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1.
Bioorg Chem ; 123: 105768, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35378372

RESUMO

Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.


Assuntos
Pirimidinas , Fatores de Transcrição , Simulação de Acoplamento Molecular , Domínios Proteicos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Fatores de Transcrição/química
2.
Proc Natl Acad Sci U S A ; 116(46): 23264-23273, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31662475

RESUMO

Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structure-guided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided "proof of concept" for the potential application of metabolic treatment in clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Fosfoglicerato Mutase/antagonistas & inibidores , Regulação Alostérica , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos Nus , Camundongos SCID , Estrutura Molecular , Terapia de Alvo Molecular , Transplante de Neoplasias , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos
3.
Int J Mol Sci ; 23(11)2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35682608

RESUMO

Millions of people worldwide suffer from acute or chronic liver inflammation caused by the hepatitis C virus (HCV). Metal ion chelators have achieved widespread success in the development of antiviral drugs. Some inhibitors with metal ion chelating structures have been proven to have good inhibitory activities on non-structural protein 5B (NS5B) polymerase. However, most of the reported metal ion chelators showed poor anti-HCV potency at the cellular level. Hence, we designed and synthesized a series of 3-hydroxyquinazoline-2,4(1H,3H)-dione derivatives with novel metal ion chelating structures. Typical compounds such as 21h, 21k, and 21t showed better anti-HCV activities than ribavirin with EC50 values less than 10 µM. 21t is currently known as one of the metal ion chelators with the best anti-HCV potency (EC50 = 2.0 µM) at the cellular level and has a better therapeutic index (TI > 25) as compared to ribavirin and the reported compound 6. In the thermal shift assay, the representative compounds 21e and 21k increased the melting temperature (Tm) of NS5B protein solution by 1.6 °C and 2.1 °C, respectively, at the test concentration, indicating that these compounds may exert an anti-HCV effect by targeting NS5B. This speculation was also supported by our molecular docking studies and ultraviolet-visible (UV-Vis) spectrophotometry assay, in which the possibility of binding of 3-hydroxyquinazoline-2,4(1H,3H)-diones with Mg2+ in the NS5B catalytic center was observed.


Assuntos
Hepatite C , Proteínas não Estruturais Virais , Antivirais/uso terapêutico , Quelantes/farmacologia , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Ribavirina/farmacologia , Proteínas não Estruturais Virais/metabolismo
4.
Acta Pharmacol Sin ; 42(1): 149-159, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32451413

RESUMO

High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer (TNBC). Thus, reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC. Sphingomyelin synthase 2 (SMS2) is the key enzyme for sphingomyelin production, which plays an important role in plasma membrane integrity and function. In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC. We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients. The knockout of SMS2 or application of 15w (a specific SMS2 inhibitor) markedly decreased the generation of M2-type macrophages in vitro, and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model. We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8+ T lymphocytes. Collectively, our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy.


Assuntos
Macrófagos/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Neoplasias de Mama Triplo Negativas/fisiopatologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Imunidade Celular/efeitos dos fármacos , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/fisiologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prognóstico , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia
5.
Chirality ; 33(12): 931-937, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34651347

RESUMO

An efficient preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine ((R)-1) from the racemate based on a recycle process of resolution/racemization was described. In the process, the desired (R)-1 was obtained by resolution with D-malic acid in 95% EtOH. Meanwhile, the undesired (S)-1 could be racemized in the presence of potassium hydroxide in DMSO. After three times of recycle process, the desired freebase (R)-1 was obtained in a yield of 61.7% with excellent ee (98.4%).

6.
Bioorg Med Chem ; 28(7): 115358, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081628

RESUMO

PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in highthroughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD < 10 nM), which well met the requirement of binding activity for the PET probe. These DBC compounds were firstly reported as α-syn ligands herein and the preliminary obtained structure has been further modified into F-labeled ones. Among them, a high-affinity tracer (5-41) with 1.03 nM (KD) has been acquired, indicating its potential as a new lead compound for developing PET radiotracer.


Assuntos
Cinamatos/química , Cinamatos/farmacologia , Desenho de Fármacos , Tomografia por Emissão de Pósitrons , alfa-Sinucleína/química , Encéfalo , Humanos , Ligantes , Estrutura Molecular , Ensaio Radioligante
7.
J Biol Chem ; 293(47): 18328-18336, 2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30305392

RESUMO

2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis. Previous studies have suggested that 2OHOA's anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. To confirm this phenomenon, in this study, we treated both A549 and U118 cells with 2OHOA and measured SMS activity. To our surprise, we found neither 2OHOA-mediated SMS activation nor sphingomyelin accumulation in the cells. However, we noted that 2OHOA significantly reduces phosphatidylcholine in these cells. We also did not observe 2OHOA-mediated SMS activation in mouse tissue homogenates. Importantly, 2OHOA inhibited rather than activated recombinant SMS1 (rSMS1) and rSMS2 in a dose-dependent fashion. Intra-gastric treatment of C57BL/6J mice with 2OHOA for 10 days had no effects on liver and small intestine SMS activities and plasma sphingomyelin levels. The treatment inhibited lysophosphatidylcholine acyltransferase (LPCAT) activity, consistent with the aforementioned reduction in plasma phosphatidylcholine. Because total cellular phosphatidylcholine is used as a predictive biomarker for monitoring tumor responses, the previously reported 2OHOA-mediated cancer suppression could be related to this phosphatidylcholine reduction, which may influence cell membrane structure and properties. We conclude that 2OHOA is not a SMS activator and that its anticancer property may be related to an effect on phosphatidylcholine metabolism.


Assuntos
Antineoplásicos/metabolismo , Neoplasias/enzimologia , Ácidos Oleicos/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Ativação Enzimática , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/química , Ativadores de Enzimas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/química , Fosfatidilcolinas/metabolismo , Esfingomielinas/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/química , Transferases (Outros Grupos de Fosfato Substituídos)/genética
8.
Molecules ; 24(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818883

RESUMO

Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis and biosynthesis to promote cancer cell proliferation, and is believed to be a promising target for cancer therapy. Herein, based on the anthraquinone scaffold, we synthesized 31 anthraquinone derivatives and investigated the structure-activity relationship (SAR). The 3-substitient of sulfonamide on the anthraquinone scaffold was essential for maintaining potency and the modifications of the hydroxyl of alizarin would cause a sharp decrease in potency. In the meantime, we determined the co-crystal structure of PGAM1 and one of the anthraquinone inhibitors 9i with IC50 value of 0.27 µM. The co-crystal structure revealed that F22, K100 and R116 of PGAM1 were critical residues for the binding of inhibitors which further validated the SAR. Consistent with the crystal structure, a competitive assay illustrated that compound 9i was a noncompetitive inhibitor. In addition, compound 9i effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound 9i may act as a new leading compound for further optimization.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fosfoglicerato Mutase/antagonistas & inibidores , Sulfonamidas/farmacologia , Antraquinonas/química , Antineoplásicos/química , Cristalização , Inibidores Enzimáticos/química , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Células Tumorais Cultivadas
9.
Pharmazie ; 74(9): 553-558, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484596

RESUMO

Insulin resistance is a typical precursor and primary feature of type 2 diabetes mellitus (T2DM). Sphingomyelin (SM) is a kind of sphingolipid located in animal brain, liver, kidney and muscle. Sphingomyelin synthase 2 (SMS2) is the key enzyme in the synthesis of sphingomyelin, inhibition of which shows protective effects on cardiovascular and glucose metabolism. We used Ly93, a selective sphingomyelin synthase 2 inhibitor, to investigate the effect of SMS2 inhibitor on insulin resistance in vitro and in vivo. Our previous studies have shown that Ly93 is able to dose-dependently inhibit the SMS activity and attenuate the atherosclerotic lesions in apoE knock out mice. In this present study, we found that high fat diet (HFD) induced insulin-resistant C57BL/6 mice treated with Ly93 were more sensitive to insulin than untreated mice, and presented lower blood insulin levels and improved insulin tolerance. Furthermore, insulin signal pathway related protein levels were detected by western blot, which indicated that SMS2 inhibitor significantly upregulated the phosphorylation of IRS-1, Akt and GSK-3ß, thus enhanced the insulin signaling. In vitro, Ly93 enhanced the phosphorylation of Akt in HepG2 cells, which was reversed by exogenous sphingomyelin. These results suggest that SMS2 inhibitor could ameliorate insulin resistance via regulating the insulin signaling. Our findings support that SMS2 is a potential target for insulin resistance.


Assuntos
Inibidores Enzimáticos/farmacologia , Resistência à Insulina , Insulina/sangue , Proteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Compostos Orgânicos/farmacologia , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Animais , Dieta Hiperlipídica , Glicogênio Sintase Quinase 3 beta/metabolismo , Células Hep G2 , Humanos , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingomielinas/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
10.
Bioorg Med Chem ; 26(20): 5479-5493, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30293796

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP competitive GSK-3ß inhibitors. Kinetic analysis revealed two typical compounds 6j and 3j showed the different non-ATP competitive mechanism of substrate competition or allosteric modulation to GSK-3ß, respectively. As expected, the two compounds showed good specificity in a panel test of 16 protein kinases, even to the closest enzymes, like CDK-1/cyclin B and CK-II. The in vivo results proved that both compounds can greatly attenuate the LPS-induced acute lung injury (ALI) and diminish inflammation response in mice by inhibiting the mRNA expression of IL-1ß and IL-6. Western blot analysis demonstrated that they negatively regulated GSK-3ß, and the mechanism of the observed beneficial effects of the inhibitors may involve both the increased phosphorylation of the Ser9 residue on GSK-3ß and protein expression of Sirtuin 1 (SIRT1). The results support that such novel BTZ compounds have a protective role in LPS-induced ALI, and might be attractive candidates for further development of inflammation pharmacotherapy, which greatly thanks to their inherently high selectivities by the non-ATP competitive mode of action. Finally, we proposed suggesting binding modes by Docking study to well explain the impacts of compounds on the target site.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Tiazepinas/química , Tiazepinas/uso terapêutico , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Glicogênio Sintase Quinase 3 beta/imunologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Tiazepinas/farmacologia
11.
Bioorg Med Chem ; 26(8): 1961-1970, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29530347

RESUMO

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Fosfoglicerato Mutase/metabolismo , Xantonas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Fosfoglicerato Mutase/antagonistas & inibidores , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Xantonas/metabolismo , Xantonas/farmacologia
12.
Molecules ; 23(6)2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29890679

RESUMO

Upregulation of phosphoglycerate mutase 1 (PGAM1) has been identified as one common phenomenon in a variety of cancers. Inhibition of PGAM1 provides a new promising therapeutic strategy for cancer treatment. Herein, based on our previous work, a series of new N-xanthone benzenesulfonamides were discovered as novel PGAM1 inhibitors. The representative molecule 15h, with an IC50 of 2.1 µM, showed an enhanced PGAM1 inhibitory activity and higher enzyme inhibitory specificity compared to PGMI-004A, as well as a slightly improved antiproliferative activity.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fosfoglicerato Mutase/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Xantonas/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/química , Benzenossulfonamidas
13.
Bioorg Med Chem Lett ; 27(15): 3511-3515, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28619536

RESUMO

Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Descoberta de Drogas , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Transferases (Outros Grupos de Fosfato Substituídos)/química , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
14.
Molecules ; 21(10)2016 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-27689988

RESUMO

Carainterol A is a eudesmane sesquiterpenoid extracted from Caragana intermedia. We have reported that carainterol A showed potent glucose consumption activity in C2C12 muscle cells and the db/db mouse model. However, the mechanism of the hypoglycemic effect of carainterol A remains elusive. In this article, we present a network pharmacology approach to predict the target and signaling pathway of carainterol A which was subsequently validated in HepG2 cells. It was demonstrated that carainterol A could increase the protein levels of IRS-1 and the downstream protein kinase AKT phosphorylation at a low micromolar level. These findings suggest that carainterol A can be a valuable lead compound and a promising chemical probe for the insulin signaling pathway.

16.
Bioorg Med Chem ; 23(18): 6173-84, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26314925

RESUMO

Sphingomyelin synthase (SMS) has been proved to be a potential drug target for the treatment of atherosclerosis. However, few SMS inhibitors have been reported. In this paper, structure-based virtual screening was performed on hSMS1. SAPA 1a was discovered as a novel SMS1 inhibitor with an IC50 value of 5.2 µM in enzymatic assay. A series of 2-(4-(N-phenethylsulfamoyl)phenoxy)acetamides (SAPAs) were synthesized and their biological activities toward SMS1 were evaluated. Among them, SAPA 1j was found to be the most potent SMS1 inhibitor with an IC50 value of 2.1 µM in in vitro assay. The molecular docking studies suggested the interaction modes of SMS1 inhibitors and PC with the active site of SMS1. Site-directed mutagenesis validated the involvement of residues Arg342 and Tyr338 in enzymatic sphingomyelin production. The discovery of SAPA derivatives as a novel class of SMS1 inhibitors would advance the development of more effective SMS1 inhibitors.


Assuntos
Acetamidas/química , Inibidores Enzimáticos/síntese química , Proteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/metabolismo , Sítios de Ligação , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Relação Estrutura-Atividade , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
17.
Molecules ; 20(4): 6978-99, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25913935

RESUMO

Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 µM and 9.0 µΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.


Assuntos
Antivirais/síntese química , Quelantes/síntese química , Quelantes/farmacologia , Magnésio/química , Quercetina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Quelantes/química , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química
18.
Beilstein J Org Chem ; 11: 2641-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26734109

RESUMO

A novel and practical asymmetric synthesis of dapoxetine hydrochloride by using the chiral auxiliary (S)-tert-butanesulfinamide was explored. The synthesis was concise, mild, and easy to perform. The overall yield and stereoselectivity were excellent.

19.
Bioorg Med Chem Lett ; 24(24): 5639-5643, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25467150

RESUMO

Glycogen synthase kinase 3ß (GSK-3ß) plays a key role in insulin metabolizing pathway and therefore inhibition of the enzyme might provide an important therapeutic approach for treatment of insulin resistance and type 2 diabetes. Recently, discovery of ATP noncompetitive inhibitors is gaining importance not only due to their generally increased selectivity but also for the potentially subtle modulation of the target. These kinds of compounds include allosteric modulators and substrate competitive inhibitors. Here we reported two benzothiazinone compounds (BTO), named BTO-5h (IC50=8 µM) and BTO-5s (IC50=10 µM) as novel allosteric modulator and substrate competitive inhibitor of GSK-3ß, respectively. Their different action modes were proved by kinetic experiments. Furthermore, BTO-5s was selected to check the kinases profile and showed little or even no activity to a panel of ten protein kinases at 100 µM, indicating it has good selectivity. Docking studies were performed to give suggesting binding modes which can well explain their impacts on the enzyme. Moreover, cell experiments displayed both compounds reduced the phosphorylation level of glycogen synthase in an intact cell, and greatly enhanced the glucose uptake in both HpG2 and 3T3-L1 cells. All of these results suggested BTO-5s and BTO-5h maybe have potentially therapeutic value for anti-diabetes. The results also offer a new scaffold for designing and developing selective inhibitors with novel mechanisms of action.


Assuntos
Benzotiazóis/química , Glucose/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Células 3T3-L1 , Regulação Alostérica , Animais , Benzotiazóis/metabolismo , Benzotiazóis/farmacologia , Sítios de Ligação , Ligação Competitiva , Transporte Biológico/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células Hep G2 , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Especificidade por Substrato
20.
Bioorg Med Chem Lett ; 23(16): 4528-31, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23856047

RESUMO

A series of diketo tetrazoles and diketo triazoles were designed and synthesized as bioisosteres of α,γ-diketo acid, the active site inhibitor of HCV (Hepatitis C virus) polymerase NS5B. Among the synthesized compounds, 4-(4-fluorobenzyloxy)phenyl diketo triazole (30) exhibited anti-HCV activity with an EC50 value of 3.9 µM and an SI value more than 128. The reduction of viral protein and mRNA levels were also validated, supporting the anti-HCV activity of compound 30. These results provide convincing evidence that the diketo tetrazoles and diketo triazoles can be developed as bioisosteres of α,γ-diketo acid to exhibit potent inhibitory activity against HCV.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Antivirais/química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/farmacologia , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
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