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1.
Future Med Chem ; 11(20): 2715-2734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571504

RESUMO

Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.

2.
Eur J Med Chem ; 179: 502-514, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276895

RESUMO

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Proteínas Nucleares/antagonistas & inibidores , Fenantridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Fenantridinas/administração & dosagem , Fenantridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
3.
Eur J Med Chem ; 177: 247-258, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158742

RESUMO

Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-ß (Aß) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aß aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.


Assuntos
Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Nootrópicos/farmacologia , Quinolinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/química , Animais , Barreira Hematoencefálica/metabolismo , Quelantes/síntese química , Quelantes/farmacocinética , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Desenho de Drogas , Canal de Potássio ERG1/antagonistas & inibidores , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Nootrópicos/toxicidade , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Peixe-Zebra
4.
J Enzyme Inhib Med Chem ; 34(1): 808-817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30879350

RESUMO

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.


Assuntos
Cumarínicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade
5.
Pulm Pharmacol Ther ; 53: 100-106, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30394340

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS: In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-ß1 (TGF-ß1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS: Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-ß1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-ß1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION: PBD-617 not only inhibited TGF-ß1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-ß1/Smad3 and p38 signaling pathways.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/farmacologia , Animais , Bleomicina/administração & dosagem , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Masculino , Ratos , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/administração & dosagem , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Cell Biosci ; 8: 60, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30479742

RESUMO

Background: Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. Results: In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1ß-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling. Conclusions: Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.

7.
J Pharm Pharmacol ; 70(7): 910-918, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29582419

RESUMO

OBJECTIVES: Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs. METHODS: Several novel cyclopropyl derivatives were designed and synthesized. The binding affinities of these compounds as well as the selectivity on subtype of estrogen receptor (ER) were assessed by fluorescence polarization. The antagonistic activity was also evaluated by dual-luciferase reporter assay. KEY FINDINGS: Our data identified five compounds (9a, 9b, 9d, 9e and 9f) with a higher selectivity on ERα than ERß subtype, warranting further development as a subtype-selective ER modulator. The study of antiestrogen activity also demonstrated that compounds 9a, 9c-f acted as full functional antagonists for ERα. These compounds had no or very low cytotoxicity. CONCLUSIONS: Although these cyclopropyl derivatives showed lower binding affinities on ERs compared to 17ß-estradiol, five of these compounds exhibited binding to ERα only and therefore might serve as a promising lead compound for further development of novel subtype-selective SERMs.


Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Ligação Proteica , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclopropanos/síntese química , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/farmacologia , Humanos , Ligantes , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade , Tamoxifeno/análogos & derivados , Tamoxifeno/síntese química , Tamoxifeno/farmacologia
8.
Mini Rev Med Chem ; 16(17): 1403-1414, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27290915

RESUMO

BRD4, an epigenetic regulator that recognizes and binds the acetylated lysine residues in histone, has been reported as a potential therapeutic target for cancers. Since the first BRD4 inhibitor JQ1 developed in 2010, numerous BRD4 inhibitors have been discovered in past five years. In this review, we have systematically summarized a series of BRD4 binding compounds, which are divided into five categories based on the similarity of their chemical structures and respectively referred as JQ1 derivatives, tetrahydroquinoline derivatives, 3,5- dimethylisoxazole derivatives, 2-thiazolidinone derivatives and others. The binding affinities for each class of compounds are also discussed.


Assuntos
Proteínas Nucleares/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/antagonistas & inibidores , Azepinas/química , Azepinas/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular , Histonas/química , Histonas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Proteínas Nucleares/metabolismo , Fator B de Elongação Transcricional Positiva/química , Fator B de Elongação Transcricional Positiva/metabolismo , Domínios Proteicos , Bibliotecas de Moléculas Pequenas/metabolismo , Fatores de Transcrição/metabolismo , Triazóis/química , Triazóis/metabolismo
9.
Chem Pharm Bull (Tokyo) ; 63(10): 780-91, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26423034

RESUMO

Estrogen receptor α (ERα) and estrogen receptor ß (ERß) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype-selective ligands can improve the target-site selectivity and decrease the off-target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERα ligands (Hypo 1) and the ERß ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R=0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration-time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERα/ERß binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERα ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG.


Assuntos
Descoberta de Drogas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bases de Dados de Produtos Farmacêuticos , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica
10.
Yao Xue Xue Bao ; 49(8): 1175-80, 2014 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-25322561

RESUMO

The purpose of this study is to investigate the enantioselectivity of norgestrel (NG) transdermal permeation and the potential influence of linalool and lipids on the enantioselectivity. In vitro skin permeation studies of NG across the excised rat skins were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by enantioselective HPLC. The possible enantioselective permeation of NG across intact rat back skin and lipids extracted rat back skin and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of l-NG when donor solutions (EtOH/H2O 2 : 8, v/v) containing l-NG or dl-NG. It may be mainly attributed to the solubility discrepancy between enantiomer and racemate. The enantioselective permeation of dl-NG across intact rat skin was observed when the donor solutions containing dl-linalool. The permeation flux of l-NG was 22% higher than that of d-NG. But interestingly, the enantioselective permeation of dl-NG disappeared under the same experimental condition except that the lipid extracted rat skin was used. Attenuated total reflection-fourier transform infrared spectroscopy analysis of stratum corneum showed that the wave number for asymmetric CH2 stretching vibrations of lipids treated with dl-linalool was greater than that of the control. The results indicated that the enantioselective permeation of NG may be contributed by the interaction between dl-linalool and lipids. More than half of lipids were composed of ceramides. The stereospecific interaction maybe existed among chiral enhancer (linalool), lipids (ceramides) and/or chiral drugs (NG).


Assuntos
Monoterpenos/farmacologia , Norgestrel/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Lipídeos/farmacologia , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
11.
Artif Cells Nanomed Biotechnol ; 42(6): 423-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24066968

RESUMO

In order to study the liver targeting of the N-galactosylated chitosan (GC) polymer in liver, we first conjugated the lactobionic acid with chitosan (CS) to obtain the carrier of GC with different degree of substitution of lactosyl group. Western blot was performed to detect the expression levels of the asialoglycoprotein receptors (ASGPR) in the cell lines of HepG2, SMMC-7721, and HL-7702. The protein level of ASGPR was lower in HepG2 compared to HL-7702 and SMMC-7721. Although all treated by CS, viabilities of HL-7702 and HepG2 did not experience any significant drop, while viability of SMMC-7721 decreased 15% on average from control. It was the first data about the inhibitory effect of GC on the liver cells. Fluorescein isothiocyanate (FITC) labeled GC (GC-FITC) was injected intravenously into mice at a dose of 0.02 µmol/mouse. GC-FITC showed maximum liver localization at 5 min and even detectable at 48 h after injection. Further, the accumulation of GC in liver was about 5.4-fold higher than that of CS. In conclusion, GC demonstrated its higher efficacy in drug liver targeting and thus could be a more promising drug or gene carrier in future therapies.


Assuntos
Receptor de Asialoglicoproteína/metabolismo , Quitosana/administração & dosagem , Sistemas de Liberação de Medicamentos , Fígado/efeitos dos fármacos , Administração Intravenosa , Animais , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Dissacarídeos/química , Feminino , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
12.
Bioorg Med Chem Lett ; 24(1): 220-3, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24332090

RESUMO

A total of 24 pirfenidone derivatives were designed, synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. These compounds showed the remarkable proliferation inhibition against MRC-5 compared to pirfenidone as the positive control. The possible mechanism of this kind of derivatives as antifibrotic agents was explored. The molecular docking and p38 binding affinity assays demonstrated that the antifibrotic potential of the pirfenidone derivatives was possibly through the inhibition of p38 MAPK signaling pathway. The data from this study suggested that p38 might be a potential therapeutic target for the new generation antifibrotics. All the pirfenidone derivatives are reported here for the first time.


Assuntos
Fibrose/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridonas/síntese química , Piridonas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Mini Rev Med Chem ; 13(2): 265-72, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23061622

RESUMO

Platinum complexes such as cisplatin and caboplatin are widely used in cancer chemotherapy. However, their clinical applications are substantially limited by unexpected toxic side effects. In this review, we discuss the current progress on the design and synthesis of estradiol-linked platinum complexes as the targeted antitumor drugs. Many of them display a high antitumor activity against the growth of breast cancer cell lines in vitro. The estradiol-linked platinum complexes could be used as target therapeutics for breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Estradiol/administração & dosagem , Estradiol/química , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Técnicas de Química Sintética/métodos , Sistemas de Liberação de Medicamentos/métodos , Estradiol/síntese química , Estradiol/farmacologia , Feminino , Humanos , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia
14.
Chem Pharm Bull (Tokyo) ; 60(2): 270-4, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22293490

RESUMO

An improved chemical reaction protocol with short time and easy work-up was described here for 2-phenylbenzofuran derivatives. The final purified products, 2-phenylbenzofuran derivatives 5a-g and the intermediate diols 4a-g, were evaluated for their estrogen receptor (ER) binding affinity and selective activity in vitro. Among these fourteen tested compounds, 4g and 5g showed higher binding affinity on ER subtypes, ERα and ERß. Compound 4g exhibited preferable ERα binding, while 5g was more estrogen selective for ERß. The molecular docking was also performed to explore the detailed interactive interface between ER and the compounds.


Assuntos
Benzofuranos/síntese química , Receptor alfa de Estrogênio/agonistas , Fenóis/síntese química , Benzofuranos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Fenóis/química , Ligação Proteica , Relação Estrutura-Atividade , Fatores de Tempo
15.
Biomed Chromatogr ; 24(8): 799-807, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20017213

RESUMO

The enantio-separations of eight 2-arylpropionic acid nonsteroidal anti-inflammatory drugs (2-APA NSAIDs) were established using reversed-phase high-performance liquid chromatography with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as chiral mobile phase additive for studying the stereoselective skin permeation of suprofen, ketoprofen, naproxen, indoprofen, fenoprofen, furbiprofen, ibuprofen and carprofen. The effects of the mobile phase composition, concentration of HP-beta-CD and column temperature on retention and enantioselective separation were investigated. With 2-APA NSAIDs as acidic analytes, the retention times and resolutions of the enantiomers were strongly related to the pH of the mobile phase. In addition, both the concentration of HP-beta-CD and temperature had a great effect on retention time, but only a slight or almost no effect on resolutions of the analytes. Enantioseparations were achieved on a Shimpack CLC-ODS (150 x 4.6 mm i.d., 5 microm) column. The mobile phase was a mixture of methanol and phosphate buffer (pH 4.0-5.5, 20 mM) containing 25 mM HP-beta-CD. This method was flexible, simple and economically advantageous over the use of chiral stationary phase, and was successfully applied to the enantioselective determination of the racemic 2-APA NSAIDs in an enantioselective skin permeation study.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Propionatos/química , Propionatos/isolamento & purificação , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Cromatografia Líquida de Alta Pressão/instrumentação , Estereoisomerismo
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