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1.
Bioorg Med Chem Lett ; 30(13): 127220, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32386979

RESUMO

Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent - hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the -NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate "fungicide-like" properties and were devoted of cytotoxicity.


Assuntos
Antifúngicos/farmacologia , Hidrazonas/farmacologia , Pirrolidinonas/farmacologia , Antifúngicos/síntese química , Desenho de Fármacos , Fungos/efeitos dos fármacos , Hidrazonas/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirrolidinonas/síntese química , Relação Estrutura-Atividade
2.
Bioorg Chem ; 96: 103643, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035298

RESUMO

The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects. The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones. Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested. Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range. The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules. Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.


Assuntos
Acetatos/farmacologia , Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Moduladores de Tubulina/farmacologia , Acetatos/química , Antineoplásicos/química , Benzofenonas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/química , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
3.
Chemistry ; 25(24): 6113-6118, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30908789

RESUMO

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.

4.
Arch Pharm (Weinheim) ; 352(5): e1800227, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30947375

RESUMO

Unprecedented triazinyl-isoxazoles were afforded via an effective cycloaddition reaction between nitrile oxides and the scarcely described 2-ethynyl-4,6-dimethoxy-1,3,5-triazine as dipolarophile. The biological evaluation of the newly synthesized compounds showed that the inhibition of human farnesyltransferase by zinc complexation could be improved with triazine-isoxazole moieties. The replacement of the isoxazole unit by a pyrrolidin-2-one was detrimental to the inhibitory activity while the pyrrolidin-2-thione derivatives conserved the biological potential. The potential of selected compounds to disrupt protein farnesylation in Chinese hamster ovary (CHO) cells transfected with pEGFP-CAAX was also evaluated.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Isoxazóis/farmacologia , Pirrolidinonas/farmacologia , Triazinas/farmacologia , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Farnesiltranstransferase/metabolismo , Humanos , Isoxazóis/química , Estrutura Molecular , Pirrolidinonas/química , Relação Estrutura-Atividade , Triazinas/química
5.
J Sci Food Agric ; 99(4): 1780-1786, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30226928

RESUMO

BACKGROUND: To promote sustainable agriculture and healthy food, research that contributes towards a new generation of eco-friendly phytosanitary compounds is increasingly encouraged. The plant hormone salicylic acid (SA) is known for its ability to induce resistance in plants against a wide range of pathogens, whereas pyroglutamic acid (PGA), a constrained analogue of γ-aminobutyric acid, has never been studied in the context of plant protection. RESULTS: The present study investigated for the first time the protection efficacy of SA and PGA and five new conjugated derivatives against Zymoseptoria tritici, the main pathogen in wheat crops. SA and four derivatives showed significant disease severity reductions in planta (up to 49%). In vitro assays revealed that some molecules, including SA, displayed a small direct antifungal activity, whereas others, such as PGA, showed no effect. This finding suggests that, especially for molecules without any direct activity, the mode of action relies mainly on the induction of plant resistance. CONCLUSION: Further investigations are needed to identify the defence pathways involved in plant resistance mechanisms elicited or primed by the molecules. The manufacture of these products was easily achieved on a scale of tens of grams of raw materials, and is easily scalable. The synthetic pathway is simple, short and inexpensive. For all of these reasons, the production of the target molecules is attractive for producers, whereas the prospect of a generation of non-polluting compounds with lasting efficiency against Z. tritici in wheat comes at a key moment for the sustainability of agriculture. © 2018 Society of Chemical Industry.


Assuntos
Ascomicetos/fisiologia , Doenças das Plantas/imunologia , Ácido Pirrolidonocarboxílico/imunologia , Ácido Salicílico/imunologia , Triticum/imunologia , Resistência à Doença , Doenças das Plantas/microbiologia , Ácido Pirrolidonocarboxílico/química , Ácido Salicílico/química , Triticum/microbiologia
6.
Org Biomol Chem ; 15(38): 8110-8118, 2017 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-28905970

RESUMO

In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Ácido Pirrolidonocarboxílico/análogos & derivados , Sítios de Ligação , Simulação por Computador , Inibidores Enzimáticos/química , Humanos , Modelos Biológicos , Estrutura Molecular , Conformação Proteica , Ácido Pirrolidonocarboxílico/metabolismo
7.
Bioorg Med Chem ; 24(22): 6021-6030, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27707624

RESUMO

The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the "CH2" bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6-8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25nM against the melanoma MDA-MB-435 cell line.


Assuntos
Antineoplásicos/farmacologia , Fenotiazinas/farmacologia , Tubulina (Proteína)/metabolismo , 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 , Modelos Moleculares , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 24(10): 2307-17, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27073050

RESUMO

New phenothiazine derivatives 6-20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2'-fluoro-4'-methoxy substitution in compound 6 and the 2'-trifluoromethyl-4'-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6-8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke's type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Fenotiazinas/química , Fenotiazinas/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
9.
Bioorg Med Chem Lett ; 25(18): 3975-9, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26227778

RESUMO

A new family of 3-aroylindolizines bearing a dimethoxytriazine unit in their position 1 was designed, synthesized and evaluated for their ability to inhibit tubulin polymerization and cellular growth in vitro. Compound 39 was the best candidate in the current study with a GI50 value of 870 nM on SNB-75 CNS cancer cells and of 920 nM on MDA-MB-231/ATCC breast cancer cells. The standard NCI Compare results indicated that indolizine 39 may target PLK1 (polo-like kinase 1).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Indolizinas/química , Indolizinas/farmacologia , Mitose/efeitos dos fármacos , Triazinas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/farmacologia , Tubulina (Proteína)/metabolismo
10.
Bioorg Med Chem Lett ; 25(20): 4447-52, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26372651

RESUMO

A new family of CaaX competitive inhibitors of human farnesyltransferase based on phenothiazine and carbazole skeleton bearing a l-cysteine, l-methionine, l-serine or l-valine moiety was designed, synthesized and biologically evaluated. Phenothiazine derivatives proved to be more active than carbazole-based compounds. Phenothiazine 1b with cysteine residue was the most promising inhibitor of human farnesyltransferase in the current study.


Assuntos
Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Fenotiazinas/farmacologia , Aminoácidos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Cisteína/química , Cisteína/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/metabolismo , Humanos , Metionina/química , Metionina/metabolismo , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Serina/química , Serina/metabolismo , Relação Estrutura-Atividade , Valina/química , Valina/metabolismo
11.
Electrophoresis ; 35(19): 2892-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24854176

RESUMO

This work concerns the successful enantiomeric separation of pyroglutamic acid derivatives, known to be P2X7 receptor antagonists, achieved by electrokinetic chromatography. After a broad screening, two negatively charged cyclodextrins, sulfobutylether-ß-cyclodextrin (SBE-ß-CD), and highly sulfated-γ-cyclodextrin (HS-γ-CD) were chosen as stereoselective agents to cooperate with the BGE for complexation. A fused silica capillary coated with polyethylene oxide, filled with a phosphate buffer (25 mM, pH 2.5) containing various concentrations of CD, was used. Assuming a 1:1 stoichiometry, calculations of the binding constants, employing the three different linearization plots, were performed from the corrected electrophoretic mobilities values of the enantiomers, at different concentrations of SBE-ß-CD and HS-γ-CD in the BGE. The highest complexation was found with the SBE-ß-CD. Among the three equations, results showed better linearity (R(2) > 0.99) using the y-reciprocal fit. This plotting method was then performed to determine the binding constants of each enantiomer at different temperature for compounds 1 and 2 with SBE-ß-CD and HS-γ-CD in order to access to the thermodynamic parameters of the eight complexes. The linearity of the Van't Hoff plot, in the range of 288-303 K leading to negative enthalpy values, showed that the complexation phenomenon is enthalpically controlled and thermodynamically favored.


Assuntos
Cromatografia Capilar Eletrocinética Micelar/métodos , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/isolamento & purificação , gama-Ciclodextrinas/química , Reprodutibilidade dos Testes , Estereoisomerismo , Termodinâmica
12.
Chemistry ; 20(32): 10117-30, 2014 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-25042333

RESUMO

A rapid domino π-cationic arylation of aromatic carboxylic acids, mediated by Eaton's reagent, has been developed for the synthesis of Iasi-red polymethoxylated polycyclic aromatic hydrocarbons (PAHs). This route is currently the easiest method to obtain such popular PAH compounds, which bear in addition numerous methoxy groups. The domino process was generalized, the structure of the obtained red products and the mechanism of their formations were elucidated, and some of their photophysical properties were determined. Newly synthesized polymethoxylated-PAHs were tested for their interaction with tubulin polymerization as well as for their cytotoxicity on a panel of NCI-60 human cancer cell lines. Interestingly, one of these rubicene derivatives exhibited remarkable cytotoxicity in vitro, including inhibition of leukemia, colon, melanoma, CNS, and ovarian cancer cell lines with GI50 values in the low nanomolar range (GI50 < 10 nM).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular Tumoral , Humanos , Indicadores e Reagentes , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Polimerização/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química
13.
Bioorg Med Chem Lett ; 24(14): 3180-5, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24856060

RESUMO

Novel phenothiazine derivatives bearing an amino acid residue were synthesized via peptide chemistry, and evaluated for their inhibitory potential on human farnesyltransferase. The phenothiazine unit proved to be an important bulky unit in the structure of the synthesized inhibitors. Propargyl ester 20 bearing a tyrosine residue exhibited the best biological potential in vitro in the present study. Further syntheses and biological evaluation of phenothiazine derivatives are necessary in order to gain a full view of SAR in this family of farnesyltransferase inhibitors.


Assuntos
Farnesiltranstransferase/antagonistas & inibidores , Peptídeos/química , Fenotiazinas/farmacologia , Relação Dose-Resposta a Droga , Farnesiltranstransferase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Fenotiazinas/síntese química , Fenotiazinas/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 24(5): 1322-6, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24508127

RESUMO

A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.


Assuntos
Adamantano/análogos & derivados , Amidoidrolases/antagonistas & inibidores , Anti-Inflamatórios/química , Canabinoides/química , Inibidores Enzimáticos/química , Isoxazóis/química , Receptor CB2 de Canabinoide/agonistas , Adamantano/química , Adamantano/farmacologia , Adamantano/uso terapêutico , Amidoidrolases/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Colite/tratamento farmacológico , Colite/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 23(21): 5887-92, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24054122

RESUMO

A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity on human protein farnesyltransferase. Most of these novel compounds possessed in vitro inhibition potencies in the micromolar range. The nature of the substituents on the pyridine and phenyl units proved to be important in determining inhibitory activity and generally, the replacement of the cyanoacrylonitrile function by a cyanoethylacrylate group decreased the biological potential on farnesyltransferase. These results completed our SAR study on this original class of N-ylides.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/metabolismo , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 23(1): 147-52, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23200248

RESUMO

A new family of microtubule-targeting agents with a phenothiazine A-ring was synthesized and evaluated for anti-proliferative activity and interaction with tubulin. These new derivatives showed significant activities against cellular proliferation and tubulin polymerization, rather similar to those of phenstatin. Phenothiazine derivative 21 proved to be the most potent compound synthesized with GI(50) values ranging from 29 to 93 nM on different cell lines. The same compound showed a better inhibition of COLO 205, A498, and MCF7 cell lines than the parent phenstatin.


Assuntos
Antineoplásicos/síntese química , Fenotiazinas/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Fenotiazinas/química , Fenotiazinas/toxicidade , Polimerização/efeitos dos fármacos , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidade
17.
Bioorg Med Chem ; 21(11): 2932-40, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23618708

RESUMO

With the aim of investigating the influence of fluorine, in particular on the A-ring, a new series of fluoro analogues (7a-l) of phenstatin (3) was synthesized and tested for interactions with tubulin polymerization and evaluated for cytotoxicity on an NCI-60 human cancer cell lines panel. We have shown that the replacement of 3,4,5-trimethoxyphenyl A-ring of phenstatin with 2,4,5-trifluoro-3-methoxyphenyl unit, results in the conservation of both antitubulin and cytotoxic effect. Fluoro isocombretastatin 7k was the most effective anticancer agent in the present study and demonstrated the highest antiproliferative potential on leukemia cell lines SR (GI50=15 nM) and HL-60(TB) (GI50=23 nM) and on melanoma cell line MDA-MB-435 (GI50=19 nM).


Assuntos
Antimitóticos/síntese química , Antineoplásicos/síntese química , Benzofenonas/síntese química , Compostos de Flúor/síntese química , Organofosfatos/síntese química , Pró-Fármacos/síntese química , Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos de Flúor/farmacologia , Halogenação , Humanos , Concentração Inibidora 50 , Mitose/efeitos dos fármacos , Organofosfatos/farmacologia , Pró-Fármacos/farmacologia
18.
Bioorg Med Chem ; 21(17): 5383-94, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23849204

RESUMO

Recent investigations showed that anandamide, the main endogenous ligand of CB1 and CB2 cannabinoid receptors, possesses analgesic, antidepressant and anti-inflammatory effects. In the perspective to treat inflammatory bowel disease (IBD), our approach was to develop new selective CB2 receptor agonists without psychotropic side effects associated to CB1 receptors. In this purpose, a new series of 3-carboxamido-5-aryl-isoxazoles, never described previously as CB2 receptor agonists, was designed, synthesized and evaluated for their biological activity. The pharmacological results have identified great selective CB2 agonists with in vivo anti-inflammatory activity in a DSS-induced acute colitis mouse model.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Isoxazóis/química , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Células HT29 , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Isoxazóis/uso terapêutico , Isoxazóis/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Sci Rep ; 13(1): 90, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36596821

RESUMO

The current worldwide context promoting agroecology and green agriculture require the discovery of new ecofriendly and sustainable plant protection tools. Plant resistance inducers, called also elicitors, are one of the most promising alternatives fitting with such requirements. We produced here a set of 30 molecules from pyroglutamic acid, bio-sourced from sugar beet byproducts, and examined for their biological activity on the major agro-economically pathosystem wheat-Zymoseptoria tritici. Foliar application of the molecules provided significant protection rates (up to 63% disease severity reduction) for 16 among them. Structure-activity relationship analysis highlighted the importance of all chemical groups of the pharmacophore in the bioactivity of the molecules. Further investigations using in vitro and in planta antifungal bioassays as well as plant molecular biomarkers revealed that the activity of the molecules did not rely on direct biocide activity towards the pathogen, but rather on the activation of plant defense mechanisms dependent on lipoxygenase, phenylalanine ammonia-lyase, peroxidase, and pathogenesis-related protein pathways. This study reports a new family of bio-sourced resistance inducers and provides new insights into the valorization of agro-resources to develop the sustainable agriculture of tomorrow.


Assuntos
Beta vulgaris , Triticum , Triticum/microbiologia , Doenças das Plantas/microbiologia , Imunidade Vegetal , Verduras , Açúcares
20.
Bioorg Med Chem ; 19(20): 6042-54, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21920767

RESUMO

Previous investigations on the incubation of phenstatin with rat and human microsomal fractions revealed the formation of nine main metabolites. The structures of eight of these metabolites have been now confirmed by synthesis and their biological properties have been reported. Eaton's reagent was utilized as a convenient condensing agent, allowing, among others, a simple multigram scale preparation of phenstatin. Synthesized metabolites and related compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell line panel, and for their effect on microtubule assembly. Metabolite 23 (2'-methoxyphenstatin) exhibited the most potent in vitro cytotoxic activity: inhibition of the growth of K-562, NCI-H322M, NCI-H522, KM12, M14, MDA-MB-435, NCI/ADR-RES, and HS 578T cell lines with GI(50) values <10nM. It also showed more significant tubulin polymerization inhibitory activity than parent phenstatin (3) (IC(50)=3.2 µM vs 15.0 µM) and induced G2/M arrest in murine leukemia DA1-3b cells. The identification of this active metabolite led to the design and synthesis of analogs with potent in vitro cytotoxicity and inhibition of microtubule assembly.


Assuntos
Antineoplásicos/síntese química , Benzofenonas/síntese química , Benzofenonas/farmacologia , Organofosfatos/síntese química , Organofosfatos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofenonas/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Microtúbulos/metabolismo , Organofosfatos/metabolismo , Ratos , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
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