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1.
Molecules ; 24(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987238

RESUMO

The behavior of 2-naphthol and 7-bromo-2-naphthol as organic photoacids are exploited in organic synthesis for the preparation of benzyl sulfides (using a trichloroacetimidate derivative as the starting substrate) and polycyclic amines via acid catalyzed condensation of 1,2,3,4-tetrahydroisoquinoline with aldehydes.


Assuntos
Ácidos/química , Prótons , Alcaloides/síntese química , Alcaloides/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Catálise
2.
Mar Drugs ; 17(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736380

RESUMO

In this study, as part of our continuous search for environmentally-friendly antifoulants from natural resources, subergorgic acid (SA) was identified from the gorgonian coral Subergorgia suberosa, demonstrating non-toxic, significant inhibitory effects (EC50 1.25 µg/mL, LC50 > 25 µg/mL) against the settlement of Balanus amphitrite. To further explore the bioactive functional groups of SA and synthesize more potent antifouling compounds based on the lead SA, the structure-activity relationships of SA were studied, followed by rational design and synthesis of two series of SA derivatives (one being benzyl esters of SA and another being SA derivatives containing methylene chains of various lengths). Our results indicated that (1) both the double bond and ketone carbonyl are essential elements responsible for the antifouling effect of SA, while the acid group is not absolutely necessary for maintaining the antifouling effect; (2) all benzyl esters of SA displayed good antifouling effects (EC50 ranged from 0.30 to 2.50 µg/mL) with the most potent compound being 5 (EC50 0.30 µg/mL, LC50 > 25 µg/mL), which was over four-fold more potent than SA; and (3) the introduction of a methylene chain into SA reduces the antifouling potency while the length of the methylene chain may differently influence the antifouling effect, depending on the functional group at the opposite site of the methylene chain. Not only has this study successfully revealed the bioactive functional groups of SA, contributing to the mechanism of SA against the settlement of B. amphitrite, but it has also resulted in the identification of a more potent compound 5, which might represent a non-toxic, high-efficiency antifoulant.


Assuntos
Antozoários/química , Incrustação Biológica/prevenção & controle , Sesquiterpenos/química , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Estrutura Molecular , Sesquiterpenos/síntese química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Thoracica/efeitos dos fármacos
3.
Molecules ; 24(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669410

RESUMO

The biology of the group of plant hormones termed cytokinins is reviewed to reveal areas where further studies of cytokinin-binding proteins could be significant. Such areas include: inhibition of human tumour cell growth by cytokinin ribosides, the role of cytokinins in the development of diverse micro-organisms including the cyanobacteria and Mycobacterium tuberculosis, the very rapid responses of plant cells to exogenous cytokinins, and other aspects of cytokinin plant biology. Photoaffinity labelling (PAL) coupled to the recent advances in HPLC of proteins and mass spectral analysis and sequencing of proteins, may have relevance to these areas. To facilitate PAL, we present experimental details for two methods for synthesis of 8-azido-N6-benzyladenine, which has the azido affinity group in the preferred position of the purine ring. Synthesis from [2-³H]adenosine yielded the above-mentioned PAL reagent with ³H in the purine ring and also gave labelled 9-riboside and 8-azido-N6,9-dibenzyladenine. 8-Azido-N6-benzyladenine was also prepared from 6,8-dichloropurine by a facile synthesis, which would allow a label to be sited in the benzyl group where substituents can also be introduced to vary cytokinin activity. The use of inactive cytokinin analogues in assessing the significance of PAL is discussed.


Assuntos
Compostos de Benzil/síntese química , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Técnicas de Química Sintética , Citocininas/metabolismo , Processos Fotoquímicos , Purinas/síntese química , Adenosina/análogos & derivados , Adenosina/química , Compostos de Benzil/química , Cloroquinolinóis/química , Estrutura Molecular , Purinas/química , Coloração e Rotulagem
4.
Molecules ; 23(9)2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177664

RESUMO

Inspired by the well-established clinical evidence about the interplay between apoptotic TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) mechanism and reactive oxygen species (ROS)-mediated oxidative stress, a set of novel ONC201 hybrids containing the impiridone core and one or two differently positioned ferrocenylalkyl groups were synthesised in our present work. These two types of residues have been implicated in the aforementioned mechanisms associated with cytotoxic activity. A straightforward, primary amine-based synthetic approach was used allowing the introduction of a variety of N-substituents into the two opposite regions of the heterocyclic skeleton. Reference model compounds with benzyl and halogenated benzyl groups were also synthesised and tested. The in vitro assays of the novel impiridones on five malignant cell lines disclosed characteristic structure-activity relationship (SAR) featuring significant substituent-dependent activity and cell-selectivity. A possible contribution of ROS-mechanism to the cytotoxicity of the novel metallocenes was suggested by density functional theory (DFT)studies on simplified models. Accordingly, unlike the mono-ferrocenylalkyl-substituted products, the compounds containing two ferrocenylalkyl substituents in the opposite regions of the impiridone core display a much more pronounced long-term cytotoxic effect against A-2058 cell line than do the organic impiridones including ONC201 and ONC212. Furthermore, the prepared bis-metallocene derivatives also present substantial activity against COLO-205- and EBC-1 cell lines.


Assuntos
Antineoplásicos/síntese química , Compostos Ferrosos/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Metalocenos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Humanos , Metalocenos/química , Metalocenos/farmacologia , Modelos Moleculares , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
5.
Arch Pharm (Weinheim) ; 351(7): e1800029, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29963738

RESUMO

meta-Cyanobenzyl-substituted N-heterocyclic carbene (NHC) precursors were synthesized by the reaction of a series of N-(alkyl)benzimidazolium with 3-bromomethyl-benzonitrile. These benzimidazolium salts were characterized by using 1 H NMR, 13 C NMR, FTIR spectroscopy, and elemental analysis techniques. The molecular and crystal structures of 2f and 2g complexes were obtained by using the single-crystal X-ray diffraction method. The derivatives of these novel NHC precursors were effective inhibitors of α-glycosidase (AG), the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with Ki values in the range of 1.01-2.12 nM for AG, 189.56-402.44 nM for hCA I, 112.50-277.37 nM for hCA II, 95.45-352.58 nM for AChE, and 132.91-571.18 nM for BChE. In the last years, inhibition of the CA enzyme has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances such as obesity, glaucoma, cancer, and epilepsy.


Assuntos
Butirilcolinesterase/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Cristalização , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Relação Estrutura-Atividade , Difração de Raios X
6.
Anticancer Drugs ; 29(6): 503-512, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29697412

RESUMO

Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N-methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-tertbutyl-D-leucine-N-methyl-D-leucinebenzyl (A7), the only stereomer condensed by two D-leucines, showed the highest antineoplastic activity. A7-treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase-3, as well as increased intracellular Ca levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the D/L conformation of the amino-acid residue are critical for their activity.


Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Neoplasias/tratamento farmacológico , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Neoplasias/patologia
7.
Viruses ; 10(3)2018 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-29522484

RESUMO

Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 µM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment.


Assuntos
Adamantano/análogos & derivados , Antivirais/farmacologia , Compostos de Benzil/farmacologia , Herpes Genital/prevenção & controle , Herpes Simples/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Sobrevivência Celular/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Feminino , Herpes Genital/virologia , Herpes Simples/virologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células Vero , Carga Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
Int J Biol Macromol ; 113: 8-19, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29454949

RESUMO

Iron-carboxylate (MIL-100(Fe)) and HKUST-1 (Cu3(BTC)2, BTC=1,3,5-benzenetricarboxylic acid) as nanoporous metal organic framework supports were compared for immobilization of porcine pancreatic lipase (PPL). These immobilizations improved thermal, pH and operational stability of PPL compared to the soluble enzyme. Stability of MIL-100(Fe) was better than HKUST-1 as support. MIL-100(Fe) encapsulated Keggin phosphotungstic acid H3PW12O40 (PW) (PW@MIL-100(Fe)) was synthesized to develop novel enzyme immobilized system and characterized by Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), Brunauer-Emmett-Teller (BET), X-ray diffraction (XRD) and Barrett Joyner Halenda (BJH) analysis. Relative activity for immobilized lipase on PW@MIL-100(Fe) was more than MIL-100(Fe) in pH range of 3-9. At the elevated temperature of 70°C, the PW@MIL-100(Fe) was the most stable one. PW@MIL-100(Fe)/PPL substrate exhibited the higher stability at 4°C and 25°C, along with other supports. Moreover, PW@MIL-100(Fe) was chosen as the best support for immobilization of PPL and was also applied for the synthesis of benzyl cinnamate by enzymatic esterification of cinnamic acid. The immobilized enzyme retained 90.4% of its initial activity during synthesis of benzyl cinnamate after 5 successive catalytic rounds and reached 80.0% yield after 8 reuses.


Assuntos
Compostos de Benzil/química , Compostos de Benzil/síntese química , Biocatálise , Cinamatos/química , Cinamatos/síntese química , Lipase/química , Lipase/metabolismo , Estruturas Metalorgânicas/química , Compostos de Tungstênio/química , Técnicas de Química Sintética , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Esterificação , Química Verde , Concentração de Íons de Hidrogênio , Temperatura Ambiente
9.
Eur J Med Chem ; 143: 97-106, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29172086

RESUMO

A series of N-benzyl tetrahydropiperidinylidene pyrrolidinium salts have been synthesized and investigated for their antiplasmodial and antitrypanosomal activities as well as for their cytotoxic effects. The antibacterial, antimycobacterial and anticancer potencies of selected compounds were examined, too. Physicochemical parameters were calculated and structure-activity-relationships are discussed.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Compostos de Benzil/farmacologia , Piridinas/farmacologia , Compostos de Amônio Quaternário/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Bactérias/efeitos dos fármacos , Compostos de Benzil/síntese química , Compostos de Benzil/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Piridinas/síntese química , Piridinas/química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Ratos , Saccharomyces cerevisiae/efeitos dos fármacos , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos
10.
Eur J Pharmacol ; 820: 8-17, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29225193

RESUMO

The purinergic receptor P2X ligand-gated ion channel 7 (P2X7 receptor) is a promising imaging target to detect neuroinflammation. Herein, we report development of a potent iodinated radiotracer for P2X7 receptor, [123I]TZ6019. The radiosynthesis of [123I]TZ6019 was accomplished by allylic-tin precursor iodination using [123I]NaI with good radiochemical yield of 85% and high radiochemical purity of > 99%. Human embryonic kidney 293 (HEK-293) cell line stably transfected with the human P2X7 receptor was used to characterize the binding affinity of TZ6019 by fluorescence, radioactive competitive, and saturation binding assays. A radioligand competitive binding assay with [123I]TZ6019 demonstrated that the nonradioactive compound TZ6019 has an IC50 value of 9.49 ± 1.4nM, and the known P2X7 receptor compound GSK1482160 has an IC50 value of 4.30 ± 0.86nM, consistent with previous reports. The radioligand saturation binding assay and competitive assay revealed that [123I]TZ6019 specifically bound to the human P2X7 receptor with high affinity (Ki = 6.3 ± 0.9nM). In vitro autoradiography quantification with brain slices collected from 9-month old P301S tau transgenic mice along with wild type controls, revealed higher binding of [123I]TZ6019 (35% increase) in the brain of P301S transgenic mice (n = 3, p = 0.04) compared to wild type controls. The immunofluorescence microscopy confirmed that expression of P2X7 receptor was colocalized with astrocytes in the tauopathy P301S transgenic mice. [123I]TZ6019 has specific binding for P2X7 receptor and has great potential to be a radiotracer for screening new compounds and quantifying expression of P2X7 receptor in neuroinflammation related diseases.


Assuntos
Doença de Alzheimer/metabolismo , Compostos de Benzil/metabolismo , Pirrolidinas/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animais , Astrócitos/metabolismo , Compostos de Benzil/síntese química , Compostos de Benzil/química , Ligação Competitiva , Encéfalo/metabolismo , Técnicas de Química Sintética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligantes , Camundongos , Pirrolidinas/síntese química , Pirrolidinas/química , Radioquímica
11.
Molecules ; 22(12)2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215558

RESUMO

Enzymes serve as biocatalysts for innumerable important reactions, however, their application has limitations, which can in many cases be overcome by using appropriate immobilization strategies. Here, a new support for immobilizing enzymes is proposed. This hybrid organic-inorganic support is composed of chitosan-a natural, nontoxic, biodegradable, and edible biopolymer-and sodium polyphosphate as the inorganic component. Lipase B from Candida antarctica (CALB) was immobilized on microspheres by encapsulation using these polymers. The characterization of the composites (by infrared spectroscopy, thermogravimetric analysis, and confocal Raman microscopy) confirmed the hybrid nature of the support, whose external part consisted of polyphosphate and core was composed of chitosan. The immobilized enzyme had the following advantages: possibility of enzyme reuse, easy biocatalyst recovery, increased resistance to variations in temperature (activity declined from 60 °C and the enzyme was inactivated at 80 °C), and increased catalytic activity in the transesterification reactions. The encapsulated enzymes were utilized as biocatalysts for transesterification reactions to produce the compound responsible for the aroma of jasmine.


Assuntos
Compostos de Benzil/síntese química , Quitosana/química , Enzimas Imobilizadas/química , Proteínas Fúngicas/química , Lipase/química , Polifosfatos/química , Adsorção , Biocatálise , Candida/química , Candida/enzimologia , Enzimas Imobilizadas/isolamento & purificação , Esterificação , Proteínas Fúngicas/isolamento & purificação , Lipase/isolamento & purificação , Microesferas , Análise Espectral/métodos
12.
Chemistry ; 23(62): 15775-15782, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-28857290

RESUMO

Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure-activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.


Assuntos
Compostos de Benzil/química , Imidazóis/química , Glicoproteínas de Membrana/antagonistas & inibidores , Compostos de Benzil/síntese química , Compostos de Benzil/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Polarização de Fluorescência , Humanos , Ligações de Hidrogênio , Imidazóis/síntese química , Imidazóis/toxicidade , Glicoproteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Resorcinóis/química , Relação Estrutura-Atividade
13.
Carbohydr Res ; 450: 10-11, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28822278

RESUMO

N-Phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) is a reagent widely used for the preparation of glycosyl N-phenyltrifluoroacetimidates. However, the most commonly applied method requires carbon tetrachloride, a hepatotoxic reagent that has been phased out under the Montreal Protocol. We report a new synthesis of N-phenyltrifluoroacetimidoyl chloride (PTFAI-Cl) using dichlorotriphenylphosphane and triethylamine.


Assuntos
Compostos de Benzil/síntese química , Cloretos/química , Cloretos/síntese química , Hidrocarbonetos Halogenados/síntese química , Técnicas de Química Sintética , Glicosilação , Química Verde , Estereoisomerismo
14.
Bioorg Med Chem Lett ; 27(17): 3945-3949, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28789893

RESUMO

A library of 89 synthetic benzenesulfonyl derivatives of heterocycles with drug-like properties was assayed for in vitro antiparasitic activity and the results were added to our previously reported derivatives for a comprehensive SAR evaluation. Four compounds showed an IC50 between 0.25 and 3µM against Leishmania donovani and low cytotoxicity. Compound G{16} (1-(2,3,5,6-tetramethylphenylsulfonyl)-2-methylindoline), was particularly interesting with an IC50 similar to the reference drug miltefosine. Seven compounds showed an IC50 below 6µM against Trypanosoma cruzi, and three of them (E{3}, E{9} and G{3}) were identified as lead scaffolds for further optimization based on their activity-toxicity profile. Two promising structures (B{15} and G{15}) showed moderate inhibitory activity against Plasmodium falciparum. In general, the presence of a benzenesulfonyl moiety improves the antiparasitic activity of the heterocycles included in this study (with the exception of Trypanosoma brucei rhodesiense), validating the criteria used in the selection of the privileged structures and diversification used to generate this library. SAR analysis showed that the presence of lipophilic and electron withdrawing groups were favorable for the antiparasitic activity.


Assuntos
Antiparasitários/farmacologia , Compostos de Benzil/farmacologia , Compostos Heterocíclicos/farmacologia , Mioblastos/efeitos dos fármacos , Animais , Antiparasitários/síntese química , Antiparasitários/química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Leishmania donovani/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
15.
Eur J Med Chem ; 136: 104-113, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28486208

RESUMO

MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [11C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in vitro inhibitory activity, ex vivo distribution, brain kinetics and specificity of [11C]MA-PB-1 binding were studied. Ex vivo biodistribution and microPET showed good brain uptake which could be blocked by pretreatment with both MA-PB-1 and a structurally non-related MAGL inhibitor MJN110. These initial results suggest that [11C]MA-PB-1 is a suitable tracer for in vivo imaging of MAGL.


Assuntos
Compostos de Benzil/farmacologia , Encéfalo/enzimologia , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Piperazinas/farmacologia , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Macaca mulatta , Camundongos , Estrutura Molecular , Monoacilglicerol Lipases/metabolismo , Piperazinas/síntese química , Piperazinas/química , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Distribuição Tecidual
16.
Chem Biol Drug Des ; 90(5): 936-942, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28489276

RESUMO

Histone deacetylase (HDAC) inhibitors have been identified for the treatment of cancer. Lately, we designed and synthesized a series of substituted N-benzylpyrimidin-2-amine derivatives as potent HDAC inhibitors. In vitro HDAC inhibitory activities and antiproliferative activities of target compounds were investigated. Some target compounds showed potent HDAC inhibitory activities and possessed obvious antiproliferative activity against tumor cells. Target compounds 6a, 6d, 8a, 8c, and 8f not only exhibited almost equally enzymatic inhibitory activity with SAHA, but showed better antiproliferative activities.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Aminação , Antineoplásicos/síntese química , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Linhagem Celular Tumoral , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Pirimidinas/síntese química
17.
Eur J Med Chem ; 135: 117-124, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28441580

RESUMO

The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT6R ligand, occurred to be a moderate 5-HT6R agent, useful as a lead structure for further modifications. A series of new derivatives (3-19) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT6R. The most active compounds displayed a potent affinity for the 5-HT6R in the nanomolar range (Ki = 20-30 nM), some of them (4, 11 and 19) were tested in the rat forced swim test that revealed their antidepressant-like effect. SAR-analysis on the basis of both, RBA and docking results, indicated that action on the receptor is related to the hydrophobicity and the size of aromatic moiety substituted by a methylene linker at the position 4 of 1,3,5-triazine.


Assuntos
Compostos de Benzil/farmacologia , Projeto Auxiliado por Computador , Descoberta de Drogas , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Triazinas/farmacologia , Compostos de Benzil/síntese química , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
18.
Sci Rep ; 7: 46352, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28397855

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a well-known antitumor target. Exogenous ROS insult can lead to selective cytotoxicity against cancer cells. A combination of STAT3 inhibition and "oxidation therapy" may be a new strategy to address the multidrug-resistance issue due to their important roles in the survival and drug resistance of cancer cells. Here, a series of novel curcumin-BTP hybrids were designed and evaluated as STAT3 inhibitors with ROS production activity. Compound 6b exerted the best antitumor activity and selectivity for MCF-7 and MCF-7/DOX cells (IC50 = 0.52 µM and 0.40 µM, respectively), while its IC50 value for MCF-10A breast epithelial cells was 7.72 µM. Furthermore, compound 6b suppressed STAT3 phosphorylation, nuclear translocation and DNA-binding activity and the expression of STAT3 specific oncogenes. Increases in the level of IL-6-induced p-STAT3 were also inhibited by 6b without influencing IFN-γ-induced p-STAT1 expression. Additionally, 6b effectively promoted intracellular ROS accumulation, induced cancer cell apoptosis and cell cycle arrest, abolished the colony formation ability of breast cancer cells, and inhibited P-gp expression in MCF-7/DOX cells. Finally, 6b suppressed the growth of implanted human breast cancer in vivo. Our findings highlight that 6b may be a promising therapeutic agent for drug-sensitive and drug-resistant breast cancers.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Curcumina/química , Curcumina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Compostos de Benzil/síntese química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Curcumina/síntese química , Modelos Animais de Doenças , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Células MCF-7 , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
19.
SLAS Discov ; 22(4): 440-446, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28328315

RESUMO

Analysis of interactions between molecules is of fundamental importance in life science research. In this study, we applied weak affinity chromatography, based on high-performance liquid chromatography and mass spectrometry, as a powerful tool for direct analysis of the components of a chemical reaction mixture for their binding to a target protein. As a demonstration of the potential of this method, we analyzed the binding of the compounds of the reaction mixture to the chaperone heat shock protein 90 (Hsp90). It was possible to analyze quantitatively the binding of the components of the mixture to the target independently from each other without any preceding process such as purification. This feature has wide implications in biological sciences as crude mixtures, either natural or synthetic, can be analyzed directly for their possible binding to a target. This method could lead to savings in costs and labor through shortening chemical research project development time.


Assuntos
Compostos de Benzil/química , Cromatografia de Afinidade/métodos , Proteínas de Choque Térmico HSP90/análise , Bibliotecas de Moléculas Pequenas/química , Benzoquinonas/química , Compostos de Benzil/síntese química , Cromatografia Líquida de Alta Pressão/métodos , Fluoresceína-5-Isotiocianato/química , Corantes Fluorescentes/química , Proteínas de Choque Térmico HSP90/química , Humanos , Lactamas Macrocíclicas/química , Ligação Proteica , Soluções , Espectrometria de Massas em Tandem/métodos
20.
Amino Acids ; 49(5): 965-974, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28258324

RESUMO

The enantiomers of amino acid benzyl esters are very important synthetic intermediates. Many of them are currently prepared by treatment with benzyl alcohol and p-toluenesulfonic acid in refluxing benzene or carbon tetrachloride, to azeotropically remove water, and then precipitated as tosylate salt by adding diethyl ether. Here, we report a very efficient preparation of eight L- or D-amino acid benzyl esters (Ala, Phe, Tyr, Phg, Val, Leu, Lys, Ser), in which these highly hazardous solvents are dismissed using cyclohexane as a water azeotroping solvent and ethyl acetate to precipitate the tosylate salt. With some work-up modifications and lower yield, the procedure can be applied also to methionine. Chiral HPLC analysis shows that all the benzyl esters, including the highly racemizable ones such as those of phenylglycine, tyrosine and methionine, are formed enantiomerically pure under these new reaction conditions thus validating the solvents replacement. Contrariwise, toluene cannot be used in place of benzene or carbon tetrachloride because leading to partially or totally racemized amino acid benzyl esters depending on the polar effect of the amino acid α-side chain as expressed by Taft's substituent constant (σ*).


Assuntos
Aminoácidos/química , Compostos de Benzil/síntese química , Ésteres/síntese química , Química Verde , Acetatos/química , Cicloexanos/química , Estereoisomerismo
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