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1.
Analyst ; 146(22): 6893-6901, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34633394

RESUMO

A graphene oxide (GO)-based nanocarrier that imparts tumor-selective delivery of dual-drug with enhanced therapeutic index, is introduced. GO is conjugated with Au@Ag and Fe3O4 nanoparticles, which facilitates it with SERS tracking and magnetic targeting abilities, followed by the covalent binding of the anti-HER2 antibody, thus allowing it to both actively and passively target SKBR3 cells, human breast cancer cells expressed with HER2. Intracellular drug delivery behaviors are probed using SERS spectroscopy in a spatiotemporal manner, which demonstrates that nanocarriers are internalized into the lysosomes and release the drug in response to the acidic microenvironment. The nanocarriers loaded with dual-drug possess increased cancer cytotoxicity in comparison to those loaded with a single drug. Attractively, the enhanced cytotoxicity against cancer cells is achieved with relatively low concentrations of the drug, which is demonstrated to be involved in the drug adsorption status. These results may give us the new prospects to design GO-based delivery systems with rational drug dosages, thus achieving optimal therapeutic response of the multi-drug with increased tumor selectivity and reduced side effects.


Assuntos
Grafite , Nanopartículas , Aminacrina , Linhagem Celular Tumoral , Doxorrubicina , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos
2.
Bioorg Med Chem Lett ; 35: 127815, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33486051

RESUMO

Fungal resistance remains a significant threat and a leading cause of death worldwide. Thus, overcoming microbial infections have again become a serious clinical problem. Although acridine derivatives are widely analyzed as anticancer agents, only a few reports have demonstrated their antifungal activity. In an effort to develop biologically active antifungals, twelve novel C-857 (9-(2'-hydroxyethylamino)-1-nitroacridine) and C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) derivatives were synthesized. The evaluation of biological properties suggests that starting compounds: C-1748, C-857 and IE3 (2-[(4-methyl-1-nitroacridin-9-yl)amino]ethyl lysinate), IE4 (2-[(1-nitroacridin-9-yl)amino]ethyl lysinate) antifungal mode of action differ from that determined for IE5 (N'-{3-[(4-methyl-1-nitroacridin-9-yl)amino]propyl}lysinamide), IE6 (N'-{3-[(1-nitroacridin-9-yl)amino]propyl}lysinamide) and IE10 (3,3'-Bis-(1-nitroacridin-9-ylamino)-aminoethylaminoethylaminoethylamine). Although MIC values determined for the latter were higher, in contrast to C-857 and C-1748, newly synthesized IE5, IE6 and IE10 reduced C. albicans hyphal growth in different inducing media. Those compounds also exhibited antibiofilm activity, whereas IE10 was the most effective. Moreover, only IE6 exhibited antifungal activity against fluconazole resistant C. albicans strains with MICs values in the range of 16-64 µg mL-1. Our results also indicate that, in contrast to other analyzed derivatives, novel synthetized compounds IE6 and IE10 with antifungal activity target yeast topoisomerase II activity.


Assuntos
Aminacrina/análogos & derivados , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Farmacorresistência Fúngica/efeitos dos fármacos , Inibidores da Topoisomerase II/farmacologia , Aminacrina/síntese química , Aminacrina/química , Aminacrina/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/enzimologia , Relação Dose-Resposta a Droga , Fluconazol/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
3.
Chem Biodivers ; 18(1): e2000702, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33205910

RESUMO

The efficient and short techniques for conjugation of 9-aminoacridine with different peptidyl fragments are necessary for the development of active pharmaceutical ingredients (API). They need to be adopted to generate a new branch of acridine conjugates, enhancing their bioavailability for the examination in biological systems. The branch of developing acridine conjugates, built via different linkers and synthesized in this study, are expected as potential effective chemotherapeutics with dual mechanism of action. Recently, the methodology based on a solid-phase technique has been successfully demonstrated in preparing a number of promising compounds. However, the reaction conditions for amide bond formation between 1-nitro-9-aminoacridine and peptidyl fragments need to be optimized. In this study, the optimization of amide bond formation was demonstrated with the use of the solid-phase synthesis to build a new promising group of 1-nitro-9-aminoacridines conjugated to lactoferrin fragments via especially carboxy linker length.


Assuntos
Aminacrina/análogos & derivados , Peptídeos/química , Técnicas de Síntese em Fase Sólida/métodos , Amidas/química , Aminacrina/química , Lactoferrina/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
4.
Pak J Pharm Sci ; 33(2): 659-668, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32276912

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder mainly characterized by progressive deterioration of memory and impaired cognitive function. The most promising approach for symptomatic relief of AD is to inhibit acetylcholinesterase (AChE). On the basis of this approach in-house library of 9-aminoacridine derivatives were constructed and allowed to docked against human acetylcholinesterase (hAChE) (PDB ID: 4EY7), using MOE 2018.01 and PyRx 0.9.2 (AutoDock Vina). Top ranked and best fitted molecules were synthesized by targeting the 9-amino group of aminoacridine with substituted phenacyl halides. Anti-Alzheimer's potential was checked by in vitro AChE inhibition, antioxidant activity (DPPH scavenging ability) and fibril disaggregation. Subjected ligands suggested as promising multitargeted candidate with pronounced results in term of IC50 values (AChE inhibition 2.400-26.138µM), however, none of them showed potential towards fibril inhibition.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminacrina/síntese química , Inibidores da Colinesterase/síntese química , Simulação de Acoplamento Molecular/métodos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminacrina/uso terapêutico , Antioxidantes/síntese química , Antioxidantes/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Cristalografia por Raios X/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Relação Estrutura-Atividade
5.
Nano Lett ; 20(3): 1542-1551, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32039606

RESUMO

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.


Assuntos
Aminacrina , Descoberta de Drogas , AVC Isquêmico/tratamento farmacológico , Aminacrina/química , Aminacrina/farmacocinética , Aminacrina/farmacologia , Animais , Células HEK293 , Humanos , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Lipossomos , Masculino , Camundongos , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Peptídeos Cíclicos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
6.
Mol Cell Biochem ; 460(1-2): 123-150, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313023

RESUMO

A series of nine tetrahydroacridine derivatives with iodobenzoic moiety were synthesized and evaluated for their cytotoxic activity against cancer cell lines-A549 (human lung adenocarcinoma), HT-29 (human colorectal adenocarcinoma) and somatic cell line-EA.hy926 (human umbilical vein cell line). All compounds displayed high cytotoxicity activity against A549 (IC50 59.12-14.87 µM) and HT-29 (IC50 17.32-5.90 µM) cell lines, higher than control agents-etoposide and 5-fluorouracil. Structure-activity relationship showed that the position of iodine in the substituent in the para position and longer linker most strongly enhanced the cytotoxic effect. Among derivatives, 1i turned out to be the most cytotoxic and displayed IC50 values of 14.87 µM against A549 and 5.90 µM against HT-29 cell lines. In hyaluronidase inhibition assay, all compounds presented anti-inflammatory activity, however, slightly lower than reference compound. ADMET prediction showed that almost all compounds had good pharmacokinetic profiles. 1b, 1c and 1f compounds turned out to act against chemoresistance in cisplatin-resistant 253J B-V cells. Compounds intercalated into DNA and inhibited cell cycle in G0/G1 phase-the strongest inhibition was observed for 1i in A549 and 1c in HT-29. Among compounds, the highest apoptotic effect in both cell lines was observed after treatment with 1i. Compounds caused DNA damage and H2AX phosphorylation, which was detected in A549 and HT-29 cells. All research confirmed anticancer properties of novel tetrahydroacridine derivatives and explained a few pathways of their mechanism of cytotoxic action.


Assuntos
Aminacrina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Iodobenzoatos/farmacologia , Neoplasias Pulmonares/patologia , Células A549 , Aminacrina/química , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Citoproteção/efeitos dos fármacos , DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HT29 , Histonas/metabolismo , Humanos , Hialuronoglucosaminidase/metabolismo , Concentração Inibidora 50 , Mutagênicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Ensaio Tumoral de Célula-Tronco
7.
Chem Biol Interact ; 309: 108698, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31176713

RESUMO

Structure-guided design of novel pharmacologically active molecules relies at least in part on functionally relevant accuracy of macromolecular structures for template based drug design. Currently, about 95% of all macromolecular X-ray structures available in the PDB (Protein Data Bank) were obtained from diffraction experiments at low, cryogenic temperatures. However, it is known that functionally relevant conformations of both macromolecules and pharmacological ligands can differ at higher, physiological temperatures. We describe in this article development and properties of new human acetylcholinesterase (AChE) crystals of space group P31 and a new unit cell, amenable for room-temperature X-ray diffraction studies. We co-crystallized hAChE in P31 unit cell with the reversible inhibitor 9-aminoacridine that binds at the base of the active center gorge in addition to inhibitors that span the full length of the gorge, donepezil (Aricept, E2020) and AChE specific inhibitor BW284c51. Their new low temperature P31 space group structures appear similar to those previously obtained in the different P3121 unit cell. Successful solution of the new room temperature 3.2 Å resolution structure of BW284c51*hAChE complex from large P31 crystals enables us to proceed with studying room temperature structures of lower affinity complexes, such as oxime reactivators bound to hAChE, where temperature-related conformational diversity could be expected in both oxime and hAChE, which could lead to better informed structure-based design under conditions approaching physiological temperature.


Assuntos
Acetilcolinesterase/química , Cristalografia por Raios X , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Aminacrina/química , Aminacrina/metabolismo , Sítios de Ligação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Dimerização , Humanos , Simulação de Dinâmica Molecular , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Temperatura
8.
Sci Rep ; 9(1): 4987, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899037

RESUMO

One of the greatest challenges of modern medicine is to find cheaper and easier ways to produce transporters for biologically active substances, which will provide selective and efficient drug delivery to the target cells, while causing low toxicity towards healthy cells. Currently, metal-based nanoparticles are considered a successful and viable solution to this problem. In this work, we propose the use of novel synthesis method of platinum nanoparticles (PtNPs) connected with their precise biophysical characterization and assessment of their potential toxicity. To work as an efficient nanodelivery platform, nanoparticles should interact with the desired active compounds spontaneously and non-covalently. We investigated possible direct interactions of PtNPs with ICR-191, a model acridine mutagen with well-established biophysical properties and mutagenic activity, by Dynamic Light Scattering, fluorescence spectroscopy, and Isothermal Titration Calorimetry. Moreover, to determine the biological activity of ICR-191-PtNPs aggregates, we employed Ames mutagenicity test, eukaryotic cell line analysis and toxicity test against the model organism Caenorhabditis elegans. PtNPs' interesting physicochemical properties associated to the lack of toxicity in a tested range of concentrations, as well as their ability to modulate ICR-191 biological activity, suggest that these particles successfully work as potential delivery platforms for different biologically active substances.


Assuntos
Aminacrina/análogos & derivados , Sistemas de Liberação de Medicamentos/efeitos adversos , Nanopartículas Metálicas/química , Compostos de Mostarda Nitrogenada/química , Platina/química , Aminacrina/síntese química , Aminacrina/química , Aminacrina/uso terapêutico , Fenômenos Biofísicos , Humanos , Nanopartículas Metálicas/uso terapêutico , Mutagênicos/química , Mutagênicos/uso terapêutico , Mutagênicos/toxicidade , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/uso terapêutico
9.
Drug Dev Ind Pharm ; 45(2): 212-221, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30256663

RESUMO

The acridine derivatives can interact with the double-stranded DNA, which is regarded as the biological target of the anticancer drugs in cancer treatment. We designed and synthesized a new series of 1,3-dimethyl-6-nitroacridine derivatives as potential DNA-targeted anticancer agents. These compounds could partially intercalate into the calf thymus DNA, differing from the parent acridine. The results showed that the substitutions of the acridine ring had great effect on DNA binding affinity. The binding constants determined by UV-vis spectroscopy were found to be 105 M-1 grade. Anticancer activity of these compounds was screened using MTT assay. Most compounds inhibited 50% cancer cell growth at concentration below 30 µM, the results were consistent with the DNA binding ability. Compounds 1 and 6 were found to have more effective cytotoxicity, especially in human breast cancer cell lines. To investigate the action mechanism, we studied cell apoptosis, morphological changes, and cell cycle distribution in MCF-7 and MDA-MB-231 cells. Compounds 1 and 6 caused MCF-7 and MDA-MB-231 cells death due to apoptosis, and induced cell apoptosis in a dose-dependent manner. They also had significant effect on cell cycle progression and arrested cell cycle at G2/M phase. The results demonstrated that compounds 1 and 6 are promising candidates for cancer treatment.


Assuntos
Aminacrina/análogos & derivados , Aminacrina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , DNA de Neoplasias/efeitos dos fármacos , Animais , Neoplasias da Mama/ultraestrutura , Bovinos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade
10.
Sci Rep ; 8(1): 10315, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985415

RESUMO

Biomolecule abundance levels change with the environment and enable a living system to adapt to the new conditions. Although, the living system maintains at least some characteristics, e.g. homeostasis. One of the characteristics maintained by a living system is a power law distribution of biomolecule abundance levels. Previous studies have pointed to a universal characteristic of biochemical reaction networks, with data obtained from lysates of multiple cells. As a result, the spatial scale of the data related to the power law distribution of biomolecule abundance levels is not clear. In this study, we researched the scaling law of metabolites in mouse tissue with a spatial scale of quantification that was changed stepwise between a whole-tissue section and a single-point analysis (25 µm). As a result, metabolites in mouse tissues were found to follow the power law distribution independently of the spatial scale of analysis. Additionally, we tested the temporal changes by comparing data from younger and older mice. Both followed similar power law distributions, indicating that metabolite composition is not diversified by aging to disrupt the power law distribution. The power law distribution of metabolite abundance is thus a robust characteristic of a living system regardless of time and space.


Assuntos
Modelos Biológicos , Aminacrina/química , Animais , Fígado/química , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Life Sci ; 206: 1-9, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29738780

RESUMO

DNA is considered to be one of the most promising targets for anticancer agents. Acridine analogues have anticancer activity based on DNA binding and topoisomerases inhibition. However, due to the side effects, resistance and low bioavailability, a few have entered into clinical usage and the mechanisms of action are not fully understood. Novel acridine derivatives are needed for effective cancer therapy. A series of novel 3-nitroacridine-based derivatives were synthesized, their DNA binding and anticancer activities were evaluated. The chemical modifications at position 9 of the 3-nitroacridine were crucial for DNA affinity, thus optimizing anticancer activity. UV-Vis and circular dichroism (CD) spectroscopy indicated interaction of compounds with DNA, and the binding modes were intercalation and groove binding. MTT assay and clonogenic assay showed that compounds 1, 2 and 3 had obvious cell growth inhibition effect. They induced cell apoptosis in human breast cancer cells in a dose-dependent manner, and exhibited anticancer effect via DNA damage as well as cell cycle arrest at G0/G1 phage. Using confocal fluorescent microscope, the apoptotic features were observed. The results suggested that compounds 1-3 with high DNA binding affinity and good inhibitory effect of cancer cell proliferation can be developed as prime candidates for further chemical optimization.


Assuntos
Aminacrina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/ultraestrutura , Linhagem Celular Tumoral , DNA de Neoplasias/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Fase G1/efeitos dos fármacos , Humanos , Células MCF-7 , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Ensaio Tumoral de Célula-Tronco
12.
Colloids Surf B Biointerfaces ; 164: 134-143, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29413590

RESUMO

C60 fullerene is reported to directly interact with biomolecules, such as aromatic mutagens or anticancer drugs. Therefore, it is extensively studied for its potential application in the fields of drug delivery and chemoprevention. Understanding the nature of fullerene-drugs interactions might contribute to optimization and modification of the existing chemotherapy systems. Possible interactions between ICR-191, a model acridine mutagen, with well-established biophysical properties and mutagenic activity, and C60 fullerene aqueous solution were investigated by broad range of biophysical methods, such as Dynamic Light Scattering, Isothermal Titration Calorimetry, and Atomic Force Microscopy. Additionally, to determine biological activity of ICR-191-C60 fullerene mixtures, Ames mutagenicity test was employed. It was demonstrated that C60 fullerene interacts non-covalently with ICR-191 and has strong affinity to bacterial membranes. The obtained results provide practical insight into C60 fullerene interactions with aromatic compounds.


Assuntos
Fulerenos/química , Hidrocarbonetos Aromáticos/metabolismo , Aminacrina/análogos & derivados , Aminacrina/metabolismo , Transporte Biológico , Fenômenos Biofísicos , Microscopia de Força Atômica , Modelos Moleculares , Mutagênicos/toxicidade , Compostos de Mostarda Nitrogenada/metabolismo , Salmonella typhimurium/efeitos dos fármacos
13.
Bioorg Med Chem ; 26(4): 855-868, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29325885

RESUMO

Bovine viral diarrhea virus (BVDV) infection is still a plague that causes important livestock pandemics. Despite the availability of vaccines against BVDV, and the implementation of massive eradication or control programs, this virus still constitutes a serious agronomic burden. Therefore, the alternative approach to combat Pestivirus infections, based on the development of antiviral agents that specifically inhibit the replication of these viruses, is of preeminent actuality and importance. Capitalizing from a long-standing experience in antiviral drug design and development, in this work we present and characterize a series of small molecules based on the 9-aminoacridine scaffold that exhibit potent anti-BVDV activity coupled with low cytotoxicity. The relevant viral protein target - the RNA-dependent RNA polymerase - the binding mode, and the mechanism of action of these new antivirals have been determined by a combination of in vitro (i.e., enzymatic inhibition, isothermal titration calorimetry and site-directed mutagenesis assays) and computational experiments. The overall results obtained confirm that these acridine-based derivatives are promising compounds in the treatment of BVDV infections and, based on the reported structure-activity relationship, can be selected as a starting point for the design of a new generation of improved, safe and selective anti-BVDV agents.


Assuntos
Aminacrina/química , Antivirais/química , Vírus da Diarreia Viral Bovina/fisiologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Aminacrina/metabolismo , Aminacrina/farmacologia , Animais , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Calorimetria , Bovinos , Vírus da Diarreia Viral Bovina/enzimologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Estrutura Terciária de Proteína , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Replicação Viral/efeitos dos fármacos
14.
Anal Chim Acta ; 1000: 155-162, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-29289304

RESUMO

In matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) analysis and imaging of lipids, comprehensive ionization of lipids simultaneously by a universal matrix is a very challenging problem. Ion suppression of readily ionizable lipids to others is common. To overcome this obstacle and enhance the coverage of MALDI MS analysis and imaging of lipids, we developed a novel strategy employing a mixture of matrices, each of which is capable of selective ionization of different lipid classes. Given that MALDI MS with either 9-aminoacridine (9-AA) or N-(1-naphthyl) ethylenediamine dihydrochloride (NEDC) yields weak in-source decay which is critical for analysis of complex biological samples and possesses orthogonal selectivity for ionization of lipid classes, we tested the mixtures of NEDC and 9-AA with different ratios for analysis of standard lipids and mouse brain lipid extracts. We determined 1.35 of NEDC/9-AA as an optimized molar ratio. It was demonstrated that an enhanced coverage with the optimized mixture was obtained, which enabled us to analyze and map all the major classes of phospholipids and sulfatide from either lipid extracts or tissue slides, respectively. We believe that this powerful novel strategy can enhance lipidomics analysis and MALDI MS imaging of lipids in a high-throughput and semi-quantitative fashion.


Assuntos
Aminacrina/química , Etilenodiaminas/química , Lipídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
J Chem Theory Comput ; 13(8): 3898-3910, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28641006

RESUMO

In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices.


Assuntos
Aminacrina/análogos & derivados , Antineoplásicos/química , Complexos de Coordenação/química , DNA/química , Substâncias Intercalantes/química , Elétrons , Irídio/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Teoria Quântica , Ródio/química , Rutênio/química
16.
Bioorg Med Chem ; 25(14): 3845-3852, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28566208

RESUMO

Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors. Among the synthesized acridine derivatives, several acridine-3-amide and 3-urea derivatives, such as 10 (IC50: 6.9µM), 13 (IC50: 2.6µM), and 20 (IC50: 4.8µM), showed more potent inhibitory activity than the lead compound 1 (IC50: 15.4µM). Compounds 10 and 20 were confirmed to inhibit phosphorylation of NCC in vivo.


Assuntos
Anti-Hipertensivos/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Aminacrina/química , Aminacrina/metabolismo , Aminacrina/farmacologia , Animais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Immunoblotting , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Simportadores de Cloreto de Sódio-Potássio/química , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Relação Estrutura-Atividade , Proteína Quinase 1 Deficiente de Lisina WNK
17.
Age Ageing ; 46(5): 767-773, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28419192

RESUMO

Background: inhibition of acetylcholinesterase (AChE) has been a effective treatment for Alzheimer's disease (AD). Octohydroaminoacridine, a new AChE inhibitor, is a potential treatment for AD. Method: we conducted a multicenter, randomised, double blind, placebo-controlled, parallel-group Phase II clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate AD. Patients were randomised to receive placebo thrice daily, octohydroaminoacridine 1 mg/thrice daily (TID) (low-dose group), 2 mg/TID (middle-dose group) or 4 mg/TID (high-dose group). Doses in the middle-dose and high-dose group were titrated over 2-4 weeks. Changes from baseline to Week 16 were assessed with the AD Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician's Interview-Based Impression of Change Plus (CIBIC+), activities of daily living (ADL) and the neuropsychiatric inventory (NPI). ADAS-cog was the primary end point of the study. A two-way analysis of covariance and least squares mean t-test were used. Results: at Week 16, the changes from baseline in ADAS-cog were 1.4, -2.1, -2.2 and -4.2 for placebo, low-, middle- and high-dose groups, respectively. Patients in the high-dose group had better performance in CIBIC+ and ADL scores at the end of the study. There was no significant difference in the change in NPI score among the groups. The effects of octohydroaminoacridine were dose dependent, and were effective within 16 weeks of treatment. No evidence was found for more adverse events that occurred in different drug groups than placebo group. Conclusions: octohydroaminoacridine significantly improved cognitive function and behaviour in patients with mild-to-moderate AD and this effect was dose dependent.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminacrina/análogos & derivados , Inibidores da Colinesterase/administração & dosagem , Acetilcolinesterase/metabolismo , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Aminacrina/administração & dosagem , Aminacrina/efeitos adversos , China , Inibidores da Colinesterase/efeitos adversos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
18.
Anal Chim Acta ; 962: 52-59, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28231880

RESUMO

With the development of matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI), molecular interrogation of tissue sections over a wide mass range has become feasible, but small molecule analysis is still far from being fully reached due to the limited sensitivity and matrix interference. Herein, graphene oxide (GO) is used as a MALDI matrix to image small molecules in tissues in negative ion mode. Finally, 212 of molecules including 190 of lipids and 22 of low molecular weight metabolites were detected and spatially visualized in mouse brain tissue sections without the interference of matrix ions/clusters, and the structures of 69 of the lipids were confirmed by using in situ tandem mass spectrometry. A further application of GO matrix could reveal distinct spatio-molecular signatures in viable and necrotic tumor regions derived from a mouse breast cancer tissue. In addition, GO as a MALDI matrix has exhibited a better performance in MSI of lipids relative to N-(1-naphthyl) ethylenediamine dihydrochloride and 9-aminoacridine.


Assuntos
Grafite/química , Imagem Molecular/métodos , Óxidos/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Aminacrina/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Linhagem Celular Tumoral , Etilenodiaminas/química , Metabolismo dos Lipídeos , Camundongos
19.
Artigo em Inglês | MEDLINE | ID: mdl-27611591

RESUMO

Trans-activator of Transcription (Tat) antagonists could block the interaction between Tat protein and its target, trans-activation responsive region (TAR) RNA, to inhibit Tat function and prevent human immunodeficiency virus type 1 (HIV-1) replication. For the first time, a small fluorescence ligand, ICR 191, was found to interact with TAR RNA at the Tat binding site and compete with Tat. It was also observed that the fluorescence of ICR 191 could be quenched when binding to TAR RNA and recovered when discharged via competition with Tat peptide or a well-known Tat inhibitor, neomycin B. The binding parameters of ICR 191 to TAR RNA were determined through theoretical calculations. Mass spectrometry, circular dichroism and molecular docking were used to further confirm the interaction of ICR 191 with TAR RNA. Inspired by these discoveries, a primary fluorescence model for the discovery of Tat antagonists was built using ICR 191 as a fluorescence indicator and the feasibility of this model was evaluated. This ligand-RNA interaction could provide a new strategy for research aimed at discovering Tat antagonists.


Assuntos
Aminacrina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos/métodos , Corantes Fluorescentes/metabolismo , Repetição Terminal Longa de HIV , RNA Viral/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Aminacrina/química , Aminacrina/metabolismo , Aminacrina/farmacologia , Ligação Competitiva , Dicroísmo Circular , Corantes Fluorescentes/química , Framicetina/química , Framicetina/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , RNA Viral/química , Espectrometria de Fluorescência , Espectrometria de Massas por Ionização por Electrospray , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
20.
Mol Pharmacol ; 91(2): 135-144, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27903755

RESUMO

The α1-adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1-adrenergic ligands, yet there is little information describing this drug class at the α1-adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α1A- and α1B-adrenergic receptors. The 9-aminoacridines increase the rate of [3H]prazosin dissociation from the α1A- and α1B-adrenergic receptors and noncompetitively inhibit receptor activation by the endogenous agonist norepinephrine. The structurally similar compound, tacrine, which is a known allosteric modulator of the muscarinic receptors, is also shown to be a modulator of the α1-adrenergic receptors, which suggests a general lack of selectivity for allosteric binding sites across aminergic G protein-coupled receptor. Conjugation of two 9-aminoacridine pharmacophores, using linkers of varying length, increases the potency and efficacy of the allosteric effects of this ligand, likely through optimization of bitopic engagement of the allosteric and orthosteric binding sites of the receptor. Such a bivalent approach may provide a mechanism for fine tuning the efficacy of allosteric compounds in future drug design efforts.


Assuntos
Aminacrina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Aminacrina/química , Animais , Bioensaio , Células COS , Chlorocebus aethiops , Humanos , Cinética , Norepinefrina/farmacologia , Prazosina/farmacologia , Trítio/metabolismo
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