RESUMO
Compounds containg catechol or bisphosphonate were tested as inhibitors of the zinc metalloproteases, thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) which are bacterial virulence factors, and the human matrix metalloproteases MMP-9 and -14. Inhibition of virulence is a putative strategy in the development of antibacterial drugs, but the inhibitors should not interfere with human enzymes. Docking indicated that the inhibitors bound MMP-9 and MMP-14 with the phenyl, biphenyl, chlorophenyl, nitrophenyl or methoxyphenyl ringsystem in the S1'-subpocket, while these ringsystems entered the S2'- or S1 -subpockets or a region involving amino acids in the S1'- and S2'-subpockets of the bacterial enzymes. An arginine conserved among the bacterial enzymes seemed to hinder entrance deeply into the S1'-subpocket. Only the bisphosphonate containing compound RC2 bound stronger to PLN and TLN than to MMP-9 and MMP-14. Docking indicated that the reason was that the conserved arginine (R203 in TLN and R198 in PLN) interacts with phosphate groups of RC2.
Assuntos
Antibacterianos/farmacologia , Catecóis/farmacologia , Difosfonatos/farmacologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/enzimologia , Catecóis/síntese química , Catecóis/química , Difosfonatos/síntese química , Difosfonatos/química , Humanos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Metaloendopeptidases/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Células THP-1RESUMO
Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and 1H/13C/19F NMR spectra. The analysis of structure-activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antibacterianos , Antineoplásicos , Helicobacter pylori/crescimento & desenvolvimento , Neoplasias Gástricas/tratamento farmacológico , Timol/química , Adenocarcinoma/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Gástricas/metabolismoRESUMO
Background: Galium is a plant rich in iridoid glycosides, flavonoids, anthraquinones, and small amounts of essential oils and vitamin C. Recent works showed the antibacterial, antifungal, antiparasitic, and antioxidant activity of this plant genus. Methods: For the determination of the multicomponent phenolic pattern, liquid phase microextraction procedures were applied, combined with HPLC-PDA instrument configuration in five Galium species aerial parts (G. verum, G. album, G. rivale, G. pseudoaristatum, and G. purpureum). Dispersive Liquidâ»Liquid MicroExtraction (DLLME) with NaCl and NAtural Deep Eutectic Solvent (NADES) medium and Ultrasound-Assisted (UA)-DLLME with ß-cyclodextrin medium were optimized. Results: The optimal DLLME conditions were found to be: 10 mg of the sample, 10% NaCl, 15% NADES or 1% ß-cyclodextrin as extraction solvent-400 µL of ethyl acetate as dispersive solvent-300 µL of ethanol, vortex time-30 s, extraction time-1 min, centrifugation at 12000× g for 5 min. Conclusions: These results were compared with microwave-assisted extraction procedures. G. purpureum and G. verum extracts showed the highest total phenolic and flavonoid content, respectively. The most potent extract in terms of antioxidant capacity was obtained from G. purpureum, whereas the extract obtained from G. album exhibited the strongest inhibitory effect against tyrosinase.
Assuntos
Bioensaio/métodos , Galium/química , Microextração em Fase Líquida/métodos , Micro-Ondas , Fenóis/isolamento & purificação , Flavonoides/análiseRESUMO
INTRODUCTION: For the determination of harpagoside and the wide phenolic pattern in Harpagophytum procumbens root and its commercial food supplements, dispersive liquid-liquid microextraction (DLLME), ultrasound-assisted DLLME (UA-DLLME), and sugaring-out liquid-liquid extraction (SULLE) were tested and compared. OBJECTIVES: In order to optimise the extraction efficiency, DLLME and UA-DLLME were performed in different solvents (water and aqueous solutions of glucose, ß-cyclodextrin, (2-hydroxypropyl)-ß-cyclodextrin, sodium chloride, natural deep eutectic solvent, and ionic liquid). MATERIAL AND METHODS: The plant material was ground and sieved to obtain a uniform granulometry before extraction. Commercial food supplements, containing H. procumbens are commercially available in Italy. RESULTS: The most effective sodium chloride-aided-DLLME was then optimised and applied for analyses followed by HPLC-PDA. For comparison, microwave-assisted extraction was performed using the same solvents and the best results were obtained using 1% of ß-cyclodextrin or 15% of sodium chloride. CONCLUSION: All commercial samples respected the European Pharmacopoeia monograph for this plant material, showing a harpagoside content ≥ 1.2%. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Suplementos Nutricionais/análise , Glicosídeos/análise , Harpagophytum/química , Microextração em Fase Líquida/métodos , Fenóis/análise , Raízes de Plantas/química , Piranos/análise , 2-Hidroxipropil-beta-Ciclodextrina/química , Cromatografia Líquida de Alta Pressão/métodos , Glucose/química , Itália , Limite de Detecção , Micro-Ondas , Cloreto de Sódio/química , Solventes/química , Água/químicaRESUMO
The present study aims to highlight the therapeutic potential of Asphodeline lutea (AL), a wild edible plant of the Mediterranean diet. Roots, aerial parts, and flowers of AL at two different phenological stages were collected from three locations in Italy. The inhibitory activities of extracts on strategic enzymes linked to human diseases were assessed. The antioxidant properties were evaluated in vitro, using six standard bioassays. The phenolic and anthraquinone profiles were also established using HPLC-PDA. Zinc, cadmium, lead, and copper contents were also determined. All the samples inhibited acetylcholinesterase (from 1.51 to 2.20 mg GALAEs/g extract), tyrosinase (from 7.50 to 25.3 mg KAEs/g extract), and α-amylase (from 0.37 to 0.51 mmol ACAEs/g extract). Aloe-emodin and physcion were present in all parts, while rhein was not detected. The phenolic profile and the heavy metals composition of specimens gathered from three different regions of Italy were different. It can be argued that samples collected near the street can contain higher concentrations of heavy metals. The experimental data confirm that the A. lutea species could be considered as a potential source of bioactive metabolites, and its consumption could play a positive and safe role in human health maintenance.
Assuntos
Antioxidantes/química , Asphodelaceae/química , Fenóis/química , Acetilcolinesterase/efeitos dos fármacos , Antraquinonas/química , Antioxidantes/isolamento & purificação , Inibidores da Colinesterase/química , Cromatografia Líquida de Alta Pressão , Flores/química , Humanos , Itália , Monofenol Mono-Oxigenase/antagonistas & inibidores , Fenóis/isolamento & purificação , Extratos Vegetais/química , Raízes de Plantas/química , alfa-Amilases/antagonistas & inibidoresRESUMO
This study was performed to evaluate the metabolite recovery from different extraction methods applied to Thymusalgeriensis aerial parts. A high-performance liquid chromatographic method using photodiode array detector with gradient elution has been developed and validated for the simultaneous estimation of different phenolic compounds in the extracts and in their corresponding purified fractions. The experimental results show that microwave-assisted aqueous extraction for 15 min at 100 °C gave the most phenolics-enriched extract, reducing extraction time without degradation effects on bioactives. Sixteen compounds were identified in this extract, 11 phenolic compounds and five flavonoids, all known for their biological activities. Color analysis and determination of chlorophylls and carotenoids implemented the knowledge of the chemical profile of this plant.
Assuntos
Carotenoides/química , Fenóis/química , Compostos Fitoquímicos/química , Thymus (Planta)/química , Carotenoides/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Fenóis/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Componentes Aéreos da Planta/química , Extratos Vegetais/químicaRESUMO
A method using high-performance liquid chromatography coupled with a photodiode array detector was proposed for the rapid characterization of different phenolic constituents from the extracts of Atriplex mollis aerial parts. Atriplex species are known for their multiple biological activities, but no information is available in the literature about A. mollis. With the aim to firstly characterize the main secondary metabolites of this plant, so as to orient better the biological evaluation, we applied three different extraction procedures and compared the chromatographic results. Microwave-assisted extraction gave the best yield and recovery of important compounds such as gallic acid, catechin, chlorogenic acid, p-OH benzoic acid, rutin, sinapinic acid, t-ferulic acid, naringenin and benzoic acid. These constituents belong to three important chemical classes: phenolic acids, flavonoids and monoterpenes. Color evaluation and analysis of chlorophylls (a and b) and carotenoids complete the preliminary profile of this plant. From these analyses, Atriplex mollis is a source of bioactive compounds (especially rutin, t-ferulic acid and gallic acid) and could be recommended as a plant of phyto-pharmaceutical relevance, opening new perspectives on this salt-tolerant plant.
Assuntos
Atriplex/química , Componentes Aéreos da Planta/química , Carotenoides/química , Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/química , Hidroxibenzoatos/química , Monoterpenos/químicaRESUMO
A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.
Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Metaloproteinases da Matriz/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/classificação , Ativação Enzimática/efeitos dos fármacos , Humanos , Ácidos Fosforosos/química , Isoformas de ProteínasRESUMO
This paper reports the MEPS-HPLC-DAD method for the simultaneous determination of 12 azole drugs (bifonazole, butoconazole, clotrimazole, econazole, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terconazole, tioconazole and voriconazole) administered to treat different systemic and topical fungal infections, in biological samples. Azole drugs separation was performed in 36 min. The analytical method was validated in the ranges as follows: 0.02-5 µg mL-1 for ravuconazole; 0.2-5 µg mL-1 for terconazole; 0.05-5 µg mL-1 for the other compounds. Human plasma and urine were used as biological samples during the analysis, while benzyl-4-hydroxybenzoate was used as an internal standard. The precision (RSD%) and trueness (Bias%) values fulfill with International Guidelines requirements. To the best of our knowledge, this is the first HPLC-DAD procedure coupled to MEPS, which provides the simultaneous analysis of 12 azole drugs, available in the market, in human plasma and urine. Moreover, the method was successfully applied for the quantitative determination of two model drugs (itraconazole and miconazole) after oral administration in real samples.
Assuntos
Imidazóis/análise , Microextração em Fase Sólida , Triazóis/análise , Adsorção , Cromatografia Líquida de Alta Pressão , Estrutura MolecularRESUMO
We designed and synthesised novel N-substituted 1,3-thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii efficacy. This scaffold was functionalised both at the N1-hydrazine portion with three structurally different moieties and at the lactam nitrogen with substituted benzyl groups selected on the basis of our previous structure-activity relationships studies. Using three different assay methods, the compounds were assessed in vitro to determine both the levels of efficacy against the tachyzoites of T. gondii (IC50 = 5-148 µM), as well as any evidence of cytotoxicity towards human host cells (TD50 = 68 to ≥320 µM). Results revealed that ferrocene-based thiazolidinones can possess potent anti-tachyzoite activity (TI =2-64).
Assuntos
Antiprotozoários/farmacologia , Tiazolidinas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Toxoplasma/crescimento & desenvolvimentoRESUMO
BMIM PF6 (1-butyl-3-methylimidazolium hexafluorophosphate) and BMIM Tf2N (1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) are two conventional room-temperature ionic liquids widely employed and investigated as reaction media. Despite the presence of the same imidazolium ring in their structure they are different in many chemical and physical properties due to the nature of the anions. The thermal cis-trans isomerization of an electronically activated azobenzene have been used as reaction model to compare the behavior of PF6- and Tf2N-. Rotation is the mechanism by which the investigated azobenzene is converted into the trans isomer spontaneously in the dark both in BMIM PF6 and in BMIM Tf2N. The kinetic rate constants of the process have been determined at different temperatures and the activation energies of the reaction have been calculated according to the Arrhenius and Eyring equations. The results presented herein highlight different solute-solvent interactions involving the PF6- and Tf2N- anions during the cis-trans isomerization.
Assuntos
Compostos Azo/química , Líquidos Iônicos/química , EstereoisomerismoRESUMO
Monovarietal virgin olive oils (VOOs) are very effective to study relationships among sensory attributes, the compounds responsible for flavour, and factors affecting them. The stimulation of the human sensory receptors by volatile and non-volatile compounds present in monovarietal virgin olive oils gives rise to the sensory attributes that describe their peculiar delicate and fragrant flavours. The formation of these compounds is briefly illustrated and the influence of the agronomic and technological factors that affect their concentrations in the oil is examined. The relationships between compounds responsible for the olive oil flavour and sensory attributes are discussed. Several approaches for the varietal differentiation of monovarietal virgin olive oils are also overviewed.
Assuntos
Azeite de Oliva/química , Olfato , Paladar , Compostos Orgânicos Voláteis/químicaRESUMO
New catechol-containing chemical entities have been investigated as matrix metalloproteinase inhibitors as well as antioxidant molecules. The combination of the two properties could represent a useful feature due to the potential application in all the pathological processes characterized by increased proteolytic activity and radical oxygen species (ROS) production, such as inflammation and photoaging. A series of catechol-based molecules were synthesized and tested for both proteolytic and oxidative inhibitory activity, and the detailed binding mode was assessed by crystal structure determination of the complex between a catechol derivative and the matrix metalloproteinase-8. Surprisingly, X-ray structure reveals that the catechol oxygens do not coordinates the zinc atom.
Assuntos
Antioxidantes/farmacologia , Catecóis/farmacologia , Metaloproteinase 8 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Catecóis/síntese química , Catecóis/química , Relação Dose-Resposta a Droga , Humanos , Metaloproteinase 8 da Matriz/isolamento & purificação , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVES: Bisphosphonates (BPs) are drugs clinically used in resorptive diseases. It was already proved that some clinically relevant BPs can inhibit a class of enzymes called matrix metalloproteinases (MMPs), required during tissue remodelling. Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present study was to compare the effect of zoledronic acid (ZA), the most potent bisphosphonate available as therapy, with new sulfonamide containing BPs in an in vitro model of human gingival fibroblasts (HGFs). MATERIALS AND METHODS: Western blot was used to measure procollagen I, ß1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability; L-lactate-dehydrogenase (LDH) measurement was performed for toxicity evaluation and ELISA for prostaglandin E2 (PGE2) secretion assessment. RESULTS: When compared with ZA, the treatment with the newly synthesized compounds shows increasing viability, procollagen I expression and decreased expression of ß1 integrin in HGFs. Higher levels of released LDH, PGE2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthesized compounds-treated samples. CONCLUSIONS: These findings allowed to conclude that new tested BPs did not affect HGFs viability and adhesion, did not induce cellular toxicity, were not responsible for inflammatory event induction and could preserve the physiological matrix turnover. CLINICAL RELEVANCE: It could be hypothesized that the new molecules were better tolerated by soft tissues, resulting in lesser side effects.
Assuntos
Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Imidazóis/farmacologia , Adulto , Biomarcadores/análise , Western Blotting , Conservadores da Densidade Óssea/síntese química , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Difosfonatos/síntese química , Ensaio de Imunoadsorção Enzimática , Humanos , Imidazóis/síntese química , Técnicas In Vitro , Inflamação , Dente Serotino , Ácido ZoledrônicoRESUMO
Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.
Assuntos
Desenho de Fármacos , Hidroxiquinolinas/química , Metaloproteinase 2 da Matriz/química , Inibidores de Metaloproteinases de Matriz/química , Naftiridinas/química , Ensaios Enzimáticos , Humanos , Hidroxiquinolinas/síntese química , Cinética , Inibidores de Metaloproteinases de Matriz/síntese química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Naftiridinas/síntese química , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Zinco/químicaRESUMO
INTRODUCTION: Vibrio cholerae bacteria cause an infection characterized by acute diarrheal illness in the intestine. Cholera is sustained by people swallowing contaminated food or water. Even though symptoms can be mild, if untreated disease becomes severe and life-threatening, especially in low-income countries. AREAS COVERED: After a description of the most recent literature on the pathophysiology of this infection, we searched for patents and literature articles following the PRISMA guidelines, filtering the results disclosed from 2020 to present. Moreover, some innovative molecular targets (e.g., carbonic anhydrases) and pathways to counteract this rising problem were also discussed in terms of design, structure-activity relationships and structural analyses. EXPERT OPINION: This review aims to cover and analyze the most recent advances on the new druggable targets and bioactive compounds against this fastidious pathogen, overcoming the use of old antibiotics which currently suffer from high resistance rate.
Assuntos
Antibacterianos , Cólera , Desenho de Fármacos , Desenvolvimento de Medicamentos , Patentes como Assunto , Vibrio cholerae , Humanos , Antibacterianos/farmacologia , Cólera/tratamento farmacológico , Cólera/microbiologia , Vibrio cholerae/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Terapia de Alvo Molecular , Farmacorresistência Bacteriana , Diarreia/tratamento farmacológico , Diarreia/microbiologiaRESUMO
Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8(+/+) mice, in contrast to MMP8(-/-) mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.
Assuntos
Barreira Hematoencefálica/metabolismo , Endotoxemia/metabolismo , Matriz Extracelular/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Animais , Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Colágeno/metabolismo , Corticosterona/sangue , Feminino , Masculino , Camundongos , Camundongos KnockoutRESUMO
The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs. In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform. In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies.
Assuntos
Difosfonatos/química , Inibidores de Metaloproteinases de Matriz/química , Metaloproteinases da Matriz/química , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Difosfonatos/metabolismo , Difosfonatos/toxicidade , Durapatita/química , Durapatita/metabolismo , Células Hep G2 , Humanos , Metaloproteinase 14 da Matriz/química , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/química , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/química , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/toxicidade , Metaloproteinases da Matriz/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Exploring the chemical diversity and molecular mechanisms of natural products continues to be an important research area for identifying novel promising therapeutic approaches for fighting cancer. This is a complex disease and poses important challenges, which require not only targeted interventions to improve chemotherapy efficacy and tolerability, but also adjuvant strategies to counteract chemoresistance development and relapses. AREAS COVERED: After a brief description of the recent literature on the anticancer potential of natural compounds, we searched for patents following the PRISMA guidelines, filtering the results published from 2019 onwards. In addition, some relevant publications from the overall scientific literature were also discussed. EXPERT OPINION: This review comprehensively covers and analyzes the most recent advances on the anticancer mechanism of licensed natural compounds and their chemical optimization. Patentability of natural compounds was discussed according to the recent legislation in the U.S.A. and Europe.