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1.
J Chromatogr A ; 1623: 461192, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32505285

RESUMO

An imidazolium ionic-liquid-modified phenolic resin (ILPR) was synthesized using 3-aminophenol as a functional monomer, glyoxylic acid as a green cross-linker, and polyethylene glycol 6000 as a porogen. The obtained ILPR showed better extraction of benzoylurea plant hormones thidiazuron and forchlorfenuron than the unmodified phenolic resin because the imidazolium IL provides more interaction modes with the analytes. ILPR, as a tailored adsorbent for solid-phase extraction, was coupled with high-performance liquid chromatography (ILPR‒SPE‒HPLC) for the simultaneous determination of thidiazuron and forchlorfenuron in cucumbers. Good linearity of the ILPR‒SPE‒HPLC method was obtained, ranging from 0.0100 to 5.00 µg g-1 with a correlation coefficient (r) ≥ 0.9999. The recoveries of spiked samples ranged from 91.4% to 100.7% with a relative standard deviation of ≤ 6.0%.


Assuntos
Cucumis sativus/química , Formaldeído/química , Imidazóis/química , Líquidos Iônicos/química , Fenóis/química , Compostos de Fenilureia/isolamento & purificação , Polímeros/química , Piridinas/isolamento & purificação , Extração em Fase Sólida/métodos , Tiadiazóis/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Formaldeído/síntese química , Líquidos Iônicos/síntese química , Cinética , Fenóis/síntese química , Polímeros/síntese química , Reprodutibilidade dos Testes
2.
Molecules ; 25(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046220

RESUMO

Honokiol (2) is a natural bisphenol neolignan showing a variety of biological properties, including antitumor activity. Some studies pointed out 2 as a potential anticancer agent in view of its antiproliferative and pro-apoptotic activity towards tumor cells. As a further contribution to these studies, we report here the synthesis of a small library of bisphenol neolignans inspired by honokiol and the evaluation of their antiproliferative activity. The natural lead was hence subjected to simple chemical modifications to obtain the derivatives 3-9; further neolignans (12a-c, 13a-c, 14a-c, and 15a) were synthesized employing the Suzuki-Miyaura reaction, thus obtaining bisphenols with a substitution pattern different from honokiol. These compounds and the natural lead were subjected to antiproliferative assay towards HCT-116, HT-29, and PC3 tumor cell lines. Six of the neolignans show GI50 values lower than those of 2 towards all cell lines. Compounds 14a, 14c, and 15a are the most effective antiproliferative agents, with GI50 in the range of 3.6-19.1 µM, in some cases it is lower than those of the anticancer drug 5-fluorouracil. Flow cytometry experiments performed on these neolignans showed that the inhibition of proliferation is mainly due to an apoptotic process. These results indicate that the structural modification of honokiol may open the way to obtaining antitumor neolignans more potent than the natural lead.


Assuntos
Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacologia , Compostos de Bifenilo/química , Proliferação de Células/efeitos dos fármacos , Lignanas/síntese química , Lignanas/farmacologia , Fenóis/síntese química , Fenóis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HCT116 , Células HT29 , Humanos , Lignanas/química , Células PC-3
3.
Molecules ; 25(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963211

RESUMO

The design and synthesis of a novel tert-butyl-calix[4]arene functionalized at 1, 3 positions of the lower rim with two terminal 2-hydroxybenzeledene-thiosemicarbazone moieties is reported. The new ligand with multi-dentate chelating properties was fully characterized by several techniques: ESI-Mass spectroscopy, FT-IR, 1H-NMR, and single crystal X-ray diffraction. The solid state structure confirms that the calix[4]arene macrocycle has the expected open cone conformation, with two opposite phenyl rings inclined outwards with large angles. The conformation of the two alkoxythiosemicarbazone arms produces a molecule with a C2 point group symmetry. An interesting chiral helicity is observed, with the two thiosemicarbazone groups oriented in opposite directions like a two-blade propeller. A water molecule is encapsulated in the center of the two-blade propeller through multiple H-bond coordinations. The antibacterial, antifungal, anticancer, and cytotoxic activities of the calix[4]arene-thiosemicarbazone ligand and its metal derivatives (Co2+, Ni2+, Cu2+, and Zn2+) were investigated. A considerable antibacterial activity (in particular against E. coli, MIC, and MBC = 31.25 µg/mL) was observed for the ligand and its metal derivatives. Significant antifungal activities against yeast (C. albicans) were also observed for the ligand (MIC = 31.25 µg/mL and MBC = 125 µg/mL) and for its Co2+ derivative (MIC = 62.5 µg/mL). All compounds show cytotoxicity against the tested cancerous cells. For the Saos-2 cell line, the promising anticancer activity of ligand L (IC50 < 25 µg/mL) is higher than its metal derivatives. The microscopic analysis of DAPI-stained cells shows that the treated cells change in morphology, with deformation and fragmentation of the nuclei. The hemo-compatibility study demonstrated that this class of compounds are suitable candidates for further in vivo investigations.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Técnicas de Química Sintética , Modelos Moleculares , Fenóis/química , Fenóis/farmacologia , Tiossemicarbazonas/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Calixarenos/síntese química , Linhagem Celular Tumoral , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Hemólise , Humanos , Ligantes , Fenóis/síntese química , Análise Espectral , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 186: 111880, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753513

RESUMO

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aß1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Antioxidantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fenóis/farmacologia , Ácido Tióctico/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/metabolismo , Fenóis/síntese química , Fenóis/química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Ácido Tióctico/síntese química , Ácido Tióctico/química , Células Tumorais Cultivadas
5.
J Enzyme Inhib Med Chem ; 35(1): 377-382, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31856608

RESUMO

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81-65.4 µM) and PfCA (KIs 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.


Assuntos
Antiprotozoários/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Diatomáceas/enzimologia , Fenóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fenóis/síntese química , Fenóis/química , Plasmodium falciparum/enzimologia , Relação Estrutura-Atividade
6.
J Mol Model ; 25(12): 362, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31773345

RESUMO

Sunscreen-based photoprotection is an important strategy to prevent photoaging and skin cancer. Among the effective and modern sunscreens, triazine compounds are known as an important class based on their physical-chemical properties, such as photostability and UV broad-spectrum absorption (UVA and UVB). Molecular modeling and quantum mechanical calculations approaches can be helpful to orientate the design of sunscreens. Herein, a case study is presented to demonstrate the importance of the molecular modeling as a design tool for promising sunscreen candidates based on the synthesis research previously described of bemotrizinol, a broad-spectrum photostable organic UV filter present in many sunscreens products. Time-dependent density functional theory (TD-DFT) calculations performed in gas phase on the isolated organic UV filters proved to reproduce the experimental UV absorption, guiding the choice of the most efficient candidate as sunscreen. The present work highlights the importance of molecular modeling as an effective tool to support synthesis research, increasing the possibility of obtaining promising compounds with reduced costs and effluent production. Graphical abstractA case study to demonstrate the importance of the molecular modeling as a design tool for promising sunscreen candidates is presented. The method proved to be a valuable tool to reproduce the experimental UV absorption and to determinate the most efficient molecule as sunscreen among the candidates.


Assuntos
Desenho Assistido por Computador , Desenho de Fármacos , Modelos Moleculares , Fenóis/farmacologia , Protetores Solares/farmacologia , Triazinas/farmacologia , Estabilidade de Medicamentos , Estrutura Molecular , Fenóis/síntese química , Relação Estrutura-Atividade , Protetores Solares/síntese química , Triazinas/síntese química
7.
Molecules ; 24(22)2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752322

RESUMO

Phytophthora cinnamomi is a phytopathogen that causes extensive damage in different crops, and therefore, produces important economic losses all around the world. Chemical fungicides are a key factor for the control of this disease. However, ecological and environmental considerations, as well as the appearance of strains that are resistant to commercial fungicides, have prompted the quest for new antifungal agents which are of low ecological impact. In this work, a series of new 2-allylphenol derivatives was synthesized, and their structures were confirmed by FT-IR, NMR, and MS. Some of the synthesized compounds, more specifically nitro derivatives, exhibit strong growth inhibition of P. cinnamomi with EC50 as low as 10.0 µg/mL. This level of activity is similar to that exhibited by METALAXYL MZ 58 WP, a commonly-used commercial fungicide; therefore, these compounds might be of agricultural interest due to their potential use as fungicides against P. cinnamomi. The results indicate that this activity depends on the chemical structures of the 2-allylphenol derivatives, and that it is strongly enhanced in molecules where nitro and hydroxyl groups adopt a -para configuration. These effects are discussed in terms of the electronic distribution of the aromatic ring induced by substituent groups.


Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Fenóis/síntese química , Fenóis/farmacologia , Phytophthora/efeitos dos fármacos , Antiparasitários/química , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Testes de Sensibilidade Parasitária , Fenóis/química , Doenças das Plantas/parasitologia
8.
J Enzyme Inhib Med Chem ; 34(1): 1-11, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456445

RESUMO

The over expression of melanogenic enzymes like tyrosinase caused many hyperpigmentaion disorders. The present work describes the synthesis of hydroxy substituted 2-[(4-acetylphenyl)amino]-2-oxoethyl derivatives 3a-e and 5a-e as antimelanogenic agents. The tyrosinase inhibitory activity of synthesized derivatives 3a-e and 5a-e was determined and it was found that derivative 5c possesses excellent activity with IC50 = 0.0089 µM compared to standard kojic acid (IC50 = 16.69 µM). The presence of hydroxyl groups at the ortho and the para position of cinnamic acid phenyl ring in compound 5c plays a vital role in tyrosinase inhibitory activity. The compound 5d also exhibited good activity (IC50 = 8.26 µM) compared to standard kojic acid. The enzyme inhibitory kinetics results showed that compound 5c is a competitive inhibitor while 5d is a mixed-type inhibitor. The mode of binding for compounds 5c and 5d with tyrosinase enzyme was also assessed and it was found that both derivatives irreversibly bind with target enzyme. The molecular docking and molecular dynamic simulation studies were also performed to find the position of attachment of synthesized compounds at tyrosinase enzyme (PDB ID 2Y9X). The results showed that all of the synthesized compounds bind well with the active binding sites and most potent derivative 5c formed stable complex with target protein. The cytotoxicity results showed that compound 5c is safe at a dose of 12 µg/mL against murine melanoma (B16F10) cells. The same dose of 5c was selected to determine antimelanogenic activity; the results showed that it produced antimelenogenic effects in murine melanoma (B16F10) cells. Based on our investigations, it was proposed that compound 5c may serve as a lead structure to design more potent antimelanogenic agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Radical Hidroxila/farmacologia , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/antagonistas & inibidores , Fenóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Radical Hidroxila/síntese química , Radical Hidroxila/química , Cinética , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Fenóis/síntese química , Fenóis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
9.
Eur J Med Chem ; 181: 111550, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376562

RESUMO

Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aß42, lacking neurotoxicity up to 5 µM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antineoplásicos/farmacologia , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenóis/farmacologia , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Butirilcolinesterase/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Electrophorus , Cavalos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fenóis/síntese química , Fenóis/química , Relação Estrutura-Atividade , Tacrina/síntese química , Tacrina/química , Células Tumorais Cultivadas
10.
Eur J Med Chem ; 181: 111578, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401536

RESUMO

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 µM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 µM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 µM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Carbamatos/síntese química , Células Hep G2 , Humanos , Isocitrato Liase/antagonistas & inibidores , Isocitrato Liase/metabolismo , Mycobacterium tuberculosis/enzimologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Salicilanilidas/síntese química , Salicilanilidas/química , Salicilanilidas/farmacologia , Tuberculose/tratamento farmacológico
11.
J Photochem Photobiol B ; 198: 111594, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31446177

RESUMO

Two distinct classes of compounds, (E)-2-(((3-amino-4-nitrophenyl) imino) methyl)-5-(diethylamino) phenol (SB) and 5-(diethylamino)-2-(5-nitro-1H-benzo[d]imidazol-2-yl) phenol (IM) were synthesized. SB, a bright red colored compound was crystallized in acetonitrile as a triclinic crystal system while IM, yellow colored compound crystallized as a monoclinic crystal system in dimethylformamide by vapor diffusion of diethylether. These compounds were characterized using spectroscopic techniques (IR, UV-visible, 1H, and 13C NMR), and X-ray crystallography. SB and IM displayed classical and non-classical H-bonding involving C-H…O and π…π interactions. These compounds detected hypochlorite ions in aqueous DMSO (1: 9, v/v, HEPES buffer, pH 7.4), and detection was visible via color changes by naked eye. We also performed UV-visible and fluorescence titrations, showing detection limits of 8.82 × 10-7 M for SB and 2.44 × 10-7 M for IM. The fluorometric responses from SB and IM were also studied against different ROS and anions. DFT calculations were performed to strengthen the proposed sensing mechanisms of both SB and IM. Hypochlorite, which is endogenously generated by myeloperoxidase in endosomes, was specifically visualized using SB and IM in lipopolysaccharide-treated RAW264.7 cells. These probes were also used to image the generation of hypochlorite by RAW264.7 cells during phagocytosis of non-fluorescent polystyrene beads.


Assuntos
Ácido Hipocloroso/metabolismo , Fenóis/química , Animais , Ânions/química , Teoria da Densidade Funcional , Concentração de Íons de Hidrogênio , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Fagocitose , Fenóis/síntese química , Poliestirenos/química , Poliestirenos/metabolismo , Células RAW 264.7 , Espectrofotometria
12.
Drug Deliv ; 26(1): 756-764, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31357893

RESUMO

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Fenóis/administração & dosagem , Pteridinas/administração & dosagem , Sorafenibe/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Derivados de Hidroxietil Amido , Camundongos Nus , Micelas , Fenóis/síntese química , Fenóis/farmacocinética , Fenóis/uso terapêutico , Polietilenoglicóis , Pteridinas/síntese química , Pteridinas/farmacocinética , Pteridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sorafenibe/farmacocinética , Sorafenibe/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Chem Commun (Camb) ; 55(60): 8876-8879, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31286121

RESUMO

Here we report template-free synthesis of imine-linked calix[4]arene hollow nanocapsules and their utility in the effective delivery of a poorly soluble cancer drug into tumor cells. These stimuli-responsive nanocapsules show high drug loading and release which resulted in a 40-fold higher cytotoxicity for breast cancer cell line over normal cells.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/química , Camptotecina/farmacologia , Portadores de Fármacos/química , Nanocápsulas/química , Fenóis/química , Antineoplásicos/química , Calixarenos/síntese química , Calixarenos/toxicidade , Camptotecina/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanocápsulas/toxicidade , Fenóis/síntese química , Fenóis/toxicidade
14.
Chem Biol Interact ; 310: 108753, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319075

RESUMO

Multitarget ligands (MTL) based on sterically hindered phenol and containing a quaternary ammonium moiety (SHP-n-Q) were synthesized. These compounds are inhibitors of cholinesterases with antioxidant properties. The inhibitory selectivity is 10-fold potent for BChE than for AChE. IC50 of SHP-n-Q for BChE is 20 µM. SHP-n-Q and their nanosystems exhibit more pronounced antioxidant properties than the synthetic antioxidant (hindered phenol, butylated hydroxytoluene). These compounds display a low hemolytic activity against human red blood cells. The nanotechnological approach was used to increase the bioavailability of SHP-n-Q derivatives. For water soluble SHP-n-Q derivative, the self-assembled structures have a size close to 100 nm at critical association concentration (0.01 M). Mixed cationic liposomes based on l-α-phosphatidylcholine and SHP-n-Q of 100 nm diameter were prepared. The stability, encapsulation efficacy and release from liposomes of a model drug, Rhodamine B, depend on the structure of SHP-n-Q. Cationic liposomes based on l-α-phosphatidylcholine and SHP-3-Q show a good stability in time (1year) and a sustained release (>65 h). They are promising templates for the development of anti-Alzheimer MT-drug delivery systems.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Fenóis/química , Acetilcolinesterase/química , Compostos de Amônio , Antioxidantes/farmacologia , Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Lipossomos/química , Nanoestruturas , Fenóis/síntese química , Relação Estrutura-Atividade
15.
J Fluoresc ; 29(5): 1079-1087, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342231

RESUMO

Two novel bisphenol-A derivatives (R1 and R2) linked pyrene and napthylthiazole moieties were synthesized via condensation reaction, and positively applied for the selective recognition of Zn2+ ion in EtOH/H2O. Their optical properties were observed by using UV-vis and fluorescence measurements. R1 and R2 exhibited high selectivity and sensitivity towards Zn2+ over other metal ions. This fluorescence selectivity may be owing to inhibited excited-state intramolecular proton transfer (ESIPT) and photoinduced electron transfer (PET). The fluorescence titration analysis indicated detection limits of R1 and R2 for Zn2+ at 17.5 nM and 0.94 µM, respectively. Moreover, R1 and R2 were successfully applied to the detection of Zn2+ with different concentrations in water samples.


Assuntos
Compostos Benzidrílicos/química , Corantes Fluorescentes/química , Fenóis/química , Zinco/análise , Compostos Benzidrílicos/síntese química , Etanol/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Fenóis/síntese química , Soluções , Espectrometria de Fluorescência , Água/química
16.
ACS Appl Mater Interfaces ; 11(26): 22973-22978, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31252497

RESUMO

Misfolding and abnormal assembly of proteins cause many intractable diseases. The modulation of the assembly process of these proteins could contribute to understanding and controlling amyloid protein aggregation. Previous works focused mainly on the inhibition of the assembly process. To broaden the interaction modality of modulators with proteins for developing new modulators, in this work, we designed and synthesized two reactive poly ( p-phenylene vinylene) polymers, respectively, functionalized with N-hydroxysuccinimide ester (PPV-NHS) and pentafluorophenol ester (PPV-PFP), which exhibited the prevention or co-assembly effect on the aggregation process of islet amyloid polypeptide (IAPP). Cell assays demonstrated that both of the two polymers could effectively eliminate the cytotoxicity of IAPP. Moreover, PPV-NHS also could irreversibly disrupt preformed IAPP fibrils. We envision that PPV-NHS and PPV-PFP might offer a new design method for the modulation of protein assembly.


Assuntos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polímeros/química , Agregação Patológica de Proteínas/tratamento farmacológico , Sequência de Aminoácidos/genética , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Fluorbenzenos/síntese química , Fluorbenzenos/química , Fluorbenzenos/farmacologia , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/síntese química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Polímeros/síntese química , Polímeros/farmacologia , Agregação Patológica de Proteínas/genética , Succinimidas/síntese química , Succinimidas/química , Succinimidas/farmacologia
17.
Eur J Med Chem ; 178: 93-107, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176098

RESUMO

Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17ß-HSD1 and 17ß-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17ß-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17ß-HSD1 and 17ß-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17ß-HSD1 and 17ß-HSD2.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Estradiol Desidrogenases/antagonistas & inibidores , Fenóis/farmacocinética , Tiofenos/farmacocinética , Animais , Sítios de Ligação , Desenho de Fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Estradiol Desidrogenases/química , Estradiol Desidrogenases/metabolismo , Células HEK293 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Fenóis/metabolismo , Ligação Proteica , Solubilidade , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/metabolismo
18.
Drug Dev Res ; 80(5): 666-679, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31112325

RESUMO

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti-inflammatory effects. The objective of this study was to investigate the anti-inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP-VT), in mice. The results of this study indicated that ISP-VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP-VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor-α and interleukin-6), and vascular permeability. ISP-VT also significantly reduced the expression of cyclooxygenase-2 (COX-2) in subplantar tissue of mice. ISP-VT inhibited COX-2 selectively compared to the standard drug. Our results showed that although ISP-VT binds to COX-1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP-VT significantly reduced rectal temperature in yeast-induced hyperthermia in mice. Our results showed that the main mechanism ISP-VT-induced anti-inflammatory activity is by inhibition of COX-2. In conclusion, our results indicate that ISP-VT has potential as an anti-inflammatory and antipyretic therapeutic compound.


Assuntos
Anti-Inflamatórios/administração & dosagem , Carragenina/efeitos adversos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inflamação/tratamento farmacológico , Fenóis/efeitos adversos , Ácido Vanílico/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Modelos Moleculares , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
19.
Int J Nanomedicine ; 14: 2619-2636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043778

RESUMO

Background: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems has opened a new window to overcome these problems. There has been a strong interest development of new platform and system for delivof chemotherapeutic agents. Purpose: In the present study, a green synthesis method was chosen and performed for preparation of a novel amphoteric calix[4]arene (Calix) macrocycle with low toxicity to the human body. Materials and methods: The amphoteric Calix was coated on the surface of Fe3O4 magnetic nanoparticles and used as a magnetic nanocarrier for simultaneous delivery of two anticancer agents, doxorubicin and methotrexate, against MCF7 cancer cells. Several chemical characterizations were done for validation of prepared nanocarrier, and in vitro loading and release studies of drugs were performed with good encapsulation efficiency. Results: In vitro biological studies including hemolysis assay, erythrocytes sedimentation rate, red blood cells aggregation, cyto cellular internalization, and apoptosis evaluations were performed. Based on results, the developed nanocarrier has many advantages and capability for an efficient codelivery of DOX and MTX, which has a highly potent ability to kill cancer cells. Conclusion: All these results persuade us, this nanocarrier could be effectively used for cancer therapy of MCF7 breast cancer cells and is suitable for use in further animal studies in future investigations.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Calixarenos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Fenóis/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Calixarenos/síntese química , Varredura Diferencial de Calorimetria , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Difusão Dinâmica da Luz , Endocitose , Feminino , Humanos , Células MCF-7 , Nanopartículas de Magnetita/ultraestrutura , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Tamanho da Partícula , Fenóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022940

RESUMO

Light-driven phase change materials (PCMs) have received significant attention due to their capacity to convert visible light into thermal energy, storing it as latent heat. However, continuous photo-thermal conversion can cause the PCMs to reach high thermal equilibrium temperatures after phase transition. In our study, a novel light-driven phase change material system with temperature-control properties was constructed using a thermochromic compound. Thermochromic phase change materials (TC-PCMs) were prepared by introducing 2-anilino-6-dibutylamino-3-methylfluoran (ODB-2) and bisphenol A (BPA) into 1-hexadecanol (1-HD) in various proportions. Photo-thermal conversion performance was investigated with solar radiation (low power of 0.09 W/cm2) and a xenon lamp (at a high power of 0.14 W/cm2). The TC-PCMs showed a low equilibrium temperature due to variations in absorbance. Specifically, the temperature of TC-PCM180 (ODB-2, bisphenol A and 1-HD ratio 1:2:180) could stabilize at 54 °C approximately. TC-PCMs exhibited reversibility and repeatability after 20 irradiation and cooling cycles.


Assuntos
Compostos de Anilina/síntese química , Compostos Benzidrílicos/síntese química , Álcoois Graxos/síntese química , Fluoresceínas/síntese química , Fenóis/síntese química , Compostos de Anilina/química , Compostos de Anilina/efeitos da radiação , Compostos Benzidrílicos/química , Compostos Benzidrílicos/efeitos da radiação , Álcoois Graxos/química , Álcoois Graxos/efeitos da radiação , Fluoresceínas/química , Fluoresceínas/efeitos da radiação , Temperatura Alta , Luz , Transição de Fase/efeitos da radiação , Fenóis/química , Fenóis/efeitos da radiação , Temperatura
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