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1.
Bioorg Med Chem Lett ; 30(7): 126969, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32014384

RESUMO

In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.

2.
Bioorg Med Chem Lett ; 30(7): 127019, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32057582

RESUMO

A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.

3.
Acta Pharmacol Sin ; 41(5): 661-669, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932644

RESUMO

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg-1· d-1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-ß/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-ß1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-ß-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-ß/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (-173/-163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

4.
Bioorg Med Chem Lett ; 29(12): 1541-1545, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31014912

RESUMO

Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2'-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.

5.
Chem Biodivers ; 16(2): e1800560, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30467968

RESUMO

A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Relação Estrutura-Atividade , Sulfetos , Sulfóxidos
6.
Bioorg Med Chem Lett ; 29(3): 357-361, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30580917

RESUMO

The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2' ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 µM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 µM).


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Triterpenos Pentacíclicos/farmacologia , Sulfonamidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
7.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
8.
Sci Rep ; 7(1): 5093, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28698545

RESUMO

Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8.


Assuntos
Anisóis/uso terapêutico , Antituberculosos/uso terapêutico , Butiratos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Tuberculose/tratamento farmacológico , Anisóis/química , Anisóis/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Butiratos/química , Butiratos/farmacologia , Domínio Catalítico , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/ultraestrutura , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estereoisomerismo , Especificidade por Substrato/efeitos dos fármacos , Tuberculose/microbiologia
9.
Yao Xue Xue Bao ; 52(2): 189-97, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29979499

RESUMO

Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ileal apical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigations have been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinal inflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutic target of these diseases. In this review, advances in the study of above-mentioned issues were summarized.


Assuntos
Ácidos e Sais Biliares/fisiologia , Íleo/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Simportadores/fisiologia , Transporte Biológico , Homeostase , Humanos , Intestinos/fisiopatologia
10.
Int J Syst Evol Microbiol ; 66(10): 4156-4161, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27470940

RESUMO

The taxonomic position of an actinobacterium, designated CPCC 204279T, which was isolated from a rhizosphere soil sample of the herb Limonium sinense collected from Xinjiang Province, China, was established using a polyphasic approach. Whole-cell hydrolysates of strain CPCC 204279T contained galactose and arabinose as diagnostic sugars and meso-diaminopimelic acid as the diamino acid. The muramic acid residues in the peptidoglycan were N-acetylated. The predominant menaquinone was MK-9(H4). The phospholipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannosides. The major fatty acids were iso-C16 : 0, iso-C16 : 0 2-OH, C16 : 1ω9c, iso-C16 : 1 and C16 : 0. The genomic DNA G+C content was 73.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CPCC 204279T should be placed in the family Pseudonocardiaceae, in which the strain formed a distinct lineage next to the genus Actinophytocola. Signature nucleotides in the 16S rRNA gene sequence showed that the strain contained the Pseudonocardiaceae family-specific 16S rRNA signature nucleotides and a genus-specific diagnostic nucleotide signature pattern. The combination of phylogenetic analysis and phenotypic characteristics supported the conclusion that strain CPCC 204279T represents a novel species of a new genus in the family Pseudonocardiaceae, for which the name Herbihabitans rhizosphaerae gen. nov., sp. nov. is proposed. Strain CPCC 204279T (=NBRC 111774T=DSM 101727T) is the type strain of the type species.


Assuntos
Actinomycetales/classificação , Filogenia , Plumbaginaceae/microbiologia , Rizosfera , Microbiologia do Solo , Actinomycetales/genética , Actinomycetales/isolamento & purificação , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Graxos/química , Ácidos Murâmicos/química , Peptidoglicano/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/química
11.
Yao Xue Xue Bao ; 51(3): 444-9, 2016 03.
Artigo em Chinês | MEDLINE | ID: mdl-29859027

RESUMO

The study aims to develop a rapid, specific and sensitive method for quantitative analysis of trace impurities in levofloxacin formulation using LC-MS/MS. The quality of the different formulations from 19 plants was evaluated in the contents of the impurities. The results indicated that there were 5 impurities in the samples, and the content was different in the products with same formulation by different plants. The products of 3 plants were in good quality with impurities level under 0.01%. Levofloxacin N(4')-methyl quaternary impurity was first reported as the formulation impurity. The impurities were tightly correlated to the reservation of drug, process control of formulation and storage during transportation. The results suggest that our method is sensitive and specific to detect the trace impurities in formulation, and can be used to monitor the quality of commercial drug product.


Assuntos
Contaminação de Medicamentos , Levofloxacino/análise , Levofloxacino/normas , Cromatografia Líquida , Espectrometria de Massas em Tandem
12.
Yao Xue Xue Bao ; 50(2): 169-73, 2015 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-25975023

RESUMO

For screening the potential drugs as anti-liver fibrosis candidates, we established a high- throughput drug screening cell model based on COL1A1 promoter. The activity of COL1A1 promoter and luciferase reporter gene can be elevated by TGF-ß1, and inhibited by candidate drugs. We constructed a recombined plasmid with COL1A1 promoter and luciferase reporter gene pGL4.17, the activity of COL1A1 promoter was reflected by fluorescence intensity. COL1A1 promoter activity was detected by Dual-Luciferase Reporter Assay System, it came that the relative luciferase activity of COL1A1 promoter was 15.98 times higher than that of control group induced by TGF-ß1, showing the recombined plasmid could be used in cell model. The recombined plasmid was transfected into human hepatic stellate cells LX2, detected the effect of potential drugs, and obtained a stable expression system through stable transfection and monoclonal cell culture. A sample which could reduce COL1A1 promoter activity signally by our cell model, decreased collagen I mRNA and protein expression detected by real-time RT-PCR and Western blotting. It indicates this novel cell model can be used in high-throughput drug screening of potential anti-liver fibrosis drugs.


Assuntos
Colágeno Tipo I/genética , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala , Cirrose Hepática/tratamento farmacológico , Regiões Promotoras Genéticas , Genes Reporter , Células Estreladas do Fígado , Humanos , Luciferases , Plasmídeos , RNA Mensageiro , Transfecção , Fator de Crescimento Transformador beta1/farmacologia
13.
Bioorg Med Chem Lett ; 25(9): 1880-3, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25838144

RESUMO

A series of tertiary amine derivatives exhibiting potent HIV-1 protease inhibiting properties were identified. These novel inhibitors were designed based on the structure of Darunavir with modification on the P2 and P2' position. This effort led to discovery of 35e and 38e, which exhibited excellent HIV-1 protease inhibition with IC50 values of 15 nM and 64 nM, respectively.


Assuntos
Aminas/química , Aminas/farmacologia , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
14.
Molecules ; 19(11): 17256-78, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25353380

RESUMO

A series of chalcones a1-20 bearing a 4-OMe groups on the A-ring were initially synthesized and their anticancer activities towards HepG2 cells evaluated. Subsequently, a series of chalcones b1-42 bearing methoxy groups at the 2' and 6'-positions of the B-ring were synthesized and their anticancer activities towards five human cancer cell lines (HepG2, HeLa, MCF-7, A549 and SW1990) and two non-tumoral human cell lines evaluated. The results showed that six compounds (b6, b8, b11, b16, b18, b22, b23 and b29) displayed promising activities, with compounds b22 and b29 in particular showing higher levels of activity than etoposide against all five cancer cell lines. Compound b29 showed a promising SI value compared with both HMLE and L02 (2.1-6.5 fold in HMLE and > 33 > 103.1 fold in L02, respectively).


Assuntos
Chalconas/química , Chalconas/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Etoposídeo/química , Etoposídeo/farmacologia , Células HeLa , Células Hep G2 , Humanos , Células MCF-7
15.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 8): o843, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25249896

RESUMO

The title compound, C14H28N2O5S, was synthesized by the reaction of 2-[(methyl-sulfan-yl)meth-yl]oxirane with di-tert-butyl oxalate in hydrazine hydrate. In the crystal, mol-ecules are linked by N-H⋯O and O-H⋯O hydrogen bonds into supra-molecular chains propagating along the b-axis direction.

16.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 6): o674, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24940254

RESUMO

The title compound, C18H30N2O5S, was synthesized by the reaction of tert-butyl 2-(iso-butyl-amino)-ethyl-carbamate with p-meth-oxy-phenyl-sulfonyl chloride. In the mol-ecule, two intra-molecular C-H⋯O hydrogen bonds are observed. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds involving the imino group N atom and the ester group O atom into chains running parallel to the b axis. The chains are further connected by C-H⋯O hydrogen bonds, forming layers parallel to the bc plane.

17.
Rapid Commun Mass Spectrom ; 28(10): 1164-74, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24711279

RESUMO

RATIONALE: Impurity analysis plays an important role to guarantee the quality and safety of pharmaceuticals. However, identification of impurities remains challenging, especially for those unknown or at trace levels. We present an integrated approach to detect and characterize the trace impurities in drugs. METHODS: Based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), an approach integrating automatic impurity screening method using multiple mass defect filters (MMDFs) and background subtraction (BS) was developed. This approach was used to acquire the structural and semi-quantitative information in a single sample run, and even to discover the impurity signals submerged by background and drug ions. This approach was illustrated by the comprehensive impurity analysis of levofloxacin. RESULTS: This approach was sensitive to detect impurities at the level of 0.02% with respect to levofloxacin concentration. Nineteen impurities were detected, fourteen of which were structurally characterized and eight impurities were reported for the first time. Impurity profiles of levofloxacin drug substances and degradation samples were obtained reliably. A plausible degradation pathway of levofloxacin was proposed including descarboxyl reaction under acid, piperazinyl ring cleavage degradation under light, and N-oxidation under oxidative condition. CONCLUSIONS: The generic approach integrating LC-MS/MS and an automatic impurity screening method was developed for the detection, characterization and monitoring of impurities, especially those unknown or at trace levels. This approach was demonstrated to be rapid, sensitive and automatic for impurity profiling of drugs.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Levofloxacino/análise , Levofloxacino/química , Espectrometria de Massas em Tandem/métodos , Contaminação de Medicamentos , Espectrometria de Massas por Ionização por Electrospray/métodos
18.
Acta Crystallogr Sect E Struct Rep Online ; 70(Pt 12): o1287, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25553050

RESUMO

In the title mol-ecule, C13H14N2O2, the dihedral angle between the pyrazole and benzene ring mean planes is 76.06 (11)°, and the conformation of the ethyl side chain is anti [C-O-C-C = -175.4 (3)°]. In the crystal, the only directional inter-actions are very weak C-H ⋯π inter-actions involving both the pyrazole and benzene rings, leading to the formation of a three-dimensional network.

19.
Molecules ; 18(6): 6883-97, 2013 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-23752471

RESUMO

The apical sodium-dependent bile salt transporter (ASBT) plays a pivotal role in maintaining bile acid homeostasis. Inhibition of ASBT would reduce bile acid pool size and lower cholesterol levels. In this report, a series of novel arylsulfonylaminobenzanilides were designed and synthesized as potential inhibitors of ASBT. Most of them demonstrated great potency against ASBT's bile acid transport activity. In particular, compound 5g2 inhibited ASBT activity with an IC50 value of 0.11 µM. These compounds represent potential cholesterol-lowering drugs.


Assuntos
Anilidas/química , Anilidas/farmacologia , Sulfonatos de Arila/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Anilidas/síntese química , Linhagem Celular , Desenho de Fármacos , Humanos , Estrutura Molecular
20.
Bioorg Med Chem Lett ; 22(22): 6947-51, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23036956

RESUMO

A series of novel 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were designed and synthesized. These derivatives were initially evaluated for their in vitro anticancer activity against human colon carcinoma HCT-116 cell line, and compounds 11a, b were chosen for further evaluation their in vitro activity against other five human cancer cell lines. These results indicate that most of the target compounds have considerable in vitro anticancer activity. The most active compound 11a was found to be 4- to 28-fold more potent than (R)-roscovitine against six human cancer cell lines. In addition, compound 11a was assessed for its activity against 12 kinases, and then evaluated for its interaction mode by docking experiments with cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß).


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Pirazóis/química , Pirróis/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Quinase 5 Dependente de Ciclina/química , Quinase 5 Dependente de Ciclina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/química , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Proteínas Quinases/química , Estrutura Terciária de Proteína , Purinas/química , Purinas/toxicidade , Pirazóis/síntese química , Pirazóis/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Roscovitina , Relação Estrutura-Atividade
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