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1.
Org Biomol Chem ; 11(26): 4367-78, 2013 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-23715382

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Nitrocompostos/química , Nitrocompostos/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 44(1): 15-20, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23600201

RESUMO

OBJECTIVE: To study the regulation of P63 on expression of MASPIN in ovarian cancer by observe MASPIN promoter activity changes before and after transient transfection of constructed P63 and MASPIN reporter gene plasmids. METHODS: The MASPIN reporter plasmid, fused with luciferase reporter gene, was constructed and transfected into SKOV3 cells together with P63 (TAP63, ANP63) express plasmid transiently. The MASPIN promoter activity was determined in both the transfected cells and controlled ones by Luciferase Assays and the transcription of MASPIN mRNA of them was evaluated with semi quantitative RT-PCR. RESULTS: The MASPIN reporter plasmid was successfully constructed and transiently transfected into SKOV3 cells together with P63 (TAP63, ANP63) expression plasmid. The data showed among the tested P63 splice variants, TAP63 remarkably activated MASPIN promoter transactivation (P < 0.05). No significant difference in the activity level of MASPIN promoter was detected in the SKOV3-vector and SKOV3-ANP63 cells (P > 0.05). The level of MASPIN mRNA expression was notably enhanced in SKOV3-TAP63 cell after transient transfected with TAP63 express plasmid (P < 0.05), but no significant difference among the SKOV3, SKOV3-vector and SKOV3-ANP63 cell (P > 0.05) was detected. CONCLUSION: TAP63 can activate the transcription activity of MASPIN promoter, as well as regulate the expression of MASPIN. Put all together, these results suggested that MASPIN is a new molecular target of P63.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/metabolismo , Serpinas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Feminino , Genes Reporter , Vetores Genéticos , Humanos , Plasmídeos , Regiões Promotoras Genéticas , RNA Mensageiro , Transfecção
3.
Yao Xue Xue Bao ; 48(10): 1570-8, 2013 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-24417084

RESUMO

The design, synthesis and bioevaluation of a series of novel L-tyrosine derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Four intermediates and twenty L-tyrosine derivatives containing phenoxyacetyl moiety TM1 were synthesized starting from L-tyrosine via four step reactions including the esterification of carboxyl group, phenoxyacetylation of a-amino group, bromoalkylation of phenolic hydroxyl group and then nucleophilic substitution reaction with various heterocyclic amines in 21%-75% overall yield. Subsequently TM1 were hydrolyzed to give sixteen corresponding target compounds TM2 in 77%-99% yield. The chemical structures of the thirty-nine new compounds were identified using 1H NMR, 13C NMR techniques and thirty-five were confirmed by HR-MS techniques. Screening results in vitro showed that the PPAR relative activation activities of the target molecules are weak overall, while compound TM2i reaches 50.01%, which hints that the molecular structures of these obtained compounds need to be modified further.


Assuntos
Hipoglicemiantes/síntese química , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Tirosina/análogos & derivados , Tirosina/síntese química , Células Hep G2 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fenoxiacetatos/síntese química , Fenoxiacetatos/química , Fenoxiacetatos/farmacologia , Relação Estrutura-Atividade , Tirosina/química , Tirosina/farmacologia
4.
Bioorg Med Chem ; 20(6): 2119-30, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22364952

RESUMO

We wish to report the further design and improved synthesis that resulted in two series of target molecules, TM-1 and TM-2, with remarkably simplified structures containing ß-amino ketone of discrete nabumetone moiety. These were obtained via a 'one-pot, two-step, three-component' protocol of Mannich reaction with yield up to 97%. A total of 28 out of 31 new compounds were characterized using (1)H NMR, (13)C NMR, ESI MS and HRMS techniques. Studies on their antidiabetic activities, screened in vitro at 10 µg mL(-1) level, indicate that TM-2 possesses peroxisome proliferator-activated receptor activation and α-glucosidase inhibition activity significantly stronger than that of TM-1, and also that of the series B compounds that were previously synthesized by the group. Analysis of the structure-activity relationship points to the sulfanilamide unit as the most probable potent group of ß-amino ketone and, on the basis of which, a tangible strategy is presented for the development of new antidiabetic drugs.


Assuntos
Butanonas/química , Butanonas/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Cetonas/química , Cetonas/farmacologia , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Butanonas/síntese química , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Inibidores de Glicosídeo Hidrolases , Humanos , Hipoglicemiantes/síntese química , Cetonas/síntese química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Nabumetona , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/síntese química , Sulfanilamidas/química , Sulfanilamidas/farmacologia , alfa-Glucosidases/metabolismo
5.
Yao Xue Xue Bao ; 47(12): 1630-9, 2012 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-23460969

RESUMO

The discovery of high performance leading antidiabetic compounds containing sulfonamide and 4-aminophenylacetic acid moieties is reported. This was achieved by the synthesis of 6 intermediates and subsequently 20 target molecules using 4-aminophenylacetic acid as the starting materials, and through a few synthetic routes aided by multi-step reactions including sulfonylation of amino group, deacylation of amides and esterification of carboxyl group, as well as acylation of amino group. The chemical structures of the twenty-four new compounds were determined using 1H NMR, 13C NMR and HR-MS techniques. Screening in vitro of their peroxisome proliferator-activated receptor (PPAR) activation activities showed weak relative PPAR activation activities to most of the target molecules. However, 4 target molecules exhibit PPAR over 58%, and as high as 81.79% for TM2-i, presenting itself as potent leading compound for antidiabetic drugs. This research also confirms that it is probable to achieve esterification of carboxyl group and deacylation of fatty acid N-phenyl amides concurrently in SOCl2/alcohol solvent system. This provides new synthetic method for the selective reaction within molecules containing both carboxyl and N-aryl amido groups of fatty acids.


Assuntos
Hipoglicemiantes/síntese química , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fenilacetatos/síntese química , Compostos de Anilina/química , Ácidos Graxos/química , Células Hep G2/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Fenilacetatos/química , Fenilacetatos/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química
6.
Yao Xue Xue Bao ; 46(4): 412-21, 2011 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-21751495

RESUMO

Twenty five new beta-aminoalcohols containing nabumetone moiety were prepared via the reduction of potassium borohydride with a convenient and efficient procedure, starting from beta-aminoketones that have been synthesized by our group. Their chemical structures were determined by IR, MS, 1H NMR, 13C NMR, HR-MS and antidiabetic activities were screened in vitro. Preliminary results revealed that the antidiabetic activity of most beta-aminoalcohols were better than that of the corresponding beta-aminoketones. Although most compounds showed weak antidiabetic activity, the alpha-glucosidase inhibitory activity of compounds 5hd(1) and 5id(2) reached 74.37% and 90.15%, respectively, which were superior to the positive control. The relative peroxisome proliferator-activated receptor response element (PPRE) activity of five compounds were more than 60%, among them compound 5ca possessed the highest activity (112.59%). As lead molecules of antidiabetic agents, compounds 5hd(1), 5id(2) and 5ca deserve further study.


Assuntos
Amino Álcoois/síntese química , Butanonas/síntese química , Hipoglicemiantes/síntese química , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , alfa-Glucosidases/metabolismo , Amino Álcoois/química , Amino Álcoois/farmacologia , Butanonas/química , Butanonas/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Nabumetona , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Elementos de Resposta
8.
Yao Xue Xue Bao ; 45(1): 66-71, 2010 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-21351452

RESUMO

Searching for new antidiabetic lead compound, 4-(1-aryl-3-oxo-5-phenylpentylamino) benzenesulfonamides were designed and synthesized directly by three component one-pot condensation of 4-phenyl-2-butanone and sulfanilamide with some aromatic aldehydes at an yield of 23%-97%. The chemical structures of the twelve new Mannich bases were confirmed by 1H NMR, 13C NMR, FTIR, ESI-MS and HR-MS. The screening results of antidiabetic activity indicated that most of these title compounds possess alpha-glucosidase inhibitory activity, among which compound le is the strongest one. And compound 11 possesses good peroxisome proliferator-activated receptor response element (PPRE) agonist activity. The structure-activity relationship of these new beta-amino ketones containing benzenesulfonamide unit was also discussed preliminarily.


Assuntos
Hipoglicemiantes/síntese química , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Sulfonamidas/síntese química , alfa-Glucosidases/metabolismo , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Relação Estrutura-Atividade , Sulfanilamida , Sulfanilamidas/química , Sulfonamidas/química , Sulfonamidas/farmacologia
9.
J Nat Prod ; 72(6): 1198-201, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19476336

RESUMO

Four new compounds including three bicoumarins, arteminorins A-C (1-3), and one neolignan, arteminorin D (4), together with 31 known ones were isolated from the aerial parts of Artemisia minor. Their structures were established on the basis of spectroscopic data and comparison with those of the related known compounds. Ethyl caffeate (27) showed in vitro cytotoxicity against the HepG2 cancer cell line. Arteminorin C (3) and luteolin (19) showed inhibitory activity on xanthine oxidase (XOD), and caffeic acid (28) exhibited inhibitory activity on protein tyrosine phosphatase 1B (PTP1B).


Assuntos
Artemisia/química , Cumarínicos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Lignanas/isolamento & purificação , Plantas Medicinais/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Ácidos Cafeicos/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Lignanas/química , Lignanas/farmacologia , Estrutura Molecular , Tibet
10.
Yao Xue Xue Bao ; 44(1): 48-55, 2009 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-19350821

RESUMO

In order to find highly active antidiabetic lead compound, sixteen 4-aminobenzoic acid derivatives were designed and synthesized directly through Mannich reaction in the solution of ethanol at 15-35 degrees C with facile method, mild reaction condition and high yield (45%-90%). Fifteen of them are new compounds. Their structures were confirmed by 1H NMR, 13C NMR, IR, ESI-MS and HR-MS. Alpha-glucosidase inhibitory activity of these compounds indicated that most of these compounds possess the activity with the order: 2c > 2b > 2h > 1a > 1f. The structure-activity relationship of these 4-aminobenzoic acid derivatives was also discussed.


Assuntos
Ácido 4-Aminobenzoico/síntese química , Hipoglicemiantes/síntese química , alfa-Glucosidases/metabolismo , para-Aminobenzoatos , Ácido 4-Aminobenzoico/farmacologia , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes/farmacologia , Bases de Mannich/química , Estrutura Molecular , Relação Estrutura-Atividade
11.
Yao Xue Xue Bao ; 44(11): 1244-51, 2009 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-21355325

RESUMO

Diabetes mellitus is a common metabolic disease with a high and growing prevalence affecting 4% of the population worldwide, the development of safe and effective therapeutic drug is the major thrust for chemists and pharmacists. To search for active antidiabetic lead compound, we designed and synthesized some novel beta-amino ketone derivatives containing sulfamethoxazole moiety directly through Mannich reaction of sulfamethoxazole, 4-bromoacetophenone and some aromatic aldehydes catalyzed by concentrated hydogen chloride or iodine in the solution of ethanol at 24-40 degrees C with convenient operation, mild reaction condition and satisfactory yield (32%-90%). Their chemical structures were characterized by 1H NMR, 13C NMR, MS and HR-MS. Biological activity tests showed that, in the range of low concentration (5-10 microg x mL(-1)), these title compounds to a certain degree possess protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and a-glucosidase inhibitory activity, moreover, some could activate peroxisome proliferator-activated receptor response element (PPRE) moderately. The PPRE agonist activities of seven compounds are almost 40% of that of Pioglitazone (the positive control), compound 12 shows the strongest activity (66.35%) among them. Thus, it was found that some of 4-(3-(4-bromophenyl)-3-oxo-1-arylpropylamino)-N-(5-methyl-isoxazol-3-yl) benzenesulfonamide containing sulfamethoxazole moiety exhibited antidiabetic activity for the first time.


Assuntos
Hipoglicemiantes/síntese química , Oxazóis/química , Sulfonamidas/química , Inibidores de Glicosídeo Hidrolases , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Pioglitazona , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Elementos de Resposta , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia
12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 38(5): 816-8, 2007 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-17953366

RESUMO

OBJECTIVE: To study the mechanism of rosiglitasone to improve glucose-uptake of 3T3-L1 adipocyte with insulin resistance induced by dexamethasone and insulin. METHODS: Insulin resistance was induced to 3T3-L1 adipocyte after chronic treatment of dexamethasone and insulin. The insulin resisted 3T3-L1 adipocyte was treated with 10(-5) mol/L of rosiglitasone for 48 h. The mRNA, protein of glucose transporter GLUT4 and CAP gene were then examined. RESULTS: (1) Rosiglitasone increased the expression of GLUT4 mRNA and protein inhibited by dexamethasone and insulin although it had not reached a normal level. (2) Rosiglitasone increased the mRNA of CAP, which remained unchanged during insulin resistance. CONCLUSION: Rosiglitasone, an insulin sensitizer, might up-regulate GLUT4 and CAP along with the peroxisome proliferators activated receptor gamma (PPAR-gamma), which not only increases the GLUT4, but also activates the CAP-depended signaling pathway; improves the translocating of GLUT4 to the cell membrane; and increases the ability of glucose-uptake of cells.


Assuntos
Adipócitos/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Tiazolidinedionas/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Proteínas do Citoesqueleto/metabolismo , Dexametasona/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Insulina/farmacologia , Camundongos , Rosiglitazona
13.
Molecules ; 12(4): 885-95, 2007 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-17851441

RESUMO

During the course of studies directed towards the discovery of novel aldose reductase inhibitors for the treatment of diabetic complications, we synthesized a series of new (Z)-3-phenyl-2-benzoylpropenoic acid derivatives and tested their in vitro inhibitory activities on rat lens aldose reductase. Of these compounds, (Z)-3-(3,4-dihydroxyphenyl)-2-(4-methylbenzoyl)propenoicacid (3k) was identified as the most potent inhibitor, with an IC50 of 0.49 microM. The theoretical binding mode of 3k was obtained by simulation of its docking into the active site of the human aldose reductase crystal structure.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Benzoatos/química , Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Propionatos/química , Aldeído Redutase/química , Aminoácidos/química , Sítios de Ligação , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
14.
J Nat Prod ; 69(9): 1374-6, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16989540

RESUMO

Three new epipolythiodioxopiperazines, chaetocochins A (1), B (2), and C (3), along with dethio-tetra (methylthio) chetomin (4) and chetomin (5), were isolated from the ethyl acetate extract of the solid-state fermented rice culture of the fungus Chaetomium cochliodes. Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1, 3, and 4 exhibited significant cytotoxicity in vitro against cancer cell lines Bre-04, Lu-04, and N-04.


Assuntos
Antineoplásicos , Chaetomium/química , Alcaloides Indólicos , Oryza/microbiologia , Piperazinas , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Piperazinas/química , Piperazinas/isolamento & purificação , Piperazinas/farmacologia
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