Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 65
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Int J Mol Sci ; 25(18)2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39337457

RESUMEN

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.


Asunto(s)
Neuropatías Amiloides Familiares , Prealbúmina , Humanos , Prealbúmina/química , Prealbúmina/metabolismo , Neuropatías Amiloides Familiares/tratamiento farmacológico , Relación Estructura-Actividad , Benzoxazoles/química , Benzoxazoles/uso terapéutico , Animales
2.
Int J Mol Sci ; 24(3)2023 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-36768470

RESUMEN

Breast cancer is the first leading tumor in women in terms of incidence worldwide. Seventy percent of cases are estrogen receptor (ER) α-positive. In these malignancies, 17ß-estradiol (E2) via ERα increases the levels of neuroglobin (NGB), a compensatory protein that protects cancer cells from stress-induced apoptosis, including chemotherapeutic drug treatment. Our previous data indicate that resveratrol (RSV), a plant-derived polyphenol, prevents E2/ERα-induced NGB accumulation in this cellular context, making E2-dependent breast cancer cells more prone to apoptosis. Unfortunately, RSV is readily metabolized, thus preventing its effectiveness. Here, four different RSV analogs have been developed, and their effect on the ERα/NGB pathway has been compared with RSV conjugated with highly hydrophilic gold nanoparticles as prodrug to evaluate if RSV derivatives maintain the breast cancer cells' susceptibility to the chemotherapeutic drug paclitaxel as the original compound. Results demonstrate that RSV conjugation with gold nanoparticles increases RSV efficacy, with respect to RSV analogues, reducing NGB levels and enhancing the pro-apoptotic action of paclitaxel, even preventing the anti-apoptotic action exerted by E2 treatment on these cells. Overall, RSV conjugation with gold nanoparticles makes this complex a promising agent for medical application in breast cancer treatment.


Asunto(s)
Neoplasias de la Mama , Nanopartículas del Metal , Profármacos , Femenino , Humanos , Neuroglobina/farmacología , Neoplasias de la Mama/metabolismo , Resveratrol/farmacología , Resveratrol/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Profármacos/farmacología , Profármacos/uso terapéutico , Globinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oro/farmacología , Estradiol/farmacología , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Línea Celular Tumoral , Apoptosis , Estrógenos/farmacología
3.
J Enzyme Inhib Med Chem ; 37(1): 1812-1820, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35758192

RESUMEN

Several epidemiological studies suggest that a diet rich in fruit and vegetables reduces the incidence of neurodegenerative diseases. Resveratrol (Res) and its dimethylated metabolite, pterostibene (Ptb), have been largely studied for their neuroprotective action. The clinical use of Res is limited because of its rapid metabolism and its poor bioavailability. Ptb with two methoxy groups and one hydroxyl group has a good membrane permeability, metabolic stability and higher in vivo bioavailability in comparison with Res. The metabolism and pharmacokinetics of Ptb are still sparse, probably due to the lack of tools that allow following the Ptb destiny both in living cells and in vivo. In this contest, we propose two Ptb fluorescent derivatives where Ptb has been functionalised by benzofurazan and rhodamine-B-isothiocyanate, compounds 1 and 2, respectively. Here, we report the synthesis, the optical and structural characterisation of 1 and 2, and, their putative cytotoxicity in two different cell lines.


Asunto(s)
Colorantes Fluorescentes , Estilbenos , Disponibilidad Biológica , Colorantes Fluorescentes/farmacología , Resveratrol/química , Resveratrol/farmacología , Estilbenos/química , Estilbenos/farmacología
4.
Int J Mol Sci ; 23(23)2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36499460

RESUMEN

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.


Asunto(s)
Sirtuinas , Estilbenos , Humanos , Resveratrol/farmacología , Sirtuina 1/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo , Sirtuinas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Estilbenos/farmacología
5.
J Enzyme Inhib Med Chem ; 36(1): 48-57, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33103482

RESUMEN

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.


Asunto(s)
Amino Alcoholes/farmacología , Encéfalo/efectos de los fármacos , Anhidrasas Carbónicas/metabolismo , Éteres/farmacología , Oximas/farmacología , Amino Alcoholes/síntesis química , Amino Alcoholes/química , Encéfalo/enzimología , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/química , Humanos , Isoenzimas/metabolismo , Estructura Molecular , Oximas/síntesis química , Oximas/química , Relación Estructura-Actividad
6.
J Enzyme Inhib Med Chem ; 36(1): 34-47, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33100043

RESUMEN

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Melanoma/tratamiento farmacológico , Quinolinas/farmacología , Neoplasias de la Úvea/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Melanoma/metabolismo , Melanoma/patología , Modelos Moleculares , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Neoplasias de la Úvea/metabolismo , Neoplasias de la Úvea/patología
7.
Molecules ; 26(21)2021 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-34770789

RESUMEN

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer's disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.


Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Epilepsia/tratamiento farmacológico , Animales , Sitios de Unión , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/química , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , Catálisis , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Diseño de Fármacos , Epilepsia/etiología , Epilepsia/metabolismo , Humanos , Isoenzimas , Modelos Moleculares , Unión Proteica , Relación Estructura-Actividad , Resultado del Tratamiento
8.
Molecules ; 26(19)2021 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-34641559

RESUMEN

Alzheimer's disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a-e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer's disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aß aggregation and fairly good inhibition of Cu-induced Aß aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/uso terapéutico , Ácidos Cumáricos/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Antioxidantes/química , Simulación por Computador , Ácidos Cumáricos/química , Humanos , Hidroxilaminas/química , Hidroxilaminas/uso terapéutico , Fragmentos de Péptidos/antagonistas & inhibidores , Relación Estructura-Actividad
9.
Bioorg Med Chem ; 28(18): 115673, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32828431

RESUMEN

Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-ß, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Fármacos Neuroprotectores/síntesis química , Prealbúmina/química , Propionatos/química , Agregado de Proteínas/efectos de los fármacos , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Molecular , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/farmacología , Prealbúmina/genética , Prealbúmina/metabolismo , Propionatos/metabolismo , Propionatos/farmacología , Unión Proteica , Relación Estructura-Actividad
10.
J Enzyme Inhib Med Chem ; 35(1): 1145-1162, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32419519

RESUMEN

Natural compounds, such as plant and fruit extracts have shown neuroprotective effect against neurodegenerative diseases. It has been reported that several natural compounds binding to transthyretin (TTR) can be useful in amyloidosis prevention. TTR is a transporter protein that under physiological condition carries thyroxine (T4) and retinol in plasma and in cerebrospinal fluid (CSF); it also has a neuroprotective role against Alzheimer's disease (AD). However, TTR also is an amyloidogenic protein responsible for familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The TTR amyloidogenic potential is speeded up by several point mutations. One therapeutic strategy against TTR amyloidosis is the stabilisation of the native tetramer by natural compounds and small molecules. In this review, we examine the natural products that, starting from 2012 to present, have been studied as a stabiliser of TTR tetramer. In particular, we discussed the chemical and structural features which will be helpful for future drug design of new TTR stabilisers.


Asunto(s)
Neuropatías Amiloides Familiares/prevención & control , Amiloide/metabolismo , Diseño de Fármacos , Fármacos Neuroprotectores/uso terapéutico , Prealbúmina/metabolismo , Humanos , Fármacos Neuroprotectores/química
11.
J Enzyme Inhib Med Chem ; 35(1): 211-226, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31760822

RESUMEN

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aß aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aß1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Benzofuranos/farmacología , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Tacrina/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Benzofuranos/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Humanos , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad , Tacrina/química
12.
J Enzyme Inhib Med Chem ; 35(1): 1194-1205, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32396745

RESUMEN

Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Antioxidantes/farmacología , Inhibidores Enzimáticos/farmacología , Iminas/química , Azúcares/química , Inhibidores Enzimáticos/química , Estructura Molecular
13.
Bioorg Med Chem ; 27(1): 196-207, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30522899

RESUMEN

Collagen degradation and proMMP-2 activation are major functions of MT1-MMP to promote cancer cell invasion. Since both processes require MT1-MMP homodimerization on the cell surface, herein we propose that the use of bifunctional inhibitors of this enzyme could represent an innovative approach to efficiently reduce tumor growth. A small series of symmetrical dimers derived from previously described monomeric arylsulfonamide hydroxamates was synthesized and tested in vitro on isolated MMPs. A nanomolar MT1-MMP inhibitor, compound 6, was identified and then submitted to cell-based assays on HT1080 fibrosarcoma cells. Dimer 6 reduced MT1-MMP-dependent proMMP-2 activation, collagen degradation and collagen invasion in a dose-dependent manner with better results even compared to its monomeric analogue 4. This preliminary study suggests that dimeric MT1-MMP inhibitors might be further developed and exploited as an alternative tool to reduce cancer cell invasion.


Asunto(s)
Ácidos Hidroxámicos/farmacología , Metaloproteinasa 14 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Sulfonamidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Colágeno/metabolismo , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/química , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Simulación de Dinámica Molecular , Estructura Molecular , Multimerización de Proteína/efectos de los fármacos , Sulfonamidas/síntesis química , Sulfonamidas/química
14.
Bioorg Chem ; 92: 103298, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31557624

RESUMEN

Diabetes is a multi-factorial disorder that should be treated with multi-effective compounds. Here we describe the access to polyhydroxylated pyrrolidines, belonging to the d-gluco and d-galacto series, through aminocyclization reactions of two differentially protected d-xylo-hexos-4-ulose derivatives. The prepared compounds proved to inhibit both alpha-glucosidase, responsible for the emergence of hyperglycemic spikes, and aldose reductase, accountable for the development of abnormalities in diabetic tissues. Accordingly, they show the dual inhibitory profile deemed as ideal for diabetes treatment. Significantly, compound 17b reduced the process of cell death and restored the physiological levels of oxidative stress when tested in the photoreceptor-like 661w cell line, thus proving to be effective in an in vitro model of diabetic retinopathy.


Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Pirrolidinas/farmacología , alfa-Glucosidasas/metabolismo , Aldehído Reductasa/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad
15.
Bioorg Med Chem ; 26(22): 5804-5815, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30429099

RESUMEN

MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport.


Asunto(s)
Ácidos Carboxílicos/farmacología , Absorción Intestinal/efectos de los fármacos , Metaloproteinasa 12 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Azúcares/química , Sulfonamidas/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
16.
J Synchrotron Radiat ; 24(Pt 1): 42-52, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28009545

RESUMEN

X-ray radiation in macromolecular crystallography can chemically alter the biological material and deteriorate the integrity of the crystal lattice with concomitant loss of resolution. Typical alterations include decarboxylation of glutamic and aspartic residues, breaking of disulfide bonds and the reduction of metal centres. Helical scans add a small translation to the crystal in the rotation method, so that for every image the crystal is shifted to expose a fresh part. On beamline PROXIMA 2A at Synchrotron SOLEIL, this procedure has been tested with various parameters in an attempt to understand how to mitigate the effects of radiation damage. Here, the strategies used and the crystallographic metrics for various scenarios are reported. Among these, the loss of bromine from bromophenyl moieties appears to be a useful monitor of radiation damage as the carbon-bromine bond is very sensitive to X-ray irradiation. Two cases are focused on where helical scans are shown to be superior in obtaining meaningful data compared with conventional methods. In one case the initial resolution of the crystal is extended over time, and in the second case the anomalous signal is preserved to provide greater effective multiplicity and easier phasing.


Asunto(s)
Cristalografía por Rayos X , Modelos Moleculares , Sustancias Macromoleculares , Rotación , Rayos X
17.
Bioorg Med Chem ; 25(12): 3068-3076, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28392277

RESUMEN

Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC50 in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.


Asunto(s)
Alanina/análogos & derivados , Alanina/farmacología , Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Aldehído Reductasa/metabolismo , Animales , Complicaciones de la Diabetes/enzimología , Complicaciones de la Diabetes/prevención & control , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratas
18.
J Struct Biol ; 194(1): 8-17, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26796656

RESUMEN

Transthyretin (TTR), a 54kDa homotetrameric protein that transports thyroxine (T4), has been associated with clinical cases of TTR amyloidosis for its tendency to aggregate to form fibrils. Many ligands with a potential to inhibit fibril formation have been studied by X-ray crystallography in complex with TTR. Unfortunately, the ligand is often found in ambiguous electron density that is difficult to interpret. The ligand validation statistics suggest over-interpretation, even for the most active compounds like diflunisal. The primary technical reason is its position on a crystallographic 2-fold axis in the most common crystal form. Further investigations with the use of polyethylene glycol (PEG) to crystallize TTR complexes have resulted in a new trigonal polymorph with two tetramers in the asymmetric unit. The ligand used to obtain this new polymorph, 4-hydroxychalcone, is related to curcumin. Here we evaluate this crystal form to understand the contribution it may bring to the study of TTR ligands complexes, which are often asymmetric.


Asunto(s)
Curcumina/química , Prealbúmina/química , Dominios Proteicos , Multimerización de Proteína , Sitios de Unión/genética , Chalconas/química , Chalconas/metabolismo , Cristalización , Cristalografía por Rayos X , Curcumina/metabolismo , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Mutación , Polietilenglicoles/química , Prealbúmina/genética , Prealbúmina/metabolismo , Unión Proteica
19.
J Enzyme Inhib Med Chem ; 31(sup1): 40-51, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27067161

RESUMEN

Transthyretin (TTR), a ß-sheet-rich tetrameric protein, in equilibrium with an unstable amyloidogenic monomeric form is responsible for extracellular deposition of amyloid fibrils, is associated with the onset of neurodegenerative diseases, such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. One of the therapeutic strategies is to use small molecules to stabilize the TTR tetramer and thus curb amyloid fibril formation. Here, we report the synthesis, the in vitro evaluation of several halogen substituted 9-fluorenyl- and di-benzophenon-based ligands and their three-dimensional crystallographic analysis in complex with TTR. The synthesized compounds bind TTR and stabilize the tetramer with different potency. Of these compounds, 2c is the best inhibitor. The dual binding mode prevalent in the absence of substitutions on the fluorenyl ring, is disfavored by (2,7-dichloro-fluoren-9-ylideneaminooxy)-acetic acid (1b), (2,7-dibromo-fluoren-9-ylideneaminooxy)-acetic acid (1c) and (E/Z)-((3,4-dichloro-phenyl)-methyleneaminooxy)-acetic acid (2c), all with halogen substitutions.


Asunto(s)
Amiloide/biosíntesis , Fluorenos/química , Fluorenos/farmacología , Prealbúmina/química , Relación Dosis-Respuesta a Droga , Fluorenos/síntesis química , Humanos , Ligandos , Estructura Molecular , Relación Estructura-Actividad
20.
J Enzyme Inhib Med Chem ; 31(5): 824-33, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26235916

RESUMEN

Transthyretin (TTR) is a 54 kDa homotetrameric protein that transports thyroxine (T4) and retinol (vitamin A), through its association with retinol binding protein (RBP). Under unknown conditions, it aggregates to form fibrils associated with TTR amyloidosis. Ligands able to inhibit fibril formation have been studied by X-ray crystallography. The use of polyethylene glycol (PEG) instead of ammonium sulphate or citrate has been evaluated as an alternative to obtain new TTR complexes with (R)-3-(9-fluoren-9-ylideneaminooxy)-2-methyl-N-(methylsulfonyl) propionamide (48R(1)) and 2-(9H-fluoren-9-ylideneaminooxy) acetic acid (ES8(2)). The previously described fluorenyl based inhibitors (S)-3-((9H-fluoren-9-ylideneamino)oxy)-2-methylpropanoic acid (6BD) and 3-((9H-fluoren-9-ylideneamino)oxy)propanoic acid (7BD) have been re-evaluated with the changed crystallization method. The new TTR complexes with compounds of the same family show that the 9-fluorenyl motif can occupy alternative hydrophobic binding sites. This augments the potential use of this scaffold to yield a large variety of differently substituted mono-aryl compounds able to inhibit TTR fibril formation.


Asunto(s)
Amiloide/antagonistas & inhibidores , Amiloide/metabolismo , Cristalografía por Rayos X/métodos , Fluorenos/química , Modelos Moleculares , Prealbúmina/química , Prealbúmina/metabolismo , Secuencias de Aminoácidos , Fluorenos/farmacología , Estructura Molecular , Polietilenglicoles/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA