12) conformational dynamics. While informative on receptor dynamics, hydrogen/deuterium exchange mass spectrometry and nuclear magnetic resonance data provide limited information regarding the specific orientations of structural elements. In contrast, label-free quantitative crosslinking mass spectrometry revealed that binding of SR11023 to PPARγ enhances interaction with co-repressor motifs by pushing H12 away from the agonist active conformation toward the H2-H3 loop region (i.e., the omega loop), revealing the molecular mechanism for active antagonism of PPARγ.


Assuntos
Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , PPAR gama/antagonistas & inibidores , PPAR gama/química , Células 3T3-L1 , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Cristalografia por Raios X , Medição da Troca de Deutério , Desenho de Drogas , Células HEK293 , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Modelos Moleculares , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
17.
Bioorg Chem ; 81: 270-277, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30165257

RESUMO

A series of novel (3'-amino-[1,1'-biphenyl]-4-yl) sulfamic acid derivatives were designed as nonphosphonate-based phosphotyrosy (pTyr) mimetics, synthesized and screened for use as HPTPß inhibitors. Compounds C22 and C2 showed favorable HPTPß inhibitory activity and better selectivity for HPTPß than for PTP1B and SHP2. Docking results suggested that compounds C2 and C22 could not only efficiently fit into the catalytic site of the HPTPß enzyme but also interact with the Lys1807, Arg1809 and Lys1811 residues of the secondary binding site, which was next to the catalytic center of the enzyme. The mode of interaction of the synthesized compound with the protein was different from the one found in a complex crystal of small molecules with HPTPß (2I4H), in which the inhibitory molecule formed hydrogen bonds with the Gln1948 and Asn1735 residues of the secondary binding site.


Assuntos
Compostos de Bifenilo/química , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/antagonistas & inibidores , Ácidos Sulfônicos/química , Compostos de Bifenilo/síntese química , Domínio Catalítico , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química
18.
Eur J Med Chem ; 156: 381-393, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30015074

RESUMO

Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 µM agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs.


Assuntos
Antidepressivos/química , Antidepressivos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Depressão/tratamento farmacológico , Lignanas/química , Lignanas/uso terapêutico , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Animais , Antidepressivos/síntese química , Antidepressivos/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Encéfalo/metabolismo , Depressão/metabolismo , Feminino , Células HEK293 , Elevação dos Membros Posteriores , Humanos , Lignanas/síntese química , Lignanas/farmacologia , Masculino , Camundongos , Ratos Sprague-Dawley , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo
19.
Eur J Med Chem ; 156: 190-205, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30006164

RESUMO

EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC50 values of 15.85, 15.60 and 18.60 µM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC50 values ranging from 4.81 to 13.54 µM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 105 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through Cdk2, Cdk4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral anticancer agent deserving further investigation.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Lignanas/química , Lignanas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/síntese química , Lignanas/farmacologia , Neoplasias Pulmonares/patologia , Magnolia/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Bioorg Med Chem ; 26(15): 4382-4389, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054191

RESUMO

In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.


Assuntos
Acetatos/química , Compostos de Bifenilo/síntese química , PPAR delta/agonistas , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Cristalografia por Raios X , Desenho de Drogas , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Simulação de Acoplamento Molecular , PPAR delta/metabolismo , Estrutura Terciária de Proteína , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA