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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.
Bioorg Chem ; 94: 103474, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31859010

RESUMO

A class of 3-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were designed, synthesized and evaluated for their in vitro biological activities against maternal embryonic leucine zipper kinase (MELK). Among these derivatives, the optimized compound 16h exhibited potent enzyme inhibition (IC50 = 32 nM) and excellent anti-proliferative effect with IC50 values from 0.109 µM to 0.245 µM on A549, MDA-MB-231 and MCF-7 cell lines. The results of flow cytometry indicated that 16h promoted apoptosis of A549 cells in a dose-dependent manner and effectively arrested A549 cells in the G0/G1 phase. Further investigation indicated that compound 16h potently suppressed the migration of A549 cells, had moderate stability in rat liver microsomes and showed moderate inhibitory activity against various subtypes of human cytochrome P450. However, compound 16h is a multi-target kinase inhibitor and recently several studies reported MELK expression is not required for cancer growth, suggesting that compound 16h suppressed the proliferation and migration of cancer cells should through an off-target mechanism. Collectively, compound 16h has the potential to serve as a new lead compound for further anticancer drug discovery.

4.
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
5.
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
6.
Bioorg Med Chem ; 26(12): 3242-3253, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29748145

RESUMO

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.


Assuntos
Antifúngicos/síntese química , Desenho de Drogas , Proteínas Fúngicas/metabolismo , Esterol 14-Desmetilase/metabolismo , Triazóis/química , Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/metabolismo , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Farmacorresistência Fúngica/efeitos dos fármacos , Estabilidade de Medicamentos , Fluconazol/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Esterol 14-Desmetilase/química , Esteróis/análise , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia
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.
Expert Opin Ther Pat ; 28(4): 331-340, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29424255

RESUMO

INTRODUCTION: Epidemiological studies have identified that high levels of low-density lipoprotein-cholesterol (LDL-C) and low levels of high-density lipoprotein-cholesterol (HDL-C) are two independent causes of cardiovascular disease (CVD). Statins, niacin and fibrate are used for the treatment of CVD. However, some defects are shown in the treatment process. Thus, there is a demand for better treatment strategies that confer preferable efficacy with fewer side effects. Cholesteryl ester transfer protein (CETP) promotes the movement of CEs from HDL to LDL and VLDL in exchange for triglycerides (TGs). AREAS COVERED: In this review, we reviewed the development and therapeutic applications of CETP inhibitors. A comprehensive review of the patents and pharmaceutical applications between 2009 and 2017 has been highlighted. EXPERT OPINION: Recently, CETP inhibitors have attracted considerable interest in atherosclerosis-related disease. There are four drugs (torcetrapib, anacetrapib, evacetrapib and dalcetrapib) that have been clinically evaluated in phase III clinical trials and showed promising results in raising HDL-C levels, but there were suboptimal performances in reducing the risk of cardiovascular events with all the compounds. The correlation between plasma HDL-C levels and CVD incidence needs further verification. The timeline is still long for CETP inhibitors to emerge from the treatment of CVD.


Assuntos
Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Desenho de Drogas , Humanos , Patentes como Assunto
9.
J Med Chem ; 61(1): 265-285, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29190083

RESUMO

Herein, we report the discovery and characterization of a novel class of PAK4 inhibitors with a quinazoline scaffold. Based on the shape and chemical composition of the ATP-binding pocket of PAKs, we chose a 2,4-diaminoquinazoline series of inhibitors as a starting point. Guided by X-ray crystallography and a structure-based drug design (SBDD) approach, a series of novel 4-aminoquinazoline-2-carboxamide PAK4 inhibitors were designed and synthesized. The inhibitors' selectivity, therapeutic potency, and pharmaceutical properties were optimized. One of the best compounds, 31 (CZh226), showed remarkable PAK4 selectivity (346-fold vs PAK1) and favorable kinase selectivity profile. Moreover, this compound potently inhibited the migration and invasion of A549 tumor cells by regulating the PAK4-directed downstream signaling pathways in vitro. Taken together, these data support the further development of 31 as a lead compound for PAK4-targeted anticancer drug discovery and as a valuable research probe for the further biological investigation of group II PAKs.


Assuntos
Desenho de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Domínio Catalítico , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Quinases Ativadas por p21/química , Quinases Ativadas por p21/metabolismo
10.
Am J Transl Res ; 9(6): 2736-2747, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28670365

RESUMO

Gastric cancer is the most common malignant tumor and globally the third leading cause of cancer-related deaths. Therefore, there exists an urgent need to identify new effective gastric cancer treatments. Given the important roles in tumorigenesis and progression, p21-activated kinase 4 (PAK4) has been regarded as an attractive high-value druggable target. In this study, we examined the effects and molecular mechanisms of action of the small molecular compound LC-0882 on gastric cancer cells in vitro. LC-0882 was found to significantly inhibit the proliferation of human gastric cancer cells by repressing phospho-PAK4/cyclin D1 and CDK4/6 expression. In addition, LC-0882 was found to attenuate cell invasion by blocking the PAK4/LIMK1/cofilin signaling pathway. Finally, analysis of immunofluorescence revealed that LC-0882 exposure decreased filopodia formation and induced cell elongation in BGC823 and SGC7901 gastric cancer cells. These findings suggest that targeting PAK4 with the novel compound LC-0882 may provide a new chemotherapeutic approach in gastric cancer treatment.

11.
Eur J Med Chem ; 137: 96-107, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28558334

RESUMO

To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Hidrocarbonetos Aromáticos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Hidrocarbonetos Aromáticos/síntese química , Hidrocarbonetos Aromáticos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
12.
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
13.
Eur J Med Chem ; 131: 1-13, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28284095

RESUMO

Upon analysis of the reported crystal structure of PAK4 inhibitor KY04031 (PAK4 IC50 = 0.790 µM) in the active site of PAK4, we investigated the possibility of changing the triazine core of KY04031 to a quinazoline. Using KY04031 as a starting compound, a library of 2, 4-diaminoquinazoline derivatives were designed and synthesized. These compounds were evaluated for PAK4 inhibition, leading to the identification of compound 9d (PAK4 IC50 = 0.033 µM). Compound 9d significantly induced the cell cycle in the G1/S phase and inhibited migration and invasion of A549 cells that over-express PAK4 via regulation of the PAK4-LIMK1 signalling pathway. A docking study of compound 9d was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of PAK4 inhibitors. Compound 9d may serve as a lead compound for anticancer drug discovery and as a valuable research probe for further biological investigation of PAK4.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Células A549 , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
14.
Bioorg Med Chem ; 25(2): 750-758, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27955926

RESUMO

Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2µg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Compostos de Bifenilo/farmacologia , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Descoberta de Drogas , Imidazóis/farmacologia , Antifúngicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 123: 514-522, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27494168

RESUMO

A series of compounds with benzothiazole and amide-imidazole scaffolds were designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. The antifungal activity of these compounds was evaluated in vitro, and their structure-activity relationships (SARs) were evaluated. The synthesized compounds showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans. The most potent compounds 14o, 14p, and 14r exhibited potent activity, with minimum inhibitory concentration (MIC) values in the range of 0.125-2 µg/mL. Preliminary mechanism studies revealed that the compound 14p might act by inhibiting the CYP51 of Candida albicans. The SARs and binding mode established in this study are useful for further lead optimization.


Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Desenho de Drogas , Antifúngicos/química , Antifúngicos/metabolismo , Benzotiazóis/química , Benzotiazóis/metabolismo , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/enzimologia , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade
16.
Eur J Med Chem ; 123: 419-430, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27490022

RESUMO

Cholesteryl ester transfer protein (CETP) is a potential target for cardiovascular disease therapy as inhibition of CETP leads to increased HDL-C in humans. Based on the structure of Merck's biphenyl CETP inhibitor, we designed novel N,N-substituted-cycloalkenyl-methylamine scaffold derivatives by utilizing core replacement and conformational restriction strategies. Consequently, twenty-eight compounds were synthesized and evaluated for their inhibitory activity against CETP. Their preliminary structure-activity relationships (SARs) studies indicate that polar substituents were tolerated in moiety A and hydrophobic alkyl groups at the 5-position of cyclohexene were critical for potency. Among them, compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl- methylamine scaffold, exhibited excellent CETP inhibitory activity (IC50 = 0.07 µM) in vitro. Furthermore, it showed an acceptable pharmacokinetic profile in S-D rats and efficient HDL-C increase in high-fat fed hamsters.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Cicloparafinas/síntese química , Cicloparafinas/farmacologia , Desenho de Drogas , Animais , Técnicas de Química Sintética , Cricetinae , Cicloparafinas/química , Cicloparafinas/farmacocinética , Dieta Hiperlipídica/efeitos adversos , Masculino , Ratos
17.
Org Biomol Chem ; 14(32): 7676-90, 2016 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-27454186

RESUMO

A new series of novel 1-phenanthryl-tetrahydroisoquinoline derivatives were designed, synthesized and biologically evaluated for their PAK4 inhibitory activities and anti-proliferative effects against three cancer cell lines A549, MCF-7 and HT-1080. Among them, compound 12a exhibited the most potent inhibitory activity against PAK4 with an IC50 value of 0.42 µM. Moreover, this compound inhibited the invasion of A549 tumor cells by regulating the PAK4-LIMK1-cofilin signaling pathway in vitro, and exhibited anti-tumor activity in vivo in the A549 tumor xenograft model. To further evaluate the binding mode of 12a with PAK4, the biotinylated 12a derivative has been synthesized and it was used for immunoprecipitation assay. Intriguingly, our observations suggest that 12a interacts with both the N- and C-termini of PAK4.


Assuntos
Antineoplásicos/farmacologia , Fenantrenos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tetra-Hidroisoquinolinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Fenantrenos/síntese química , Fenantrenos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/química , Quinases Ativadas por p21/metabolismo
18.
Bioorg Med Chem ; 24(8): 1811-8, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26993745

RESUMO

Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06 µM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett.2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem.2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69 µM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure-activity relationship (SAR) resulted in H16 (IC50 0.15 µM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal.


Assuntos
Anilidas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Descoberta de Drogas , Anilidas/química , Anilidas/metabolismo , Animais , Relação Dose-Resposta a Droga , Masculino , Mesocricetus , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 24(8): 1589-97, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27010500

RESUMO

A series of N,N-3-phenyl-3-benzylaminopropanamide derivatives were identified as novel CETP (cholesteryl ester transfer protein) inhibitors. In our previous study, lead compound L10 was discovered by pharmacophore-based virtual screening (Dong-Mei Zhao et al., 2014). Based on L10 (IC50 8.06 µM), compound HL6 (IC50 10.7 µM) was discovered following systematic structure variation and biological tests. Further optimization of the structure-activity relationship (SAR) resulted in N,N-3-phenyl-3-benzylaminopro panamides derivatives as novel CETP inhibitors. They were synthesized and evaluated against CETP by BODIPY-CE fluorescence assay. Among them, HL16 (IC50 0.69 µM) was a highly potent CETP inhibitor in vitro. In addition, HL16 exhibited favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. The molecular docking of HL16 into the CETP was performed. The binding mode demonstrated that HL16 occupied the CETP binding site and formed interactions with the key amino acid residues.


Assuntos
Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Desenho de Drogas , Propano/análogos & derivados , Administração Oral , Animais , Benzilaminas/administração & dosagem , Benzilaminas/química , Cricetinae , Relação Dose-Resposta a Droga , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Propano/administração & dosagem , Propano/química , Propano/farmacologia , Relação Estrutura-Atividade
20.
Bioorg Med Chem ; 23(6): 1356-65, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25684424

RESUMO

All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36µM (compared to liarozole (IC50=2.45µM) and S8 (IC50=3.21µM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of ß-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Modelos Moleculares , Estrutura Molecular , Fenilpropionatos/síntese química , Ácido Retinoico 4 Hidroxilase , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tretinoína/farmacologia
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