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1.
Med Chem ; 16(1): 63-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30734682

RESUMO

BACKGROUND: A convenient approach to modulation of the inflammation has an influence on the production of inflammatory mediators - icosanoids, generated in arachidonic acid (AA) metabolism. The common therapeutic activity of non-steroidal anti-inflammatory drugs (NSAID), such as aspirin, includes inhibition of two crucial enzymes of AA metabolism - cyclooxygenase- 1 and -2 (COX-1/2), with certain risk for gastrointestinal and renal intolerance. Ever since the enrolment of COX-2, particularly overabundance of its main products prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in numerous pathological processes was recognized, it became a significant therapeutic target. OBJECTIVE: The aim of this study was to examine the effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in the inflammation process. METHODS: Trifluoromethyl compounds were synthesized from N-benzyl trifluoromethyl aldimine, commercially available 2-methyl or 2-phenyl α-bromo esters (ß-lactams trans-1 and trans-2 and trifluoromethyl ß-amino ester, respectively) and methyl 2-isocyanoacetate (2-imidazoline trans-4). The reactions proceeded with high geometric selectivity, furnishing the desired products in good yields. The influence of newly synthesized compounds on PGE2 and TXA2 production in human leukemic U937 macrophages on both enzyme activity and gene expression levels was observed. RESULTS: Among the tested trifluoromethyl compounds, methyl trans-1-benzyl-5-(trifluoromethyl)- 4,5-dihydro-1H-imidazole-4-carboxylate (trans-4) can be distinguished as the most powerful antiinflammatory agent, probably due to its trifluoromethyl-imidazoline moiety. CONCLUSION: Some further structural modifications in tested compounds and particularly in the synthesis of different trifluoromethyl imidazolines could contribute to the development of new COX-2 inhibitors and potent anti-inflammatory agents.


Assuntos
Dinoprostona/biossíntese , Hidrocarbonetos Fluorados/farmacologia , Macrófagos/efeitos dos fármacos , Tromboxano A2/biossíntese , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Células U937
2.
Chemosphere ; 240: 124947, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31568943

RESUMO

This work studies the effect of the cation and anion on the biodegradability and inhibition of imidazolium- and choline-based ionic liquids (ILs) using activated sludge. Six commercial ILs, formed by combination of 1-Butyl-3-methylimidazolium (Bmim+) and N,N,N-trimethylethanolammonium (Choline+) cations and chloride (Cl-), acetate (Ac-) and bis(trifluoromethanesulfonyl)imide (NTf2-) anions were evaluated, all representative counter-ions with markedly different toxicity and biodegradability. Inherent and fast biodegradability tests were used to evaluate both the microorganism inhibition and the IL biodegradability. In addition, the ecotoxicological response (EC50) of the ILs was studied using activated sludge and Vibrio fischeri (Microtox® test). Bmim+ and NTf2- can be considered as non-biodegradable, whereas aerobic microorganisms easily degraded Choline+ and Ac-. The biodegradation pattern of each cation/anion is nearly unaffected by counter-ion nature. Moreover, concentrations of CholineNTf2 higher than 50 mg/L caused a partial inhibition on microbial activity, in good concordance with its low EC50 (54 mg/L) measured by respiration inhibition test, which alerts on the negative environmental impact of NTf2-containing ILs on the performance of sewage treatment plants.


Assuntos
Aliivibrio fischeri/efeitos dos fármacos , Biodegradação Ambiental , Colina/análise , Hidrocarbonetos Fluorados/química , Imidazóis/análise , Imidazóis/química , Imidas/química , Compostos de Amônio Quaternário/química , Ecotoxicologia , Líquidos Iônicos/análise , Esgotos/química , Purificação da Água/métodos
3.
Org Biomol Chem ; 17(47): 10097-10102, 2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31754683

RESUMO

New open-chain and water-soluble hypervalent iodine reagents were synthesized and used for the transfer of fluoroalkyl groups to sulfur atoms of cysteine and cysteine-containing peptides under biocompatible conditions. Some of the reagents displayed excellent reactivity despite their limited stability in aqueous media. In reactions with a short cysteine-containing peptide, in addition to the expected S-fluoroalkylated product, a range of side-products were obtained. The amount of side-products depended on the conditions used (type of reagent, concentration, and pH). With highly activated hypervalent iodine reagents, a new reactive mode was observed - reaction with disulfides to form fluoroalkyl thiols.


Assuntos
Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/síntese química , Indicadores e Reagentes/química , Indicadores e Reagentes/síntese química , Iodo/química , Compostos de Sulfidrila/química , Água/química , Alquilação , Estrutura Molecular , Solubilidade
4.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640159

RESUMO

We have examined the insertion of carbenes carrying leaving groups into the [nido-B11H13]2- dianion to form the [closo-1-CB11H12]- anion. The best procedure uses CF3SiMe3 and LiCl as the source of CF2. It is simple, convenient and scalable and proceeds with 70-90% yield. Density functional calculations have been used to develop a mechanistic proposal that accounts for the different behavior of CF2, requiring only one equivalent of base for successful conversion of Na[nido-B11H14]- to [closo-1-CB11H12]-, and CCl2 and CBr2, which require more.


Assuntos
Compostos de Boro/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Cloreto de Lítio/química , Estrutura Molecular
5.
J Agric Food Chem ; 67(42): 11591-11597, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31557017

RESUMO

A simple and eco-friendly dispersive solid-phase extraction method coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the determination of the chiral pesticide tefluthrin in food and environmental samples. The response surface methodology was applied to optimize separation conditions. The elution order of tefluthrin enantiomers was Z-cis-(1S,3S)-(-)-tefluthrin and Z-cis-(1R,3R)-(+)-tefluthrin on a Lux Cellulose-1 chiral column was identified via a polarimeter and vibrating circular dichroism. The average recoveries in five matrices ranged from 76.9 to 107.6%, with intraday relative standard deviations (RSDs) less than 15.6% and interday RSDs less than 12.5% for two enantiomers. The enantioselective degradation was investigated via laboratory incubation experiments. Slightly enantioselective degradation was observed under aerobic conditions; (1S,3S)-tefluthrin degraded preferentially with the enantiomer fraction value of 0.57 at 120 days of incubation. No remarkable enantioselective degradation was observed under anaerobic and sterile conditions. It was the first time that pyrethroid pesticides were determined at the enantiomer levels via UPLC-MS/MS. This novel method was successfully applied for the enantioselective analysis of tefluthrin enantiomers in authentic samples, indicating its efficacy in investigating the environmental stereochemistry of tefluthrin in the food web and environment. It is of crucial importance to improve risk assessment and regulation of chiral pesticides in an agricultural system.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos/química , Hidrocarbonetos Fluorados/química , Praguicidas/química , Poluentes do Solo/química , Solo/química , Espectrometria de Massas em Tandem/métodos , Estereoisomerismo
6.
Eur J Med Chem ; 181: 111549, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31376569

RESUMO

Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.


Assuntos
Antituberculosos/farmacologia , Benzofenantridinas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Benzofenantridinas/síntese química , Benzofenantridinas/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimento , Relação Estrutura-Atividade
7.
J Mater Sci Mater Med ; 30(8): 96, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414231

RESUMO

Critical size bone defects that do not heal spontaneously are among the major reasons for the disability in majority of people with locomotor disabilities. Tissue engineering has become a promising approach for repairing such large tissue injuries including critical size bone defects. Three-dimension (3D) porous scaffolds based on piezoelectric polymers like poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) have received a lot of attention in bone tissue engineering due to their favorable osteogenic properties. Owing to the favourable redox properties, titanium dioxide (TiO2) nanostructures have gained a great deal of attention in bone tissue engineering. In this paper, tissue engineering scaffolds based on P(VDF-TrFE) loaded with TiO2 nanowires (TNW) were developed and evaluated for bone tissue engineering. Wet-chemical method was used for the synthesis of TNW. Obtained TNW were thoroughly characterized for the physicochemical and morphological properties using techniques such as X-Ray diffraction (XRD) analysis and transmission electron microscopy (TEM). Electrospinning was used to produce TNW incorporated P(VDF-TrFE) scaffolds. Developed scaffolds were characterized by state of art techniques such as Scanning Electron Microscopy (SEM), XRD and Differential scanning calorimetry (DSC) analyses. TEM analysis revealed that the obtained TiO2 nanostructures possess nanofibrous morphology with an average diameter of 26 ± 4 nm. Results of characterization of nanocomposite scaffolds confirmed the effective loading of TNW in P(VDF-TrFE) matrix. Fabricated P(VDF-TrFE)/TNW scaffolds possessed good mechanical strength and cytocompatibility. Osteoblast like cells showed higher adhesion and proliferation on the nanocomposite scaffolds. This investigation revealed that the developed P(VDF-TrFE) scaffolds containing TNW can be used as potential scaffolds for bone tissue engineering applications.


Assuntos
Osso e Ossos/citologia , Nanofios/química , Polivinil/química , Engenharia Tecidual , Tecidos Suporte/química , Titânio/química , Compostos de Vinila/química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Hidrocarbonetos Fluorados/química , Teste de Materiais , Camundongos , Nanocompostos/química , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Ratos , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos
8.
Eur J Med Chem ; 180: 1-14, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31288149

RESUMO

SAR studies on bicalutamide, enobosarm and enzalutamide analogues, functionalised with polyfluorinated groups, is presented. Among the novel bicalutamide and enobosarm derivatives synthesised, several displayed significantly improved in vitro anticancer activity, with IC50 values in the low micromolar range against four different prostate cancer cell lines (LNCaP, VCaP, DU-145 and 22Rv1), showing up to 48-fold increase in comparison with the parent structures. In particular, SF5 enobosarm analogues were found to be most potent compounds, full AR antagonists and with favourable ADME properties. The most promising compound (48a) was evaluated for its in vivo efficacy in PC xenograft mouse model (22Rv1) with results comparable to the standard-of-care docetaxel.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Nitrilos/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Compostos de Tosil/farmacologia , Anilidas/síntese química , Anilidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cricetulus , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Nitrilos/síntese química , Nitrilos/química , Feniltioidantoína/síntese química , Feniltioidantoína/química , Feniltioidantoína/farmacologia , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Compostos de Tosil/síntese química , Compostos de Tosil/química
9.
Biomater Sci ; 7(9): 3764-3778, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31342016

RESUMO

Fluorinated polymers are strong candidates for development of new cardiovascular medical devices, due to their lower thrombogenicity as compared to other polymers used for cardiovascular implants. Few studies have reported the development of fluorinated polyesters and their potential in blood contact applications has never been examined. In this study, we developed a versatile method for preparing trifluoromethyl-functionalized poly(lactic acid) that can be potentially extended to prepare a new class of polyesters with various halogen or halocarbon substitutions. The resulting fluorinated polymer was hydrophobic relative to poly(lactic acid) and extracts from this polymer showed no in vitro cytotoxicity to NIH-3T3 mouse fibroblast cells. A preliminary consideration of the blood interactions of the CF3-functionalized polyester was evaluated by measuring the amount of the adsorbed albumin and fibrinogen from human blood plasma. The fluorinated polyester adsorbed and retained higher amounts of albumin and fibrinogen with a higher albumin/fibrinogen ratio as compared to poly(lactic acid), suggesting enhanced hemocompatibility. Plasma protein adsorption is the first event that occurs seconds after device implantation and controlling the adsorbed proteins will dictate the performance of medical implants.


Assuntos
Materiais Biocompatíveis/química , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/química , Poliésteres/química , Adsorção , Animais , Materiais Biocompatíveis/síntese química , Células Cultivadas , Fibrinogênio/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Estrutura Molecular , Células NIH 3T3 , Poliésteres/síntese química , Albumina Sérica Humana/química , Propriedades de Superfície
10.
Arch Pharm (Weinheim) ; 352(8): e1900061, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31338866

RESUMO

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.


Assuntos
Hidrocarbonetos Fluorados/farmacologia , Elastase Pancreática/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Serino Proteinase/farmacologia , Animais , Relação Dose-Resposta a Droga , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Pâncreas/enzimologia , Elastase Pancreática/metabolismo , Piperidinas/síntese química , Piperidinas/química , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Suínos
11.
Int J Pharm ; 566: 463-475, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31173800

RESUMO

This paper presents in situ time-resolved drug mass fraction measurements in pressurised metered dose inhaler (PMDI) sprays, using a novel combination of synchrotron X-ray fluorescence and scattering. Equivalent suspension and solution formulations of ipratropium bromide in HFA-134a propellant were considered. Measurements were made both inside the expansion chamber behind the nozzle orifice, and in the first few millimeters of the spray where droplet and particle formation occur. We observed a consistent spike in drug mass fraction at the beginning of the spray when the first fluid exits the nozzle orifice. Approximately 20% of the total delivered dose exits the nozzle in the first 0.1 s of the spray. The drug mass fraction in the droplets immediately upon exiting the nozzle peaked at approximately 50% of the canister mass fraction, asymptoting to approximately 20% of the canister concentration. The effect is due to a change in the drug mass fraction inside the droplets, rather than changes in droplet size or distribution. The transient was found to originate inside the expansion chamber. We propose that this effect may be a major contributor to low delivery efficiency in PMDIs, and have important implications for oropharyngeal deposition and inhalation technique. This highlights the importance of expansion chamber and nozzle design on the structure of PMDI sprays, and indicates areas of focus that may lead to improvement in drug delivery outcomes.


Assuntos
Inaladores Dosimetrados , Propelentes de Aerossol/química , Broncodilatadores/química , Desenho de Equipamento , Hidrocarbonetos Fluorados/química , Ipratrópio/química , Pressão , Soluções , Espectrometria por Raios X , Suspensões
12.
Dalton Trans ; 48(20): 6899-6909, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31038147

RESUMO

A Cu(i) fully fluorinated O-donor monodentate alkoxide complex, K[Cu(OC4F9)2], was previously shown to form a trinuclear copper-dioxygen species with a {Cu3(µ3-O)2} core, TOC4F9, upon reactivity with O2 at low temperature. Herein is reported a significantly expanded kinetic and mechanistic study of TOC4F9 formation using stopped-flow spectroscopy. The TOC4F9 complex performs catalytic oxidase conversion of hydroquinone (H2Q) to benzoquinone (Q). TOC4F9 also demonstrated hydroxylation of 2,4-di-tert-butylphenolate (DBP) to catecholate, making TOC4F9 the first trinuclear species to perform tyrosinase (both monooxygenase and oxidase) chemistry. Resonance Raman spectra were also obtained for TOC4F9, to our knowledge, the first such spectra for any T species. The mechanism and substrate reactivity of TOC4F9 are compared to those of its bidentate counterpart, TpinF, formed from K[Cu(pinF)(PR3)]. The monodentate derivative has both faster initial formation and more diverse substrate reactivity.


Assuntos
Cobre/química , Hidrocarbonetos Fluorados/química , Monofenol Mono-Oxigenase/química , Catálise , Temperatura Baixa , Cinética , Ligantes , Modelos Moleculares , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade
13.
Molecules ; 24(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083344

RESUMO

The intermolecular interaction in difluoromethane, dichloromethane, dibromomethane, and diiodomethane dimers has been investigated using high level quantum chemical methods. The potential energy curve of intermolecular interaction along the C⋯C bond distance obtained using the coupled-cluster theory with singles, doubles, and perturbative triples excitations CCSD(T) were compared with values given by the same method, but applying the local (LCCSD(T)) and the explicitly correlated (CCSD(T)-F12) approximations. The accuracy of other theoretical methods-Hartree-Fock (HF), second order Møller-Plesset perturbation (MP2), and dispersion corrected DFT theory-were also presented. In the case of MP2 level, the canonical and the local-correlation cases combined with the density-fitting technique (DF-LMP2)theories were considered, while for the dispersion-corrected DFT, the empirically-corrected BLYP-D and the M06-2Xexchange-correlation functionals were applied. In all cases, the aug-cc-pVTZ basis set was used, and the results were corrected for the basis set superposition error (BSSE) using the counterpoise method. For each molecular system, several dimer geometries were found, and their mutual orientations were compared with the nearest neighbor orientations obtained in recent neutron scattering studies. The nature of the intermolecular interaction energy was discussed.


Assuntos
Compostos Inorgânicos/análise , Compostos Inorgânicos/química , Dimerização , Hidrocarbonetos Bromados/análise , Hidrocarbonetos Bromados/química , Hidrocarbonetos Clorados/análise , Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/análise , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Iodados/análise , Hidrocarbonetos Iodados/química , Modelos Químicos , Modelos Moleculares , Teoria Quântica
14.
Chem Commun (Camb) ; 55(45): 6361-6364, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31062010

RESUMO

A simple technique for the preparation of [18F]HF has been developed and applied to the generation of an [18F]FeF species for opening sterically hindered epoxides. This method has been successfully employed to prepare four drug-like molecules, including 5-[18F]fluoro-6-hydroxy-cholesterol, a potential adrenal/endocrine PET imaging agent. This easily automated one-pot procedure produces sterically hindered fluorohydrin PET imaging agents in good yields and high molar activities.


Assuntos
Compostos de Epóxi/química , Fluoretos/química , Hidrocarbonetos Fluorados/química , Ferro/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Radioisótopos de Flúor , Hidrocarbonetos Fluorados/síntese química
15.
Org Biomol Chem ; 17(22): 5550-5560, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31112186

RESUMO

Herein, we report the synthesis of 4'-C-trifluoromethyl (4'-CF3) thymidine (T4'-CF3) and its incorporation into oligodeoxynucleotides (ODNs) through solid-supported DNA synthesis. The 4'-CF3 modification leads to a marginal effect on the deoxyribose conformation and a local helical structure perturbation for ODN/RNA duplexes. This type of modification slightly decreases the thermal stability of ODN/RNA duplexes (-1 °C/modification) and leads to improved nuclease resistance. Like the well-known phosphorothioate (PS) modification, heavy 4'-CF3 modifications enable direct cellular uptake of the modified ODNs without any delivery reagents. This work highlights that 4'-CF3 modified ODNs are promising candidates for antisense-based therapeutics, which will, in turn, inspire us to develop more potent modifications for antisense ODNs and siRNAs.


Assuntos
Hidrocarbonetos Fluorados/química , Oligodesoxirribonucleotídeos/farmacocinética , Células HeLa , Humanos , Hidrocarbonetos Fluorados/sangue , Microscopia Confocal , Conformação Molecular , Oligodesoxirribonucleotídeos/sangue , Oligodesoxirribonucleotídeos/química , Distribuição Tecidual
16.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013665

RESUMO

Here, we report the synthesis of a sulfated, fully protected hexasaccharide as a glycosaminoglycan mimetic and the study of its interactions with different growth factors: midkine, basic fibroblast growth factor (FGF-2) and nerve growth factor (NGF). Following a fluorous-assisted approach, monosaccharide building blocks were successfully assembled and the target oligosaccharide was prepared in excellent yield. The use of more acid stable 4,6-O-silylidene protected glucosamine units was crucial for the efficiency of this strategy because harsh reaction conditions were needed in the glycosylations to avoid the formation of orthoester side products. Fluorescence polarization experiments demonstrated the strong interactions between the synthesized hexamer, and midkine and FGF-2. In addition, we have developed an alternative assay to analyse these molecular recognition events. The prepared oligosaccharide was non-covalently attached to a fluorous-functionalized microplate and the direct binding of the protein to the sugar-immobilized surface was measured, affording the corresponding KD,surf value.


Assuntos
Fator 2 de Crescimento de Fibroblastos/química , Hidrocarbonetos Fluorados , Midkina/química , Oligossacarídeos , Polarização de Fluorescência , Glicosilação , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Oligossacarídeos/síntese química , Oligossacarídeos/química
17.
Chemistry ; 25(34): 7998-8002, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-30947363

RESUMO

In this communication, the synthesis of three unknown polyfluorinated cyanine dyes and their application as selective markers for mitochondria are presented. By incorporating fluorous side chains into cyanine dyes, their remarkable photophysical properties were enhanced. To investigate their biological application, several different cell lines were incubated with the synthesized cyanine dyes. It was discovered that the presented dyes can be utilized for selective near-infrared-light (NIR) staining of mitochondria, with very low cytotoxicity determined by MTT assay. This is the first time that polyfluorinated cyanine fluorophores are presented as selective markers for mitochondria. Due to the versatile applications of polyfluorinated fluorophores in bioimaging and materials science, it is expected that the presented fluorophores will be stimulating for the scientific community.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Hidrocarbonetos Fluorados/química , Microscopia de Fluorescência/métodos , Mitocôndrias/ultraestrutura , Imagem Óptica/métodos , Células A549 , Carbocianinas/síntese química , Linhagem Celular , Corantes Fluorescentes/síntese química , Halogenação , Células HeLa , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrocarbonetos Fluorados/síntese química , Raios Infravermelhos , Microscopia Confocal/métodos
18.
Top Curr Chem (Cham) ; 377(2): 9, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30835005

RESUMO

Malaria represents a significant health issue, and novel effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. The most popular antimalarial drugs are focused on the 7-chloro-4-aminoquinoline [e.g., chloroquine (CQ), amodiaquine (AQ), isoquine (IQ), and tebuquine (TBQ)], artemisinin, and atovaquone systems. Recently, endochin has been used as a platform to design a variety of novel potent and safe antimalarial agents named endochin-like quinolones (ELQs). Also, antimalarial quinolones have been constructed from other quinolones drugs such as ICI-56780 and floxacrine. Trifluoromethyl substitution has provided a significant increase in the antimalarial response of many of the designed ELQs against Plasmodium-resistant strains and for in vivo models. In particular, attachment of a substituted trifluoromethoxy (or trifluoromethyl in some cases) biaryl side chain at 2-, 3-, 4-, or 6-position of the quinolone core has shown to be crucially important to generate selective and potent novel ELQs. Furthermore, 6-chloro and 7-methoxy moieties on the quinolone core have been identified as essential pharmacophores when the trifluoromethoxy biaryl side chain is placed at 2- or 3-position of the quinolone core. Methyl or ethyl ester attached at 3-position is essential when the trifluoromethoxy aryl side chain is attached at 6- or 7-position of the quinolone core. Some promising ELQs are currently under clinical trials, representing an excellent platform for the design of new potent, selective, effective, and safe antimalarial drugs against emergent resistance malarial models.


Assuntos
Antimaláricos/síntese química , Desenho de Drogas , Hidrocarbonetos Fluorados/química , Quinolonas/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Malária Falciparum/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Quinolonas/farmacologia
19.
Med Chem ; 15(6): 676-684, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799793

RESUMO

BACKGROUND: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. OBJECTIVE: The goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. METHODS: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. RESULTS: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. CONCLUSION: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.


Assuntos
Agonismo Inverso de Drogas , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Animais , Humanos , Hidrocarbonetos Fluorados/química , Ligantes , Receptores X do Fígado/agonistas , Camundongos , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Ratos , Relação Estrutura-Atividade , Sulfonamidas/agonistas , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Células Th17
20.
Chem Biodivers ; 16(4): e1900028, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30715794

RESUMO

Di(indol-3-yl)methane (=3,3'-methanediyldi(1H-indole), DIM, 1) is a known weakly antitumoral compound formed by digestion of indole-3-carbinol (=1H-indol-3-ylmethanol), an ingredient of various Brassica vegetables. Out of a series of nine fluoroaryl derivatives of 1, three pentafluorophenyl derivatives 2c, 2h, and 2i were identified that exhibited a two to five times greater anti-proliferative effect and an increased apoptosis induction when compared with 1 in the following carcinoma cell lines: BxPC-3 pancreas, LNCaP prostate, C4-2B prostate, PC3 prostate and the triple-negative MDA-MB-231 breast carcinoma. Compound 2h was particularly efficacious against androgen-refractory C4-2B prostate cancer cells (IC50 =6.4 µm) and 2i against androgen-responsive LNCaP cells (IC50 =6.2 µm). In addition, 2c and 2h exhibited distinct activity in three cancer cell lines resistant to 1.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Indóis/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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