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1.
Eur J Med Chem ; 188: 112024, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923858

RESUMO

A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50 = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 µM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 µM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery.

2.
Eur J Med Chem ; 186: 111878, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757524

RESUMO

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Fígado/química , Fígado/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/síntese química , Piperazinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
3.
Eur J Med Chem ; 183: 111716, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550660

RESUMO

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10-8-10-9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 µM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors.


Assuntos
Antineoplásicos/síntese química , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade
4.
Org Lett ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31449423

RESUMO

An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-ß-Noscapine and (±)-ß-Hydrastine were exploited.

5.
Carbohydr Res ; 480: 67-72, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176192

RESUMO

An improved process for chemical synthesis of l-fructose with high purity in large scale from readily available l-sorbose is described. In general, this synthetic scheme is characterized by inexpensive and easily available starting materials, simple and safe experimental procedures, short time period, low environmental impact, and great potential for scaling up. The scale-up experiment (100 g) was carried out to provide 42.7 g of l-fructose with high HPLC purity of 99.65% in total yield of 50.2%. Consequently, the described improvements would be helpful for those who may wish to use l-fructose and promoting the further evaluation of applications of l-fructose.


Assuntos
Frutose/química , Frutose/síntese química , Configuração de Carboidratos , Técnicas de Química Sintética , Cinética , Modelos Moleculares , Estereoisomerismo
6.
Eur J Med Chem ; 155: 197-209, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29886323

RESUMO

We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 µM, HCT116 IC50 = 0.095 µM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Quinases Ativadas por p21/isolamento & purificação , Quinases Ativadas por p21/metabolismo
7.
Molecules ; 23(2)2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29443911

RESUMO

A series of novel 2,4-diaminoquinazoline derivatives were designed, synthesized, and evaluated as p21-activated kinase 4 (PAK4) inhibitors. All compounds showed significant inhibitory activity against PAK4 (half-maximal inhibitory concentration IC50 < 1 µM). Among them, compounds 8d and 9c demonstrated the most potent inhibitory activity against PAK4 (IC50 = 0.060 µM and 0.068 µM, respectively). Furthermore, we observed that compounds 8d and 9c displayed potent antiproliferative activity against the A549 cell line and inhibited cell cycle distribution, migration, and invasion of this cell line. In addition, molecular docking analysis was performed to predict the possible binding mode of compound 8d. This series of compounds has the potential for further development as PAK4 inhibitors for anticancer activity.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/química , Quinases Ativadas por p21/antagonistas & inibidores , Células A549 , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinases Ativadas por p21/genética
8.
Bioorg Med Chem ; 25(13): 3500-3511, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28502459

RESUMO

Utilizing a pharmacophore hybridization approach, a novel series of substituted indolin-2-one derivatives were designed, synthesized and evaluated for their in vitro biological activities against p21-activated kinase 4. Compounds 11b, 12d and 12g exhibited the most potent inhibitory activity against PAK4 (IC50=22nM, 16nM and 27nM, respectively). Among them, compound 12g showed the highest antiproliferative activity against A549 cells (IC50=0.83µM). Apoptosis analysis in A549 cells suggested that compound 12g delayed cell cycle progression by arresting cells in the G2/M phase of the cell cycle, retarding cell growth. Further investigation demonstrated that compound 12g strongly inhibited migration and invasion of A549 cells. Western blot analysis indicated that compound 12g potently inhibited the PAK4/LIMK1/cofilin signalling pathways. Finally, the binding mode between compound 12g with PAK4 was proposed by molecular docking. A preliminary ADME profile of the compound 12g was also drawn on the basis of QikProp predictions.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Indóis/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
9.
J Phys Chem Lett ; 5(14): 2479-83, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26277819

RESUMO

Redispersion of platinum nanoparticles (Pt NPs) on ceria is an important route for catalyst regeneration and antisintering. Here, we investigate the redispersion of Pt on ceria nanoparticles with defined surface planes including cubes ({100}) and octahedra ({111}). It is observed that Pt redispersion takes place only on ceria cubes in an alternating oxidation and reduction atmosphere. A quicker alternation rate is beneficial for such redispersion. On the basis of our experimental results and understandings toward this process, we proposed that the redispersion takes place at the moment of alternation of oxidation and reduction.

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