Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
J Enzyme Inhib Med Chem ; 36(1): 1874-1883, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340614

RESUMO

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Biologia Computacional/métodos , Isoenzimas/antagonistas & inibidores , Quinazolinas/química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Sulfonamidas/química
3.
J Enzyme Inhib Med Chem ; 36(1): 1783-1797, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340630

RESUMO

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.


Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Isoenzimas/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Anidrases Carbônicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/química , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Indóis/química , Isoenzimas/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Especificidade por Substrato
4.
Dalton Trans ; 50(27): 9643-9647, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34160519

RESUMO

In this paper it is demonstrated that the nature of the ligands of two Ru2(ii,iii) paddlewheel complexes dramatically affects the overall anticancer properties in cells. Herein, the complex [Ru2(EB776)4Cl] was found to be more active against a glioblastoma model with respect to its isomer [Ru2(EB106)4Cl]. These different effects depend on the steric hindrance, on the allowed conformations of the complexes and on the presence of hydrophilic regions in [Ru2(EB776)4Cl], which overall lead to a lower "steric protection".

5.
Eur J Med Chem ; 220: 113490, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33975138

RESUMO

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators. In this contribution, starting from our previous studies, we describe the synthesis of a set of new bicyclic tetrahydroindazoles featuring a secondary sulfonamide. Biological evaluation of the inhibitory activity against the hCA I, II, IV, and IX isoforms allowed drawing a structure-activity relationship profile that was rationalized through theoretical studies. This allowed dissecting the new molecules into the single portions influencing the zinc chelation properties and the selectivity profile thereby offering a new platform for the discovery of new isotype selective CA inhibitors.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Indazóis/farmacologia , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Indazóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
6.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803741

RESUMO

Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery-in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes.


Assuntos
Microglia/metabolismo , Neuroesteroides/metabolismo , Receptores de GABA/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Neuroesteroides/química , Pregnenolona/química , Pregnenolona/metabolismo
7.
J Med Chem ; 64(7): 3508-3545, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33764065

RESUMO

Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery. After a brief analysis of its physical-chemical features and synthetic procedures to obtain it, α-ketoamide-based classes of compounds are reported according to the application of this motif as either a nonreactive or reactive moiety. The goal is to highlight those aspects that may be useful to understanding the perspectives of employing the α-ketoamide moiety in the rational design of compounds able to interact with a specific target.


Assuntos
Amidas/farmacologia , Química Farmacêutica/métodos , Cetonas/farmacologia , Amidas/química , Animais , Linhagem Celular Tumoral , Humanos , Cetonas/química
8.
Eur J Med Chem ; 209: 112924, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33081988

RESUMO

The Translocator Protein 18 kDa (TSPO) has been discovered in 1977 as an alternative binding site for the benzodiazepine diazepam. It is an evolutionary well-conserved and tryptophan-rich 169-amino acids protein with five alpha helical transmembrane domains stretching the outer mitochondrial membrane, with the carboxyl-terminus in the cytosol and a short amino-terminus in the intermembrane space of mitochondrion. At this level, together with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocase (ANT), it forms the mitochondrial permeability transition pore (MPTP). TSPO expression is ubiquitary, with higher levels in steroid producing tissues; in the central nervous system, it is mainly expressed in glial cells and in neurons. TSPO is implicated in a variety of fundamental cellular processes including steroidogenesis, heme biosynthesis, mitochondrial respiration, mitochondrial membrane potential, cell proliferation and differentiation, cell life/death balance, oxidative stress. Altered TSPO expression has been found in some pathological conditions. In particular, high TSPO expression levels have been documented in cancer, neuroinflammation, and brain injury. Conversely, low TSPO expression levels have been evidenced in anxiety disorders. Therefore, TSPO is not only an interesting drug target for therapeutic purpose (anticonvulsant, anxiolytic, etc.), but also a valid diagnostic marker of related-diseases detectable by fluorescent or radiolabeled ligands. The aim of this report is to present an update of previous reviews dealing with the medicinal chemistry of TSPO and to highlight the most outstanding advances in the development of TSPO ligands as potential therapeutic or diagnostic tools, especially referring to the last five years.


Assuntos
Ansiolíticos/química , Anticonvulsivantes/química , Benzodiazepinas/química , Diazepam/química , Receptores de GABA/metabolismo , Sequência de Aminoácidos , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Proliferação de Células/efeitos dos fármacos , Humanos , Imidazóis/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Translocases Mitocondriais de ADP e ATP/metabolismo , Membranas Mitocondriais/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Piridinas/química , Quinolinas/química , Receptores de GABA/genética , Relação Estrutura-Atividade , Canais de Ânion Dependentes de Voltagem/metabolismo
9.
J Enzyme Inhib Med Chem ; 36(1): 286-294, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33334192

RESUMO

Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR.


Assuntos
Indóis/farmacologia , Receptor A2B de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
10.
Eur J Pharm Sci ; 156: 105594, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33059042

RESUMO

DNA Topoisomerases (Topos) are ubiquitous nuclear enzymes involved in regulating the topological state of DNA and, in eukaryotic organisms, Topos can be classified into two structurally and functionally different main classes: TopoI and TopoII. Both these enzymes proved to be excellent targets of clinically significant classes of anticancer drugs. Actually, TopoI or II inhibitors show considerable wide spectrum antitumor activities, an important feature to be included in many chemotherapeutic protocols. Despite their clinical efficacy, the use of inhibitors targeting only one of the two enzymes can increase the levels of the other one, favouring the onset of unwanted phenomena such as drug resistance. Therefore, targeting both TopoI and TopoII can reduce the probability of developing resistance, as well as side effects thanks to the use of lower doses, given the synergistic effect of the dual activity. Moreover, since drug resistance is also due to DNA repair systems such as tyrosyl-DNA phosphodiesterases I and II, inhibiting Topoisomerases concomitantly to Tyrosyl-DNA phosphodiesterase enzymes could allow more efficient and safe drugs. This review represents an update of previous works reporting about dual TopoI and TopoII inhibitors, but also an overview of the new strategy regarding the development of derivatives able to simultaneously inhibit Topo and TDP enzymes, with particular attention to structure-affinity relationship studies. The newly collected derivatives are described focusing attention on their chemical structures and their biological profiles. The final aim is to highlight the structural requirements necessary for the development of potent multiple modulators of these targets, thus providing new potential antitumor agents for the clinical usage.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA , Diester Fosfórico Hidrolases , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia
11.
Dalton Trans ; 49(41): 14520-14527, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33048079

RESUMO

We herein report the synthesis and multi-technique characterization of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4], a novel diruthenium(ii,iii) complex obtained by reacting [Ru2(µ-O2CCH3)4Cl] with a dual indolylglyoxylyl dipeptide anticancer agent. We soon realised that the compound is very stable under several different conditions including aqueous buffers or organic solvents. It is also completely unreactive toward proteins. The high stability is also suggested by cellular experiments in a glioblastoma cell line. Indeed, while the parent ligand exerts high cytotoxic effects in the low µM range, the complex is completely non-cytotoxic against the same line, most probably because of the lack of ligand release. To investigate the reasons for such high stability, we carried out DFT calculations that are fully consistent with the experimental findings. The results highlight that the stability of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4] relies on the nature of the ligand, including its steric hindrance that prevents the reaction of any nucleophilic group with the Ru2 core. Ligand displacement is the key step to allow reactivity with the biological targets of metal-based prodrugs. Accordingly, we discuss the implications of some important aspects that should be considered when active molecules are chosen as ligands for the synthesis of paddle-wheel-like complexes with medicinal applications.

12.
Eur J Pharm Sci ; 149: 105337, 2020 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-32311457

RESUMO

The oncogene KRAS is involved in the pathogenesis of many tumors such as pancreatic, lung and colorectal cancers, thereby representing a relevant target for the treatment of these diseases. The KRAS P1 promoter contains a nuclease hypersensitive, guanine-rich sequence able to fold into a G-quadruplex motif (G4). The stabilization of this G4 structure by small molecules is emerging as a feasible approach to downregulate KRAS expression. Here, a set of novel stabilizing molecules was identified through a virtual screening campaign on the NMR structure of the 22-mer KRAS G4. The most promising hits were then submitted to structure-activity relationships studies which allowed improving their binding affinity and selectivity over double helix DNA and different G4 topologies. The best derivative (19) underwent fluorescence titration experiments and further computational studies to disclose its binding mechanism to KRAS G4. Finally, biological assays showed that this compound is capable to reduce the viability of colorectal cancer cells in which mutated KRAS acts as a driver oncogene. Thus, 19 might represent the prototype of a new class of drugs for the treatment of tumors that, expressing mutated forms of KRAS, are refractory to current therapeutic regimens.

13.
J Enzyme Inhib Med Chem ; 34(1): 1697-1710, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31537132

RESUMO

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.


Assuntos
Benzimidazóis/química , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/síntese química , Aminas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bases de Schiff/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
14.
ACS Chem Neurosci ; 10(8): 3805-3814, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31268683

RESUMO

Translocator protein 18 kDa (TSPO) is a validated pharmacological target for the development of new treatments for neurological disorders. N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides (PIGAs) are effective TSPO modulators and potentially useful therapeutics for the treatment of anxiety, central nervous system pathologies featuring astrocyte loss, and inflammatory-based neuropathologies. For this class of compounds, no correlation exists between the TSPO binding affinity and the corresponding functional efficacy. Rather, their biological effectiveness correlates with the kinetics of the unbinding events and more specifically with the residence time (RT). So far, the structural reasons for the different recorded RT of congeneric PIGAs remain elusive. Here, to understand the different kinetics of PIGAs, their unbinding paths were studied by employing enhanced-sampling molecular dynamics simulations. Results of these studies revealed how subtle structural differences between PIGAs have a substantial effect on the unbinding energetics. In particular, during the egress from the TSPO binding site, slow-dissociating PIGAs find tight interactions with the protein LP1 region thereby determining a long RT. Further support to these findings was achieved by in vivo studies, which demonstrated how the anxiolytic effect observed for the inspected PIGAs correlated with their RT to TSPO.


Assuntos
Proteínas de Transporte/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ansiolíticos/farmacologia , Sítios de Ligação , Simulação por Computador , Masculino , Simulação de Dinâmica Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley
15.
ACS Med Chem Lett ; 10(4): 457-462, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30996779

RESUMO

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (2-4) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds 3b, 3i, and 3j revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.

16.
Biochim Biophys Acta Mol Cell Res ; 1866(5): 737-749, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30703414

RESUMO

The osteoblast generation from Mesenchymal stem cells (MSCs) is tightly coordinated by transcriptional networks and signalling pathways that control gene expression and protein stability of osteogenic "master transcription factors". Among these pathways, a great attention has been focused on p53 and its physiological negative regulator, the E3 ligase Murine double minute 2 (Mdm2). Nevertheless, the signalling that regulates Mdm2-p53 axis in osteoblasts remain to be elucidated, also considering that Mdm2 possesses numerous p53-independent activities and interacts with additional proteins. Herein, the effects of Mdm2 modulation on MSC differentiation were examined by the use of short- and long-lasting inhibitors of the Mdm2-p53 complex. The long-lasting Mdm2-p53 dissociation was demonstrated to enhance the MSC differentiation into osteoblasts. The increase of Mdm2 levels promoted its association to G protein-coupled receptors kinase (GRK) 2, one of the most relevant kinases involved in the desensitization of G protein-coupled receptors (GPCRs). In turn, the long-lasting Mdm2-p53 dissociation decreased GRK2 levels and favoured the functionality of A2B Adenosine Receptors (A2BARs), a GPCR dictating MSC fate. EB148 facilitated cAMP accumulation, and mediated a sustained activation of extracellular signal-regulated kinases (ERKs) and cAMP response element-binding protein (CREB). Such pro-osteogenic effects were not detectable by using the reversible Mdm2-p53 complex inhibitor, suggesting the time course of Mdm2-p53 dissociation may impact on intracellular proteins involved in cell differentiation fate. These results suggest that the long-lasting Mdm2 binding plays a key role in the mobilization of intracellular proteins that regulate the final biological outcome of MSCs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Indóis/farmacologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Receptor A2B de Adenosina/metabolismo
17.
Eur J Med Chem ; 165: 46-58, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30660826

RESUMO

New benzothiopyranoindoles (5a-l) and pyridothiopyranoindoles (5m-t), featuring different combinations of substituents (H, Cl, OCH3) at R2-R4 positions and protonatable R1-dialkylaminoalkyl chains, were synthesized and biologically assayed on three human tumor cell lines, showing significant antiproliferative activity (GI50 values spanning from 0.31 to 6.93 µM) and pro-apoptotic effect. Linear flow dichroism experiments indicate the ability of both chromophores to form a molecular complex with DNA, following an intercalative mode of binding. All compounds displayed a moderate ability to inhibit the relaxation activity of both topoisomerases I and II, reasonably correlated to their intercalative capacities. Cleavable assay performed with topoisomerase I revealed a significant poisoning effect for compounds 5g, 5h, 5s, and 5t. A theoretical model provided by hydrated docking calculations clarified the role of the R1-R4 substituents on the topoisomerase I poison activity, revealing a crucial role of the R2-OCH3 group.


Assuntos
Antineoplásicos/síntese química , Indóis/farmacologia , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase II/síntese química
18.
Bioorg Med Chem ; 26(22): 5885-5895, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30415894

RESUMO

The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N1 (1,2) or N10 (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A1 and A2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A1 and A2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs. Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A1 AR and A2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A1 and A2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells.


Assuntos
Benzimidazóis/farmacologia , Corantes Fluorescentes/farmacologia , Receptor A1 de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Triazinas/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Células Cultivadas , Relação Dose-Resposta a Droga , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Microscopia Confocal , Estrutura Molecular , Receptor A1 de Adenosina/química , Receptor A2B de Adenosina/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
19.
Medchemcomm ; 9(1): 81-86, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108902

RESUMO

Three A3 adenosine receptor (AR) antagonists (1-3) selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave us the chance to evaluate whether their higher lipophilicity, reduced conformational freedom and chirality might improve the potency towards the A3 AR. Racemic mixtures of 1-3 were resolved using chiral HPLC methods and the absolute configurations of the enantiomers were assigned by chiroptical spectroscopy and density functional theory calculations. We measured the affinity for human A1, A2A, A2B and A3 ARs of the racemic mixtures and the pure enantiomers of 1-3 by radioligand competition binding experiments. Cell-based assays of the most potent enantiomers confirmed their A3 AR antagonist profiles. Our research led to the identification of (S)-1 with high potency (0.5 nM) and selectivity as an A3 AR antagonist. Moreover we built a docking-model useful to design new pyrimidine derivatives.

20.
Urol Ann ; 10(3): 280-286, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30089986

RESUMO

Context: The correlation between aggressive prostate cancer and obesity mainly based on body mass index (BMI) and pathology after surgery remains controversial. Aims: The aim of the study was to correlate BMI, visceral adiposity index (VAI), and the plasmatic levels of leptin, adiponectin, and matrix metalloproteinase-3 (MMP-3), and biomarkers of adipose tissue function, with the detection of Gleason patterns 4 and 5 at biopsy. Subjects and Methods: Consecutive patients with prostate cancer at 12-core transrectal biopsy were enrolled. BMI, waist circumference (WC), blood samples to evaluate the plasmatic levels of triglycerides (TG) and high-density lipoproteins (HDL), adiponectin, leptin, and MMP-3 were obtained immediately before biopsy. The VAI was calculated according to the formula: WC/(39.68 + [1.88 × BMI]) × TG/1.03 × 1.31/HDL. Results: One hundred and forty-nine patients were entered. The median PSA, BMI, and VAI were 10.0 ng/ml, 27.6 kg/m2, and 4.6, respectively. Gleason patterns 4 or 5 were detected in 68 (45.6%) patients; in 15 (41.7%), 31 (44.9%), and 22 (50.0%) among normal weight, overweight, and obese patients, respectively (P = 0.55). The statistical analysis did not show any significant correlation between BMI, VAI, the plasmatic levels of leptin, adiponectin, MMP-3, and the detection of Gleason patterns 4 and 5 at biopsy. A statistically significant association emerged with older age (P = 0.017) and higher PSA values (P = 0.02). Conclusion: We did not find any association between BMI, VAI, the plasmatic levels of adiponectin, leptin, and MMP-3 and the detection of Gleason patterns 4 and 5 at prostate biopsy.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...