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1.
J Inorg Biochem ; 228: 111697, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34999425

RESUMO

In this study, four hybrid organic-inorganic compounds (8-H2Q)2[PdCl4] (1), (H2ClQ)2[PdCl4] (2), (H2NQ)2[PdCl4] (3) and (H2MeQ)2[PdCl4]·2H2O (4) (where 8-H2Q = 8-hydroxyquinolinium, H2ClQ = 5-chloro-8-hydroxyquinolinium, H2NQ = 5-nitro-8-hydroxyquinolinium and H2MeQ = 2-methyl-8-hydroxyquinolinium) were synthesized through organic cation modulation. Single-crystal X-ray structure analysis of compounds 1 and 3 indicates that their structures are planar and consist of [PdCl4]2- anions and 8-H2Q or H2NQ cations, respectively. Both ionic components are held together through ionic interactions and hydrogen bonds forming infinite chains linked through π-π interactions to form 2D structures. Furthermore, NMR spectroscopy, UV-Vis spectroscopy, elemental analysis, and FT-IR spectroscopy were used to explore the synthesized compounds. The DNA interaction, antimicrobial activity, antiproliferative activity, and radical scavenging effect of the compounds were evaluated. The hybrid compounds and their free ligands can interact with the calf thymus DNA via an intercalation mode involving the insertion of the aromatic chromophore between the base pairs of DNA; compound 1 has the highest binding affinity. Moreover, they have high antimicrobial efficacy against the tested 14 strains of microorganisms with minimum inhibitory concentration values ranging from <1.95 to 250 µg/mL. The antiproliferative activity of the compounds was investigated against three different cancer cell lines, and their selectivity was verified on mesenchymal stem cells. Compounds 1 and 2 displayed selective and high cytotoxicity against human lung and breast cancer cells and showed moderate cytotoxicity against colon cancer cells. Accordingly, they might be auspicious candidates for future pharmacological investigations in lung and breast cancer research.


Assuntos
Complexos de Coordenação/química , Hidroxiquinolinas/química , Paládio/química , Compostos de Quinolínio/química , Células A549 , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Quelantes/química , Cristalografia por Raios X/métodos , DNA/química , Sequestradores de Radicais Livres/química , Células HCT116 , Humanos , Hidroxiquinolinas/síntese química , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Compostos de Quinolínio/síntese química , Espécies Reativas de Oxigênio/metabolismo
2.
Chem Biol Drug Des ; 98(5): 894-902, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34453501

RESUMO

Catalyzed peroxidation of unsaturated lipid in animals and plants intimately is linked to the activity of 15-Lipoxygenase enzymes. Lipoxygenases (LOXs) are well known to play an important role in many acute and chronic syndromes such as inflammation, asthma, cancer, and allergy. In this study, a series of mono prenyloxycarbostyrils were synthesized and evaluated as potential inhibitors of soybean 15-Lipoxygenase (SLO) and their inhibitory potencies were compared to mono prenyloxycoumarins which had been reported in the previous works. The synthetic compounds inhibit lipoxygenase enzyme by competitive mechanism like the prenyloxy coumarins. The results showed that position and length of the prenyl moiety play the important role in lipoxygenase inhibitory activity. Among all of the synthetic compounds (coumarin and carbostyril derivatives), 5-farnesyloxycoumarin and 8-farnesyloxycarbostyril demonstrated the best inhibitory activity by IC50  values of 1.1 µM and 0.53 µM, respectively.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Hidroxiquinolinas/síntese química , Inibidores de Lipoxigenase/síntese química , Quinolonas/síntese química , Compostos de Bifenilo/química , Cumarínicos/química , Humanos , Hidroxiquinolinas/farmacologia , Inibidores de Lipoxigenase/farmacologia , Picratos/química , Quinolonas/farmacologia , Glycine max/enzimologia , Relação Estrutura-Atividade
3.
Chem Pharm Bull (Tokyo) ; 69(6): 557-563, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34078802

RESUMO

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Hidroxiquinolinas/farmacologia , Espermatozoides/efeitos dos fármacos , Animais , Caenorhabditis elegans/metabolismo , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Espermatozoides/metabolismo
4.
J Biol Chem ; 296: 100223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33449875

RESUMO

Cytochrome P450 (P450) 3A4 is the enzyme most involved in the metabolism of drugs and can also oxidize numerous steroids. This enzyme is also involved in one-half of pharmacokinetic drug-drug interactions, but details of the exact mechanisms of P450 3A4 inhibition are still unclear in many cases. Ketoconazole, clotrimazole, ritonavir, indinavir, and itraconazole are strong inhibitors; analysis of the kinetics of reversal of inhibition with the model substrate 7-benzoyl quinoline showed lag phases in several cases, consistent with multiple structures of P450 3A4 inhibitor complexes. Lags in the onset of inhibition were observed when inhibitors were added to P450 3A4 in 7-benzoyl quinoline O-debenzylation reactions, and similar patterns were observed for inhibition of testosterone 6ß-hydroxylation by ritonavir and indinavir. Upon mixing with inhibitors, P450 3A4 showed rapid binding as judged by a spectral shift with at least partial high-spin iron character, followed by a slower conversion to a low-spin iron-nitrogen complex. The changes were best described by two intermediate complexes, one being a partial high-spin form and the second another intermediate, with half-lives of seconds. The kinetics could be modeled in a system involving initial loose binding of inhibitor, followed by a slow step leading to a tighter complex on a multisecond time scale. Although some more complex possibilities cannot be dismissed, these results describe a system in which conformationally distinct forms of P450 3A4 bind inhibitors rapidly and two distinct P450-inhibitor complexes exist en route to the final enzyme-inhibitor complex with full inhibitory activity.


Assuntos
Clotrimazol/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/química , Indinavir/farmacologia , Itraconazol/farmacologia , Cetoconazol/farmacologia , Ritonavir/farmacologia , Esteroide Hidroxilases/antagonistas & inibidores , Animais , Biocatálise , Clonagem Molecular , Clotrimazol/química , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/química , Ensaios Enzimáticos , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/metabolismo , Indinavir/química , Itraconazol/química , Cetoconazol/química , Cinética , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ritonavir/química , Esteroide Hidroxilases/química , Esteroide Hidroxilases/genética , Esteroide Hidroxilases/metabolismo
5.
Sci Rep ; 10(1): 21691, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303858

RESUMO

A novel, expedient and effective methodology for the synthesis of distinctly substituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline systems has been developed with a new synthetic platform. This process includes ammonium acetate-mediated cyclocondensation reactions of 3-oxo-2-arylhydrazonopropanals with benzosuberone and tetralone precursors, respectively, using the high-pressure Q-tube reactor, which has been found to be superior to both conventional heating and microwave irradiation. The novel protocol benefits from its high atom efficiency, economy, ease of workup, broad substrate scope and is also applicable to gram-scale synthesis. To identify and confirm the newly synthesized targeted compounds, the X-ray single-crystal as well as all possible spectroscopic methods were utilized. The cytotoxicity of the newly synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j and 5,6-dihydrobenzo-[h]quinolines derivatives 6a-e were preliminary examined toward three cell lines of human cancer; lung cancer (A549), breast cancer (MCF-7) and colon cancer (HCT-116), by applying the MTT colorimetric assay. The achieved results reflected the promising profile of the prepared compounds in this study against cancer cells and have shown that members from the synthesized 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine 4a-j exhibited promising cytotoxicity's against MCF-7, and A549 cancer cells respectively, while the HCT-116 (colon) cancer cells were inhibited by certain examples of 5,6-dihydrobenzo[h]quinoline derivatives 6c,d. These promising results could serve as a good primary base for further research into the design of anticancer drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Química Farmacêutica/métodos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Pressão , Piridinas/síntese química , Piridinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Cristalografia por Raios X , Ciclização , Desenho de Fármacos , Compostos Heterocíclicos/química , Humanos , Hidroxiquinolinas/química , Piridinas/química , Análise Espectral
6.
Molecules ; 25(22)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233747

RESUMO

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.


Assuntos
Técnicas de Química Sintética , Hidroxiquinolinas/síntese química , Quinolonas/síntese química , Catálise , Técnicas de Química Sintética/métodos , Técnicas de Química Sintética/tendências , Hidroxiquinolinas/química , Metais/química , Estrutura Molecular , Quinolonas/química
7.
ACS Chem Biol ; 15(9): 2516-2528, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32865973

RESUMO

The chemosensory system of any animal relies on a vast array of detectors tuned to distinct chemical cues. Odorant receptors and the ion channels of the TRP family are all uniquely expressed in olfactory tissues in a species-specific manner. Great effort has been made to characterize the molecular and pharmacological properties of these proteins. Nevertheless, most of the natural ligands are highly hydrophobic molecules that are not amenable to controlled delivery. We sought to develop photoreleasable, biologically inactive odorants that could be delivered to the target receptor or ion channel and effectively activated by a short light pulse. Chemically distinct ligands eugenol, benzaldehyde, 2-phenethylamine, ethanethiol, butane-1-thiol, and 2,2-dimethylethane-1-thiol were modified by covalently attaching the photoremovable protecting group (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ). The CyHQ derivatives were shown to release the active odorant upon illumination with 365 and 405 nm light. We characterized their bioactivity by measuring activation of recombinant TRPV1 and TRPA1 ion channels expressed in HEK 293 cells and the electroolfactogram (EOG) response from intact mouse olfactory epithelium (OE). Illumination with 405 nm light was sufficient to robustly activate TRP channels within milliseconds of the light pulse. Photoactivation of channels was superior to activation by conventional bath application of the ligands. Photolysis of the CyHQ-protected odorants efficiently activated an EOG response in a dose-dependent manner with kinetics similar to that evoked by the vaporized odorant amyl acetate (AAc). We conclude that CyHQ-based, photoreleasable odorants can be successfully implemented in chemosensory research.


Assuntos
Benzaldeídos/farmacologia , Eugenol/farmacologia , Hidroxiquinolinas/química , Odorantes , Fenetilaminas/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Benzaldeídos/síntese química , Eugenol/síntese química , Feminino , Células HEK293 , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/efeitos da radiação , Masculino , Camundongos , Mucosa Olfatória/efeitos dos fármacos , Fenetilaminas/síntese química , Compostos de Sulfidrila/síntese química , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Raios Ultravioleta
8.
Molecules ; 24(23)2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771153

RESUMO

Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.


Assuntos
Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Oxiquinolina/análogos & derivados , Linhagem Celular Tumoral , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidroxiquinolinas/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Quinidina/química , Quinina/química , Estereoisomerismo
9.
Drug Dev Res ; 80(5): 566-572, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30893501

RESUMO

There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure-activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 µM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC50 of <100 µM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8-hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.


Assuntos
Antituberculosos/síntese química , Hidroxiquinolinas/síntese química , Mycobacterium tuberculosis/crescimento & desenvolvimento , Oxiquinolina/análogos & derivados , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Chlorocebus aethiops , Células Hep G2 , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Células Vero
10.
Anticancer Agents Med Chem ; 19(7): 875-915, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30706793

RESUMO

In this review, the recent synthetic approaches of amino hexahydroquinolines and their spirocyclic structures were highlighted. The synthetic routes include, two-components, three-components or fourcomponents reactions. The two-component [3+3] atom combination reaction represents the simplest method. It involves Michael addition of the electron rich ß-carbon of ß-enaminones to the activated double bond of cinnamonitriles followed by cyclization to yield hexahydroquinoline compounds. The bioactivity profiles and SAR studies of these compounds were also reviewed with emphasis to the utility of these substances as antimicrobial, anticancer and antitubercular agents, as well as calcium channel modulators.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Hidroxiquinolinas/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Espiro/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Dose-Resposta a Droga , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/química , Compostos de Espiro/química , Relação Estrutura-Atividade
11.
Bioorg Med Chem ; 27(12): 2306-2314, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30392952

RESUMO

A series of novel ß2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent ß2-adrenoceptor agonistic effects and high ß2/ß1-selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/farmacologia , Etanolaminas/farmacologia , Hidroxiquinolinas/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/síntese química , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Animais , Sítios de Ligação , Broncodilatadores/síntese química , Broncodilatadores/metabolismo , Desenho de Fármacos , Etanolaminas/síntese química , Etanolaminas/metabolismo , Cobaias , Células HEK293 , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/metabolismo , Masculino , Simulação de Acoplamento Molecular , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Traqueia/efeitos dos fármacos
12.
ChemMedChem ; 13(5): 422-430, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29334428

RESUMO

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Hidroxiquinolinas/farmacologia , Macrófagos/efeitos dos fármacos , Metaloproteases/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/química , Cinética , Macrófagos/microbiologia , Metaloproteases/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular
13.
Talanta ; 179: 326-330, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29310239

RESUMO

Developing fluorescent probes to image thiols in the living system may provide powerful tools to study the functions of thiol-containing biological molecules. In this study, we report the design and evaluation of a novel turn-on fluorescent probe NQNO for selective detection of thiols in living cells. By introducing an ortho-aldehyde group to NNO, a conventional compound representing a class of thiol-imaging strategy, we obtained NQNO with enhanced selectivity for thiols over the major interferent hydrogen sulfide (H2S). NQNO could be applied in phosphate-buffered saline (PBS), where the efficacy of NNO was usually weakened. Notably, NQNO demonstrated solid performance in imaging endogenous thiols in living cells without exerting cytotoxicity. In summary, NQNO has the potential to serve as a safe, sensitive and effective fluorescent probe for thiol imaging in biological systems.


Assuntos
Aldeídos/química , Cisteína/análise , Corantes Fluorescentes/síntese química , Glutationa/análise , Homocisteína/análise , Hidroxiquinolinas/síntese química , Imagem Óptica/métodos , Soluções Tampão , Corantes Fluorescentes/química , Células HeLa , Humanos , Sulfeto de Hidrogênio/química , Hidroxiquinolinas/química
14.
Nat Protoc ; 12(3): 461-471, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28151463

RESUMO

Magnesium plays a crucial role in many physiological functions and pathological states. Therefore, the evolution of specific and sensitive tools capable of detecting and quantifying this element in cells is a very desirable goal in biological and biomedical research. We developed a Mg2+-selective fluorescent dye that can be used to selectively detect and quantify the total magnesium pool in a number of cells that is two orders of magnitude smaller than that required by flame atomic absorption spectroscopy (F-AAS), the reference analytical method for the assessment of cellular total metal content. This protocol reports itemized steps for the synthesis of the fluorescent dye based on diaza-18-crown-6-hydroxyquinoline (DCHQ5). We also describe its application in the quantification of total intracellular magnesium in mammalian cells and the detection of this ion in vivo by confocal microscopy. The use of in vivo confocal microscopy enables the quantification of magnesium in different cellular compartments. As an example of the sensitivity of DCHQ5, we studied the involvement of Mg2+ in multidrug resistance in human colon adenocarcinoma cells sensitive (LoVo-S) and resistant (LoVo-R) to doxorubicin, and found that the concentration was higher in LoVo-R cells. The time frame for DCHQ5 synthesis is 1-2 d, whereas the use of this dye for total intracellular magnesium quantification takes 2.5 h and for ion bioimaging it takes 1-2 h.


Assuntos
Técnicas de Química Sintética/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Espaço Intracelular/metabolismo , Magnésio/metabolismo , Microscopia de Fluorescência , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/química , Hidroxiquinolinas/metabolismo
15.
Int J Mol Sci ; 17(10)2016 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-27782083

RESUMO

Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.


Assuntos
Desenho de Fármacos , Hidroxiquinolinas/química , Metaloproteinase 2 da Matriz/química , Inibidores de Metaloproteinases de Matriz/química , Naftiridinas/química , Ensaios Enzimáticos , Humanos , Hidroxiquinolinas/síntese química , Cinética , Inibidores de Metaloproteinases de Matriz/síntese química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Naftiridinas/síntese química , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Zinco/química
16.
Chem Asian J ; 11(17): 2436-42, 2016 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-27432795

RESUMO

Neurodegenerative diseases such as Parkinson's and Alzheimer's diseases are multifactorial disorders related to protein aggregation, metal dyshomeostasis, and oxidative stress. To advance understanding in this area and to contribute to therapeutic development, many efforts have been directed at devising suitable agents that can target metal ions associated with relevant biomolecules such as α-synuclein. This paper presents a new cyclodextrin-8-hydroxyquinoline conjugate and discusses the properties of four cyclodextrins 3-functionalized with 8-hydroxyquinoline as copper(II) chelators and inhibitors of copper-induced synuclein aggregation. The encouraging results establish the potential of cyclodextrin-8-hydroxyquinoline conjugates as chelators for the control of copper toxicity.


Assuntos
Cobre/química , Ciclodextrinas/química , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Agregação Patológica de Proteínas/prevenção & controle , alfa-Sinucleína/antagonistas & inibidores , Antitoxinas/farmacologia , Sítios de Ligação , Ciclodextrinas/síntese química , Ciclodextrinas/farmacologia , Hidroxiquinolinas/síntese química , alfa-Sinucleína/química
17.
Angew Chem Int Ed Engl ; 55(24): 6988-91, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27097759

RESUMO

A new method was developed for the photoinduced dearomatization of arenes through an intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer (ESIPT) in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles. It provides rapid access to novel heterocycles, cyclohexadieno-oxazolidino-quinolinols, as valuable synthons for a broad range of post-photochemical transformations.


Assuntos
Compostos Aza/química , Derivados de Benzeno/química , Compostos Heterocíclicos/síntese química , Hidroxiquinolinas/síntese química , Xilenos/química , Reação de Cicloadição , Compostos Heterocíclicos/química , Hidroxiquinolinas/química , Estrutura Molecular , Processos Fotoquímicos , Estereoisomerismo
18.
Arch Pharm (Weinheim) ; 349(5): 327-41, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27027880

RESUMO

Copper and zinc have been found to contribute to the burden of amyloid-ß (Aß) aggregations in neurodegenerative Alzheimer's disease (AD). Dysregulation of these metals leads to the generation of reactive oxygen species (ROS) and eventually results in oxidative damage and accumulation of the Aß peptide, which are the key elements of the disease. Aiming to pursue the discovery of new modulators for the disease, we here rationally focused on conjugating the core hydroxyquinoline of the metal-protein attenuating compound PBT2 and the N-methylanilide analogous moiety of the Aß imaging agent to build a new type of multi-target modulators of Aß aggregations. We found that the N,N-dimethylanilinyl imines 7a, 8a, and the corresponding amines 7b, 8b exerted efficient inhibition of Cu(2+) - or Zn(2+) -induced Aß aggregations and significant disassembly of metal-mediated Aß aggregated fibrils. Further, 7a and 7b also exhibited significant ROC scavenging effects compared to PBT2. The results suggested that 7a and 7b are promising lead compounds for the development of a new therapy for AD.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Hidroxiquinolinas/química , Hidroxiquinolinas/uso terapêutico , Agregação Patológica de Proteínas/tratamento farmacológico , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/ultraestrutura , Quelantes/síntese química , Quelantes/farmacologia , Quelantes/uso terapêutico , Clioquinol/análogos & derivados , Clioquinol/química , Clioquinol/farmacologia , Clioquinol/uso terapêutico , Cobre/efeitos adversos , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Relação Estrutura-Atividade , Zinco/efeitos adversos
19.
Mol Divers ; 20(1): 29-40, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26537729

RESUMO

Ethyl 3-(2,4-dioxocyclohexyl)propanoate has been explored as a precursor for the synthesis of N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones following conventional protecvtion, selective amidation, and deprotective-cyclization approaches. Moreover, a facile process for the selective dehydrogenative aromatization of these diones was developed to afford the corresponding N-substituted 3,4-dihydro-7-hydroxyquinolin-2(1H)-ones and N-substituted 7-hydroxyquinolin-2(1H)-ones under mild conditions.


Assuntos
Hidroxiquinolinas/síntese química , Propionatos/química , Hidroxiquinolinas/química , Micro-Ondas , Estrutura Molecular
20.
Dalton Trans ; 44(48): 20913-25, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26575390

RESUMO

Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using (77)Se, (1)H and (13)C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aß. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aß aggregation, and an ability to disassemble preformed self- and metal-induced Aß aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg(-1). Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.


Assuntos
Peptídeos beta-Amiloides/química , Antioxidantes/química , Materiais Biocompatíveis/química , Hidroxiquinolinas/química , Metais/química , Compostos Organosselênicos/química , Selênio/química , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/uso terapêutico , Azóis/química , Materiais Biocompatíveis/metabolismo , Barreira Hematoencefálica/metabolismo , Catálise , Quelantes/química , Clioquinol/química , Glutationa Peroxidase/química , Glutationa Peroxidase/metabolismo , Hidroxiquinolinas/síntese química , Hidroxiquinolinas/uso terapêutico , Isoindóis , Espectroscopia de Ressonância Magnética , Camundongos , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/uso terapêutico
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