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1.
Arch Pharm (Weinheim) ; 352(9): e1900075, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339189

RESUMO

Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC50 values in the range of 6.9-28.3 µM, far superior to phenformin and metformin. Moreover, 20 µM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/síntese química , Biguanidas/síntese química , Pirazóis/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Biguanidas/química , Biguanidas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Transdução de Sinais
2.
Carbohydr Polym ; 222: 114985, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31320093

RESUMO

In recent years, bacterial cellulose (BC)-based dressings or patches for skin or soft tissue repair have become investigative emphasis. However, most of the BC-based products used for biomedical applications present limitations due to their low flexibility, poor gas permeability and no inherent antibacterial activity. Herein, we proposed and designed a novel composite composed of natural bacterial cellulose (BC), polyethylene glycol (PEG) and polyhexamethylene biguanidine (PHMB) through new synthetic approaches. The composite membrane exhibited favorable physicochemical performance, especially transparency, water retention ability, flexibility as well as the characteristic of anti-adhesion. In vitro biochemical experiment results indicated that the composite had excellent biocompatibility and exhibited strong and sustained antibacterial effect. In vivo test further demonstrated that the composite could efficiently promote skin wound healing and regeneration in a rat model. This composite membrane possesses multiple mechanisms of promoting cutaneous wound healing and will provide new ideas for future development of wound dressings.


Assuntos
Antibacterianos/química , Bandagens , Biguanidas/química , Materiais Biocompatíveis/uso terapêutico , Celulose/química , Polietilenoglicóis/química , Cicatrização , Animais , Antibacterianos/farmacologia , Biguanidas/farmacologia , Celulose/farmacologia , Escherichia coli , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Polietilenoglicóis/farmacologia , Pele/efeitos dos fármacos , Staphylococcus aureus
3.
Biometals ; 32(4): 575-593, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31044334

RESUMO

Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn2+ is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. Biguanide forms bidentate metal complexes through the two imino nitrogens. Here, it is discussed that phenformin (phenylethyl biguanide) is a model for recruitment of endogenous Zn2+ to inhibit CysHis/CysHis(X) peptidolysis. Phenformin is a Zn2+-interactive, anti-proteolytic agent in bioassay of living tissue. Benzoyl-L-arginine amide (BAA) is a classical substrate of papain-like proteases; the amide bond is scissile. In this review, the structures of BAA and the phenformin-Zn2+ complex were compared in silico. Their chemistry and dimensions are discussed in light of the active sites of papain-like proteases. The phenyl moieties of both structures bind to the "S2" substrate-binding site that is typical of many proteases. When the phenyl moiety of BAA binds to S2, then the scissile amide bond is directed to the position of the thiolate-imidazolium ion pair, and is then hydrolyzed. However, when the phenyl moiety of phenformin binds to S2, then the coordinated Zn2+ is directed to the identical position; and catalysis is inhibited. Phenformin stabilizes a "Zn2+ sandwich" between the drug and protease active site. Hundreds of biguanide derivatives have been synthesized at the 1 and 5 nitrogen positions; many more are conceivable. Various substituent moieties can register with various arrays of substrate-binding sites so as to align coordinated Zn2+ with catalytic partners of diverse proteases. Biguanide is identified here as a modifiable pharmacophore for synthesis of therapeutic CysCt inhibitors with a wide range of potencies and specificities. Phenformin-Zn2+ Complex.


Assuntos
Biguanidas/química , Catepsinas/química , Zinco/química , Bioensaio , Fenformin/química
4.
Int J Pharm ; 561: 114-123, 2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-30822503

RESUMO

KRAS is a small GTPase that regulates cell proliferation and survival. In tumors, the KRAS gene is mutated, and leading to unregulated tumor growth. Despite the recognized importance of KRAS in cancer, attempts to develop small molecule inhibitors have proved unsuccessful. An alternative strategy is gene silencing and the use of small nucleic acid sequences (e.g. siRNA, shRNA), has been reported to successfully downregulate KRAS. In this study we developed ternary nanocomplexes to deliver an anti-KRAS siRNA to colorectal cancer cells, exploiting the interaction of hyaluronic acid (HA) with CD44 as a means to achieve selective targeting of CD44-positive cancer cells. Two different polycations, poly(hexamethylene biguanide) and chitosan, were complexed with siRNA and coated with HA. Physico-chemical properties and stability of nanoparticles were characterized, including size, surface charge, and degree of siRNA protection. We demonstrate nanoparticle internalization (flow cytometry), siRNA cytosolic release (confocal microscopy) and KRAS silencing (RT-qPCR) in CD44+/KRAS+ colorectal cancer cell line, HCT-116. Further we demonstrate that the uptake of HA-decorated nanoparticles in cancer cells is higher when co-cultured with fibroblasts.


Assuntos
Neoplasias Colorretais/terapia , Sistemas de Liberação de Medicamentos/métodos , Inativação Gênica , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Nanomedicina/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/administração & dosagem , Biguanidas/química , Linhagem Celular Tumoral , Fenômenos Químicos , Quitosana/química , Técnicas de Cocultura , Neoplasias Colorretais/genética , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Fibroblastos/metabolismo , Humanos , Nanopartículas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/deficiência , RNA Interferente Pequeno/genética
5.
ACS Appl Mater Interfaces ; 10(45): 39257-39267, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30346131

RESUMO

Antibacterial coatings have been considered as an effective method for preventing the implant-associated infections caused by the bacterial colonization. In this study, we report a water-insoluble polyelectrolyte-surfactant complex, poly(hexamethylene biguanide) hydrochloride-sodium stearate (PHMB-SS) that can be facilely coated onto the surfaces of biomedical catheter and kill the bacteria by releasing the PHMB and prevent the generation of the biofilm. The PHMB-SS-coated surfaces showed better bactericidal activity toward Staphylococcus aureus and Escherichia coli. The PHMB-SS-coated catheters could not only relatively prevent the bacterial colonization in vitro but also in an implant-associated bacterial infection animal model in vivo. Moreover, no significant cytotoxicity and host response were observed in vitro and in vivo, indicating the high biocompatibility of the coating. The water-insoluble antibacterial coating reported in this work represents a novel approach to build a simple and effective coating for the prevention of device-associated infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/química , Cateteres/microbiologia , Materiais Revestidos Biocompatíveis/química , Animais , Biguanidas/química , Biofilmes/efeitos dos fármacos , Infecções Relacionadas a Cateter/prevenção & controle , Linhagem Celular , Eritrócitos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Feminino , Fibroblastos , Camundongos , Camundongos Endogâmicos BALB C , Coelhos , Solubilidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Ácidos Esteáricos/química , Água
6.
Mater Sci Eng C Mater Biol Appl ; 93: 671-678, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30274100

RESUMO

This work is a continuation of a previous study which described the development of dense and porous chitosan-alginate polyelectrolyte complexes through the addition of different amounts of Pluronic F68 to the polymeric mixture. The present study consisted in the incorporation of an antimicrobial agent, polyhexamethylene biguanide (PHMB), to the previously developed system. PHMB was incorporated at 1 and 10% (w/w) with high incorporation efficiencies, varying from 72 to 86%. Release profiles in phosphate buffered saline were evaluated using the Korsmeyer-Peppas equation, which suggested a quasi-Fickian diffusion mechanism for all obtained formulations. The maximum release percentage was approximately 15% as a result from the high affinity between PHMB and the polysaccharides. The obtained polyelectrolyte complexes were able to prevent the growth of both Staphylococcus aureus and Pseudomonas aeruginosa on their surfaces, being considered potentially effective wound dressings.


Assuntos
Alginatos/química , Anti-Infecciosos/química , Biguanidas/química , Quitosana/química , Membranas Artificiais , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Porosidade
7.
ACS Infect Dis ; 4(11): 1546-1552, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30226750

RESUMO

The increasing problem of multidrug resistance (MDR) in bacteria calls for discovery of new molecules and diagnostic methodologies that are effective against a wide range of microbial pathogens. We have studied the role of alexidine dihydrochloride (alex) as a bioaffinity ligand against lipopolysaccharide (LPS), a pathogen-associated surface marker universally present on all Gram-negative bacteria. While the activity of alex against bacteria is biologically known, little information exists on its mechanism of action or binding stoichiometry. We have used nuclear magnetic resonance (NMR), fluorescence, and surface plasmon resonance (SPR) spectroscopies to probe the binding characteristics of alex and LPS molecules. Our results indicate that LPS:alex stoichiometry lies between 1:2 and 1:4 and has a dissociation constant ( KD) of 38 µM that is mediated through electrostatic interactions between the negatively charged phosphate groups present on LPS and the positively charged guanidinium groups present in alex. Further, molecular dynamics (MD) simulations performed to determine the conformational interaction between the two molecules show good agreement with the experimental results, which substantiate the potential of alex molecule for LPS neutralization and hence, development of efficient in vitro diagnostic assays.


Assuntos
Antibacterianos/química , Biguanidas/química , Lipopolissacarídeos/química , Sítios de Ligação , Fluorescência , Bactérias Gram-Negativas/efeitos dos fármacos , Guanidina/metabolismo , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Eletricidade Estática , Ressonância de Plasmônio de Superfície
8.
PLoS One ; 13(8): e0202081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30110396

RESUMO

BACKGROUND: Mixing sodium hypochlorite (NaOCl) with chlorhexidine (CHX) forms a brown precipitate. QMix-2in1 (QMix) was introduced as a final irrigant. Manufacturer recommends interim flushing with saline between the application of NaOCl and QMix to prevent formation of precipitation. This study assessed whether para-chloroaniline (PCA) is formed after mixing NaOCl with QMix. METHODS: Commercially available, 5.25% NaOCl solution, 2% CHX, QMix, 15% ethylenediaminetetraacetic acid (EDTA) and 98% PCA in powder form were used. Groups were prepared at room temperature. Group 1, 98% PCA in powder form; Group 2, 2% chlorhexidine (CHX); Group 3, QMix; Group 4, 5.25% sodium hypochlorite (NaOCl) mixed with QMix; Group 5, 5.25% NaOCl mixed with CHX; Group 6, 15% EDTA mixed with CHX. The precipitates were extracted and analysed with Proton Nuclear Magnetic Resonance (1H-NMR) and Infrared (IR) Spectroscopy, using PCA as an internal standard. RESULTS: No PCA was found in any of the irrigant-mixture groups tested. CONCLUSIONS: This study used the interpretation of spectral results for the amino signals of precipitate formed after mixing QMix with 5.25% NaOCl using different nondestructive analysis methods, with PCA as an internal standard (control). We conclude that mixing QMix or 2%CHX with 5.25% NaOCl does not yield free PCA.


Assuntos
Biguanidas/química , Espectroscopia de Ressonância Magnética , Polímeros/química , Hipoclorito de Sódio/química , Espectrofotometria Infravermelho , Cromatografia Gasosa-Espectrometria de Massas , Humanos
9.
J Burn Care Res ; 39(3): 413-422, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29897542

RESUMO

An enzyme mixture containing bromelain (NexoBrid®) was found to be suitable for enzymatic debridement of burn wounds, as determined by the criteria of patient comfort and pain, selectivity, and efficiency. Nevertheless, daily experience showed that pretreatment of burn wounds with several other clinical agents may inhibit debridement efficiency. Therefore, the current study was performed to identify those agents and evaluate their debridement inhibition capabilities. The impact of several common agents as well pH, on NexoBrid® debridement efficiency was evaluated in vitro. A collagen-based dermal substitute (MatriDerm®) was exposed to NexoBrid® in the presence of different agents of varying concentrations. Digestion was documented. The criteria used for judging digestion were independently classified by 3 investigators at least 3 times in succession. When a low concentration (1.0 mg/ml) of NexoBrid® was used, a ≥ 50% concentration of Prontosan® had an impact on enzymatic activity. Comparable results were obtained when even lower concentrations of Octenisept® (≥ 10%) were used. A 100-µmol/L concentration of copper inhibited the enzymatic activity of both a low (1.0 mg/ml) and high (10 mg/ml) concentration of NexoBrid®. Silver-sulfadiazine at concentrations of 10% and 90% inhibited the activity of 1 mg/ml NexoBrid®. No complete inhibition of NexoBrid® activity occurred at any concentration of iron. We recommend using polyhexanide-containing agents (Prontosan®) to rinse and presoak burn wounds. Pretreatment of burn wounds with agents containing silver and copper should be avoided. Experimentally, we found a partial inhibition of NexoBrid® activity at the distinct pH values of 3 and 11.


Assuntos
Anti-Infecciosos Locais/química , Bromelaínas/química , Queimaduras/terapia , Desbridamento/métodos , Anti-Infecciosos Locais/uso terapêutico , Betaína/análogos & derivados , Betaína/química , Betaína/uso terapêutico , Biguanidas/química , Biguanidas/uso terapêutico , Bromelaínas/uso terapêutico , Colágeno/química , Colágeno/uso terapêutico , Elastina/química , Elastina/uso terapêutico , Etanolaminas/química , Etanolaminas/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Pele Artificial , Ácidos Undecilênicos/química , Ácidos Undecilênicos/uso terapêutico
10.
Environ Sci Pollut Res Int ; 25(20): 20154-20168, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29748803

RESUMO

Hexavalent chromium is a highly toxic metal that can enter drinking water sources. Chitosan, which contains amino and hydroxyl functional groups, is considered an appropriate candidate to remove heavy metals through absorption. In this study, a novel adsorbent, magnetic nanoparticles of chitosan modified with polyhexamethylene biguanide (Ch-PHMB NPs) was synthesized and was used to successfully remove chromium from aqueous solution. Quadratic models with independent variables including pH, adsorbent dosage, time, and the initial concentration of chromium were proposed through RSM to describe the behavior of both magnetic chitosan (M-Ch) and Ch-PHMB NPs in Cr(VI) removal. Optimized models with adjusted R2 values of 0.8326 and 0.74 for M-Ch and Ch-PHMB NPs were developed. Cr(VI) removal from aqueous solution by both absorbents followed pseudo-second-order kinetics. The experimental data were best fitted to the Temkin and Freundlich models for M-Ch and Ch-PHMB NPs, respectively. M-Ch and Ch-PHMB NPs can effectively remove the hexavalent chromium from aqueous solution with pH above 7. Ch-PHMB NPs have higher removal efficiency than M-Ch, removing up to 70% of Cr(VI) from aqueous solution. However, toxicity evaluation on Daphnia magna revealed that Ch-PHMB NPs was more toxic than M-Ch nanoparticles.


Assuntos
Quitosana/química , Cromo/análise , Daphnia/efeitos dos fármacos , Água Potável/análise , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Adsorção , Animais , Biguanidas/química , Cinética , Modelos Teóricos , Nanopartículas/química , Termodinâmica , Testes de Toxicidade
11.
Eur J Med Chem ; 146: 171-184, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407948

RESUMO

The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues.


Assuntos
Biguanidas/farmacologia , Desenho de Fármacos , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Biguanidas/síntese química , Biguanidas/química , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
12.
Int J Biol Macromol ; 111: 19-27, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29292154

RESUMO

Green synthesis of novel nanocomposites series based on chitosan biguanidine grafted poly(3-hydroxybutyrate) copolymer (ChG-g-PHB) and silver nanoparticles (AgNPs) was successfully done via in situ reduction of AgNO3 in the copolymer matrix. Transmission electron microscopy verified the homogeneous dispersion of spherical shape of the AgNPs with an average particle size 12.3 to 19.2nm. X-ray diffraction pattern revealed face centered cubic structure of AgNPs. The thermal stability was improved upon increasing the AgNPs content up to 2.0%, then declined upon loading with 3.0%. Coats-Redfern model showed that the sample with 2.0% AgNPs has the highest activation energy of the thermal degradation with values of 264 and 270kJmol-1 for the 1st and 2nd degradation steps, respectively. Differential scanning calorimetry indicated that AgNPs acts as a nucleating agent for the nonisothermal melt crystallization of PHB component. Avrami equation described well the crystallization of PHB segments, with average Avrami exponent of 3.10 and 3.36 for ChG-g-PHB and its 2.0% nanocomposite, respectively. Regardless of the content of AgNPs, the antimicrobial activity of the nanocomposites is better than the neat copolymer. The sample loaded with 3.0% AgNPs showed the best antimicrobial activity with MIC value range of 0.98-1.95µgmL-1.


Assuntos
Anti-Infecciosos/química , Quitosana/química , Química Verde , Nanopartículas Metálicas/química , Anti-Infecciosos/síntese química , Biguanidas/síntese química , Biguanidas/química , Cristalização , Hidroxibutiratos/química , Poliésteres/química , Prata/química
13.
Eye Contact Lens ; 44 Suppl 2: S247-S255, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29369228

RESUMO

OBJECTIVES: To assess contact lens preservative uptake and release from multipurpose solutions (MPS) and subsequent acquisition of lens antibacterial activity. METHODS: Kinetics of uptake and release of poly (hexamethylene biguanide hydrochloride) (PHMB) or polyquaternium-1 (PQ-1) from various contact lenses were studied initially with the pure compounds and then after soaking in MPS containing these compounds. Lenses soaked in MPS were tested for antibacterial activity. RESULTS: Only lenses with a negatively charged component absorbed these preservatives. For lenses containing methacrylic acid (MA), uptake of PHMB from preservative-only solution was fast, yet little was released, in contrast to its rapid release from lenses containing other anionic groups. This trend persisted with PHMB-containing MPS. PQ-1 from preservative-only solution was only absorbed by lenses containing MA and was released from MA-containing hydrogels, but not significantly from an MA-containing silicone hydrogel. Lens uptake of PQ-1 was much lower from MPS and release was essentially undetectable from all lenses evaluated. Antibacterial lens activity was acquired by lenses containing MA after an overnight soak in MPS containing PQ-1, and for balafilcon A and omafilcon A after 5 exchanges in PHMB-containing MPS. Acquired activity was maintained during cycling between artificial tear protein solution and MPS. CONCLUSIONS: Lens preservative uptake and its subsequent release are dependent on lens chemistry, preservative nature, and other MPS components. A few lens/solution combinations acquired antibacterial activity after one or more overnight soaks in MPS, depending on the nature of the anionic lens component and the preservative. Uncharged lenses did not acquire antibacterial activity.


Assuntos
Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Soluções para Lentes de Contato/química , Lentes de Contato Hidrofílicas , Conservantes Farmacêuticos/química , Anti-Infecciosos/farmacologia , Biguanidas/química , Biguanidas/farmacologia , Soluções para Lentes de Contato/farmacologia , Humanos , Conservantes Farmacêuticos/farmacologia
14.
Mater Sci Eng C Mater Biol Appl ; 82: 210-216, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29025650

RESUMO

Chronic wound colonization by bacterial biofilms is common and can cause various complications. An anti-biofilm strategy was developed around the co-entrapment of a commercially available antiseptic, PHMB (polyhexamethylene biguanide 4mgmL-1), with EDTA (Ethylen diamine tetra acetic acid, 20mM) in a gelatin gel. The two active compounds act synergistically against bacterial biofilms, but their efficiency is strongly reduced (16-fold) when entrapped inside the 5% gelatin gel, and they weaken the mechanical properties (50-fold) of the gel. Increasing the gelatin concentration to 7% allows for good mechanical properties but large diffusional constraints. An active ephemeral gel, a chemical gel with controlled hydrolysis, was conceived and developed. When the ephemeral gel was solubilized after 48h, PHMB delivery increased, leading to good anti-biofilm activity. The various gels were examined over 24 and 48h of contact with P. aeruginosa and S. aureus biofilms, two types of bacterial biofilms frequently encountered in chronic wounds. The ephemeral gel eradicated the dense biofilms (>6.107CFU·cm-2) produced by either single or mixed strains; a similar efficiency was measured for biofilms from strains of both laboratory and clinical origin. The formulation was then adapted to develop a dressing prototype that is active against biofilms and fulfils the requirements of an efficient wound care system.


Assuntos
Antibacterianos/farmacologia , Biguanidas/química , Biofilmes/efeitos dos fármacos , Ácido Edético/química , Géis/química , Antibacterianos/síntese química , Antibacterianos/química , Bandagens , Biguanidas/farmacologia , Ácido Edético/farmacologia , Gelatina/química , Pseudomonas aeruginosa/fisiologia , Reologia , Staphylococcus aureus/fisiologia
15.
Cell Biol Toxicol ; 34(4): 279-290, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28871429

RESUMO

We recently demonstrated the cytotoxic action of a novel phenformin derivative, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on HT-29 cells under a serum- and glucose-deprived condition. In that study, we showed that the ATF6 arm of the ER stress pathway and c-Myc expression were downregulated 12 h after the treatment with 2-Cl-Phen. Through characterization of intracellular events at the early phase of the 2-Cl-Phen treatment before noticeable morphological changes, we found rapid fluctuations in the c-Myc and ATF4 proteins but not in their mRNAs in 2-Cl-Phen-treated HT-29 cells under the serum- and glucose-deprived condition. The 2-Cl-Phen-mediated downregulation of ATF4 protein was not paralleled by the phosphorylation status of PERK and eIF2α. Reduction of c-Myc expression by 2-Cl-Phen was more profound than that of ATF4 expression, and phosphorylated c-Myc was downregulated within 2 h. Pharmacological studies on the expression of c-Myc and ATF4 proteins showed that this decrease was mediated through proteasomal degradation but not by autophagy. Interestingly, treatment with lithium chloride, which is a well-known inhibitor of GSK3ß, partially recovered the expression of ATF4 protein, but its effect on the level of total c-Myc protein was negligible. Treatment with 2-Cl-Phen increased the expression of phosphorylated AMPK, but Compound C, an AMPK inhibitor, did not influence the expression of c-Myc protein in HT-29 cells. Finally, we observed that 2-Cl-Phen partially attenuated the gene expression of integrin subunit α1 (ITGA1), a downstream target of c-Myc. Taken together, these results show that 2-Cl-Phen rapidly downregulated the expression of c-Myc in addition to ER stress responses in a post-translational manner. Further elucidation and improvement of this multi-target-directed compound will provide new insights for developing therapeutic strategies against cancer.


Assuntos
Biguanidas/farmacologia , Glucose/deficiência , Fator 4 Ativador da Transcrição/metabolismo , Adenilato Quinase/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Biguanidas/química , Proteínas de Ciclo Celular/metabolismo , Meios de Cultura Livres de Soro , Regulação para Baixo/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/metabolismo , Células HT29 , Humanos , Integrina alfa1/genética , Integrina alfa1/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , eIF-2 Quinase/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-29241085

RESUMO

A new salting-out assisted liquid-liquid extraction (SALLE) sample preparation method for the determination of the polar anti-diabetic biguanide drugs (metformin, buformin and phenformin) in blood plasma, urine and lake water samples were developed. The SALLE was performed by mixing samples (plasma (0.2mL), urine or lake water (1.0mL)) with acetonitrile (0.4mL for plasma, 0.5mL for urine or lake water), sodium hydroxide powder was then added for the phase separation. The effects of type of salting-out reagent, type of extraction solvent, volumes of acetonitrile and sample, amount of sodium hydroxide, vortexing and centrifugation times on the extraction efficiency were investigated. The upper layer, containing the biguanides, was directly injected into a HPLC unit using ZIC-HILIC column (150mm×2.1mm×3.5µm) and was detected at 236nm. The method was validated and calibration curves were linear with r2>0.99 over the range of 20-2000µgL-1 for plasma and 5-2000µgL-1 for urine and lake water samples. The limits of detection were in the range (3.8-5.6)µgL-1, (0.8-1.5)µgL-1 and (0.3-0.8)µgL-1 for plasma, urine and lake water, respectively. The accuracies in the three matrices were within 87.3-103%, 87.4-109%, 82.2-109% of the nominal concentration for metformin, buformin and phenformin, respectively. The relative standard deviation for inter- and intra -day precision were in the range of 1.0-17% for all analytes in the three matrices.


Assuntos
Biguanidas/análise , Biguanidas/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Extração Líquido-Líquido/métodos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/isolamento & purificação , Acetonitrilos , Biguanidas/química , Biguanidas/urina , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lagos/química , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Cloreto de Sódio , Poluentes Químicos da Água/química , Poluentes Químicos da Água/urina
17.
FEMS Microbiol Lett ; 364(21)2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29029044

RESUMO

The bactericidal activities of polyhexamethylene biguanide hydrochloride (PHMB), 1-bromo-3-chloro-5,5-dimethylimidazolidine-2,4-dione (BCDMH) and the combination of the two (designated as PB) were compared using Escherichia coli as the test organism. PB exhibited strong bactericidal activity: 10 mg/L PHMB combined with 8 mg/L BCDMH resulted in approximately 5.74 log10 reduction (LR), whereas 320 mg/L PHMB or 20 mg/L BCDMH was about 5.53 and 6.56 LR, respectively. Analyses using scanning electron microscopy, flow cytometry and atomic absorption spectroscopy indicated that PB, PHMB and BCDMH disrupted cell membranes and changed membrane structure and permeability, resulting in the leakage of intracellular soluble proteins and ions. PB exerted stronger effects on potassium and magnesium leakage, membrane potential and permeability than BCDMH did. PB caused less protein leakage than PHMB did. These results suggest that at a relatively low concentration, PB exhibited good bactericidal activity and physiological effect on E. coli.


Assuntos
Antibacterianos/farmacologia , Biguanidas/farmacologia , Escherichia coli/efeitos dos fármacos , Hidantoínas/farmacologia , Antibacterianos/química , Biguanidas/química , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Hidantoínas/química , Magnésio/metabolismo , Potássio/metabolismo
18.
Arch Pharm (Weinheim) ; 350(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29027251

RESUMO

New 1-arylamidebiguanide hydrochloride salts were synthesized via reaction of hydrazide derivatives with dicyandiamide in acidic medium. The structure of the obtained derivatives was characterized by spectroscopic and elemental analysis tools. The anti-diabetic properties of the synthesized compounds were determined. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives showed a significant decrease of the elevated glucose in comparison with the anti-diabetic standard drug, metformin. The effects of the synthesized biguanide derivatives on the diabetic properties regarding liver function enzyme activities (AST, ALT, and ALP), lipid profiles (TC, TG, and TL), lipid peroxide, and nitrous oxide as well as histopathological characteristics were investigated and discussed.


Assuntos
Biguanidas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Administração Oral , Animais , Biguanidas/síntese química , Biguanidas/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Insulina/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Testes de Função Hepática , Masculino , Metformina/farmacologia , Óxido Nitroso/metabolismo , Ratos
19.
Cell Chem Biol ; 24(10): 1259-1275.e6, 2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-28919040

RESUMO

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.


Assuntos
Biguanidas/metabolismo , Biguanidas/farmacologia , Citocromo P-450 CYP3A/metabolismo , Heme/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biguanidas/química , Neoplasias da Mama/patologia , Domínio Catalítico , Respiração Celular/efeitos dos fármacos , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/deficiência , Citocromo P-450 CYP3A/genética , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Modelos Moleculares , Transporte Proteico/efeitos dos fármacos
20.
Eur J Pharmacol ; 814: 313-323, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28870455

RESUMO

Metformin has been associated with cardioprotection, vasorelaxation and normalization of endothelial function during type 2 Diabetes Mellitus. However, few studies have analysed its effects on vascular adrenergic system. Our study has evaluated the vasopressor responses induced by sympathetic stimulation or by i.v. bolus injections of the agonists noradrenaline (α1/2), methoxamine (α1) and UK 14,304 (α2) in rats with fructose-induced insulin resistance chronically pretreated with either metformin or EGL-6M (N-benzylbiguanide), a novel analogue of metformin. Rats were treated with fructose (15%) or tap water (control) during 16 weeks. Next, both groups were treated daily during 4 weeks with: (1) vehicle; (2) metformin (50mg/kg); or (3) EGL-6M (50mg/kg). Blood glucose and plasma insulin were determined before and after administration of glucose during oral glucose tolerance test. Animals treated with fructose showed hyperinsulinemia and insulin resistance, which were decreased by metformin and EGL-6M. In animals treated with fructose, the vasopressor responses induced by: (1) sympathetic stimulation were decreased; (2) noradrenaline were increased; and (3) methoxamine and UK 14,304 remained unaffected compared with control group. In control animals, metformin failed to modify the vasopressor responses analysed, while EGL-6M increased the vasopressor responses to sympathetic stimulation. In rats treated with fructose, metformin decreased vasopressor response to noradrenaline but did not modify the sympathetic stimulation responses. EGL-6M increased the vasopressor responses to sympathetic stimulation without modifying those to noradrenaline, methoxamine or UK 14,304. Collectively, these data suggest that EGL-6M is capable to increase insulin sensitivity and the vasopressor sympathetic outflow in rats.


Assuntos
Biguanidas/farmacologia , Frutose/efeitos adversos , Resistência à Insulina , Metformina/farmacologia , Receptores Adrenérgicos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Agonistas Adrenérgicos/farmacologia , Animais , Biguanidas/química , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Insulina/sangue , Masculino , Metformina/química , Ratos , Ratos Wistar
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