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1.
J Nephrol ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38941001

RESUMO

Implementing Advance Care Planning (ACP) for patients with End-Stage Kidney Disease (ESKD), particularly in the context of hemodialysis, presents significant challenges. Despite existing legal frameworks, disparities in advance care planning practices are evident across Europe. The present perspective introduces a multidisciplinary model, initiated in 2019. This model incorporates a specialized team comprising a nephrologist, a psychologist, a palliative care specialist, and an anesthesiologist/intensivist. Through this collaborative approach, we aimed to comprehensively address the intricate medical, emotional, and psychological dimensions in advance care planning. In this point of view, we discuss the strengths of our model, its potential for European Nephrology, and advocate for guidelines to enhance advance care planning implementation within the nephrology community.

3.
Transplant Cell Ther ; 30(5): 532.e1-532.e16, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38452872

RESUMO

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Anemia de Fanconi , Doença Enxerto-Hospedeiro , Condicionamento Pré-Transplante , Humanos , Anemia de Fanconi/terapia , Anemia de Fanconi/complicações , Feminino , Masculino , Adulto , Criança , Pré-Escolar , Adolescente , Estudos Retrospectivos , Lactente , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/epidemiologia , Adulto Jovem
4.
Eur J Med Chem ; 260: 115783, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37678143

RESUMO

In this study, we investigated the development of dual-targeted ligands that bind to both µ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8, showing selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. By means of repeated treatment of 3 daily administrations for 17 days, fentanyl (0.1 mg/kg, subcutaneously) led to tolerance development, pain threshold alterations and withdrawal symptoms in CD-1 mice, as well as astrocyte and microglia activation in the dorsal horn of the lumbar spinal cord. In contrast, compound 8 (0.32 mg/kg s.c.) maintained stable during days its analgesic effect at the higher dose tested with fewer withdrawal symptoms, allodynia development and glial cells activation. Our results suggest that targeting both MOR and CA enzymes can lead to the development of new class of potent analgesic agents with fewer side effects and reduced tolerance development. Further studies are needed to explore the potential mechanisms underlying these effects and to further optimize the therapeutic potential of these compounds.


Assuntos
Analgesia , Anidrases Carbônicas , Animais , Camundongos , Inibidores da Anidrase Carbônica/farmacologia , Receptores Opioides mu , Manejo da Dor , Fentanila/farmacologia
5.
Front Public Health ; 11: 1219661, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37663860

RESUMO

Background: Self-management of Type 2 diabetes mellitus (T2D) is challenging. Regular self-monitoring of blood glucose and healthy lifestyles are required to improve glycometabolic control, thus delaying diabetes complications, and reducing hospitalizations. Digital technologies can empower patients in their disease management promoting self-management and motivation to change behaviors. We report the results of an exploratory trial aimed at evaluating the metabolic outcomes of using digital solutions for T2D self-management developed in the ProEmpower project, a European Commission funded Pre-Commercial Procurement. Methods: Two digital solutions, DM4All and DiaWatch, which were codesigned with providers, patients, and caregivers, enabled the collection of clinical parameters by the patient using a smartphone integrated with the medical devices (glucometer, sphygmomanometer, scale, smart watch for heart rate monitoring and step counter). Data were automatically sent to the shared care plan allowing professionals to monitor adherence to treatment, set goals, and communicate more effectively with patients. At baseline and after an average follow-up of 8 months, glycosylated hemoglobin (HbA1c), body weight, blood pressure, and blood lipids were measured in 100 T2D patients using the ProEmpower solutions across different diabetes centers in Campania Region, age 45-79 years, both genders, and compared with a Control cohort of T2D patients (n = 100) with similar clinical characteristics and followed for a comparable period of observation in the same centers. Results: At baseline, the ProEmpower participants and the Control subjects were on average overweight, with a similar BMI in the two cohorts, and mean HbA1c was at acceptable levels (around 7.0%). After the 8 month exploratory trial, body weight, HbA1c, systolic and diastolic blood pressure, and plasma and LDL-cholesterol significantly decreased in the ProEmpower participants compared to baseline (p < 0.05 for all). The changes in systolic and diastolic blood pressure, and plasma and LDL-cholesterol were significantly different from those observed in the Control cohort (p < 0.05 for all). Conclusion: This pilot study showed positive effects on metabolic outcomes relevant to cardiovascular risk in T2D of adopting digital telemedicine self-monitoring solutions based on automation of measurements and coaching on healthy lifestyles promotion.


Assuntos
Diabetes Mellitus Tipo 2 , Autogestão , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peso Corporal , LDL-Colesterol , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas , Projetos Piloto
6.
Heliyon ; 9(8): e18885, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37600419

RESUMO

The human carbonic anhydrase IX (CA IX) is a hypoxia-induced transmembrane protein belonging to the α-CA enzyme family. It has a crucial role in pH regulation in hypoxic cells and acts by buffering intracellular acidosis induced by hypoxia. Indeed, it is frequently expressed in cancer cells, where it contributes to tumor progression. CA IX is also able to localize in the nucleus, where it contributes to 47S rRNA precursor genes transcription; however, the mechanisms assisting its nuclear translocation still remain unclear. The aim of our study was to deepen the understanding of the mechanisms involved in CA IX subcellular distribution. To this purpose, we implemented a site-directed mutagenesis approach targeting the C-terminal domain of CA IX and evaluated the subcellular distribution of the wild-type and mutant proteins in the SH-SY5Y cell line. The mutant proteins showed impaired binding ability and altered subcellular distribution in both normoxic and hypoxic conditions. Our data suggest that CA IX nuclear translocation depends on its transit through the secretory and the endocytic pathways.

7.
J Med Chem ; 66(12): 8118-8129, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37283561

RESUMO

Benzoxaborole is currently a scaffold of great relevance in medicinal chemistry. In 2016, it was reported to be a new and valuable chemotype for designing carbonic anhydrase (CA) inhibitors. Herein, using an in silico design, we report the synthesis and characterization of substituted 6-(1H-1,2,3-triazol-1-yl)benzoxaboroles. 6-Azidobenzoxaborole was described for the first time as a molecular platform to prepare libraries of inhibitors by a copper(I)-catalyzed azide-alkyne cycloaddition via a click chemistry strategy. With inhibition constants below 30 nM, some derivatives, such as compound 20, showed efficacy as selective hCA VII and IX inhibitors. The design hypothesis was validated by crystallographic investigation on the hCA II/20 adduct, which provided explanations over the different inhibition behavior observed against the five evaluated hCA isoforms. Overall, this study identified 20 as a new promising lead compound to develop novel anticancer agents targeting the tumor-associated hCA IX but also potent neuropathic pain relievers targeting hCA VII.


Assuntos
Anidrases Carbônicas , Anidrases Carbônicas/metabolismo , Anidrase Carbônica IX/metabolismo , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Estrutura-Atividade , Antígenos de Neoplasias/química
8.
Biology (Basel) ; 12(2)2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36829558

RESUMO

Aliphatic sulfonamides are an interesting class of carbonic anhydrase inhibitors (CAIs) proven to be effective for several carbonic anhydrase (CA) isoforms involved in pathologic states. Here we report the crystallographic structures of hCA II in complex with two aliphatic sulfonamides incorporating coumarin rings, which showed a good inhibition and selectivity for this isoform. Although these two molecules have a very similar chemical structure, differing only in the substitution of the two aliphatic hydrogen atoms with two fluorine atoms, they adopt a significantly different binding mode within the enzyme active site. Theoretical binding free energy calculations, performed to rationalize these data, showed that a delicate balance of electrostatic and steric effects modulate the protein-ligand interactions. Data presented here can be fruitfully used for the rational design of novel and effective isozyme-specific inhibitor molecules.

9.
Cells ; 12(2)2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36672233

RESUMO

Conventional chemotherapy represents the main systemic treatment used for triple-negative breast cancer (TNBC) patients, although many of them develop drug resistance. The hypoxic TME is the crucial driver in the onset of insensitivity to chemotherapy. In this research, we elucidated the role played by bone marrow-derived mesenchymal stem cells (BM-MSCs) in reducing cisplatin effects in TNBC. BT-549 and MDA-MB-231 cells, grown under hypoxic conditions in the presence of conditioned medium obtained from BM-MSCs (CM-MSCs), showed a strong cisplatin insensitivity and increased expression levels of carbonic anhydrase IX (CA IX). Therefore, we inhibited CM-MSC-induced CA IX by SLC-0111 to potentiate chemotherapy efficacy in TNBC cells. Our results showed that CM-MSCs under hypoxic conditions caused an increase in the ability of TNBC cells to form vascular structures, migrate and invade Matrigel. Cell treatment with cisplatin plus SLC-0111 was able to block these mechanisms, as well as the signaling pathways underlying them, such as p-AKT, p-ERK, CD44, MMP-2, vimentin, ß-catenin, and N-cadherin, more effectively than treatment with single agents. In addition, a significant enhancement of apoptosis assessed by annexin V, caspase-3 expression and activity was also shown. Taken together, our results demonstrated the possibility, through CA IX inhibition, of returning TNBC cells to a more chemosensitive state.


Assuntos
Células-Tronco Mesenquimais , Neoplasias de Mama Triplo Negativas , Humanos , Anidrase Carbônica IX/metabolismo , Cisplatino/farmacologia , Cisplatino/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Medula Óssea/metabolismo , Células-Tronco Mesenquimais/metabolismo
10.
Crit Rev Anal Chem ; : 1-26, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36601882

RESUMO

Despite being extremely old concepts, plasmonics and surface plasmon resonance-based biosensors have been increasingly popular in the recent two decades due to the growing interest in nanooptics and are now of relevant significance in regards to applications associated with human health. Plasmonics integration into point-of-care devices for health surveillance has enabled significant levels of sensitivity and limit of detection to be achieved and has encouraged the expansion of the fields of study and market niches devoted to the creation of quick and incredibly sensitive label-free detection. The trend reflects in wearable plasmonic sensor development as well as point-of-care applications for widespread applications, demonstrating the potential impact of the new generation of plasmonic biosensors on human well-being through the concepts of personalized medicine and global health. In this context, the aim here is to discuss the potential, limitations, and opportunities for improvement that have arisen as a result of the integration of plasmonics into microsystems and lab-on-chip over the past five years. Recent applications of plasmonic biosensors in microsystems and sensor performance are analyzed. The final analysis focuses on the integration of microfluidics and lab-on-a-chip with quantum plasmonics technology prospecting it as a promising solution for chemical and biological sensing. Here it is underlined how the research in the field of quantum plasmonic sensing for biological applications has flourished over the past decade with the aim to overcome the limits given by quantum fluctuations and noise. The significant advances in nanophotonics, plasmonics and microsystems used to create increasingly effective biosensors would continue to benefit this field if harnessed properly.

11.
Int J Mol Sci ; 23(19)2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36233343

RESUMO

Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible carbon dioxide hydration reaction. Among the eight different CA classes existing in nature, the α-class is the largest one being present in animals, bacteria, protozoa, fungi, and photosynthetic organisms. Although many studies have been reported on these enzymes, few functional, biochemical, and structural data are currently available on α-CAs isolated from photosynthetic organisms. Here, we give an overview of the most recent literature on the topic. In higher plants, these enzymes are engaged in both supplying CO2 at the Rubisco and determining proton concentration in PSII membranes, while in algae and cyanobacteria they are involved in carbon-concentrating mechanism (CCM), photosynthetic reactions and in detecting or signaling changes in the CO2 level in the environment. Crystal structures are only available for three algal α-CAs, thus not allowing to associate specific structural features to cellular localizations or physiological roles. Therefore, further studies on α-CAs from photosynthetic organisms are strongly needed to provide insights into their structure-function relationship.


Assuntos
Anidrases Carbônicas , Animais , Dióxido de Carbono , Anidrases Carbônicas/metabolismo , Fotossíntese/fisiologia , Plantas/metabolismo , Prótons , Ribulose-Bifosfato Carboxilase
12.
Comput Struct Biotechnol J ; 20: 4185-4194, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36016712

RESUMO

Melioidosis is a severe disease caused by the highly pathogenic gram-negative bacterium Burkholderia pseudomallei. Several studies have highlighted the broad resistance of this pathogen to many antibiotics and pointed out the pivotal importance of improving the pharmacological arsenal against it. Since γ-carbonic anhydrases (γ-CAs) have been recently introduced as potential and novel antibacterial drug targets, in this paper, we report a detailed characterization of BpsγCA, a γ-CA from B. pseudomallei by a multidisciplinary approach. In particular, the enzyme was recombinantly produced and biochemically characterized. Its catalytic activity at different pH values was measured, the crystal structure was determined and theoretical pKa calculations were carried out. Results provided a snapshot of the enzyme active site and dissected the role of residues involved in the catalytic mechanism and ligand recognition. These findings are an important starting point for developing new anti-melioidosis drugs targeting BpsγCA.

13.
Biomedicines ; 10(6)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35740427

RESUMO

Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment.

14.
J Exp Clin Cancer Res ; 41(1): 122, 2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35365193

RESUMO

BACKGROUND: Hypoxic tumor microenvironment (TME) contributes to the onset of many aspects of the cancer biology associated to the resistance to conventional therapies. Hypoxia is a common characteristic and negative prognostic factor in the head and neck squamous carcinomas (HNSCC) and is correlated with aggressive and invasive phenotype as well as with failure to chemo- and radio-therapies. The carbonic anhydrase isoenzymes IX and XII (CA IX/XII), regulators of extra and intracellular pH, are overexpressed in TME and are involved in adaptative changes occurring in cancer cells to survive at low O2. In this study, we aim to investigate in HNSCC cells and murine models the possibility to target CA IX/XII by the specific inhibitor SLC-0111 to potentiate the effects of cisplatin in hampering cell growth, migration and invasion. Furthermore, we analyzed the signal pathways cooperating in acquisition of a more aggressive phenotype including stemness, epithelial-mesenchymal transition and apoptotic markers. METHODS: The effects of cisplatin, CA IX/XII specific inhibitor SLC-0111, and the combinatorial treatment were tested on proliferation, migration, invasion of HNSCC cells grown in 2D and 3D models. Main signal pathways and the expression of stemness, mesenchymal and apoptotic markers were analyzed by western blotting. Molecular imaging using NIR-Annexin V and NIR-Prosense was performed in HNSCC xenografts to detect tumor growth and metastatic spread. RESULTS: HNSCC cells grown in 2D and 3D models under hypoxic conditions showed increased levels of CA IX/XII and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA IX/XII inhibitor SLC-0111 to cisplatin sensitized HNSCC cells to the chemotherapeutic agent and caused a reduction of proliferation, migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program, whereas it induced apoptosis. In HNSCC xenografts the treatment with cisplatin plus SLC-0111 caused an inhibition of tumor growth and an induction of apoptosis as well as a reduction of metastatic spread at a higher extent than single agents. CONCLUSION: Our results highlight the ability of SLC-0111 to sensitize HNSCC to cisplatin by hindering hypoxia-induced signaling network that are shared among mechanisms involved in therapy resistance and metastasis.


Assuntos
Anidrases Carbônicas , Neoplasias de Cabeça e Pescoço , Animais , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Anidrases Carbônicas/farmacologia , Proliferação de Células , Cisplatino/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Camundongos , Compostos de Fenilureia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Sulfonamidas , Microambiente Tumoral
15.
Biomolecules ; 12(3)2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35327561

RESUMO

Intrinsically Disordered Proteins (IDPs) lack stable tertiary and secondary structures and are extensively distributed across eukaryotic cells, playing critical roles in cell signaling and regulation [...].


Assuntos
Proteínas Intrinsicamente Desordenadas , Humanos , Proteínas Intrinsicamente Desordenadas/química , Conformação Proteica , Estrutura Secundária de Proteína
16.
Int J Mol Sci ; 23(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35216276

RESUMO

The Chromatin Assembly Factor 1 is a heterotrimeric complex responsible for the nucleosome assembly during DNA replication and DNA repair. In humans, the largest subunit P150 is the major actor of this process. It has been recently considered as a tumor-associated protein due to its overexpression in many malignancies. Structural and functional studies targeting P150 are still limited and only scarce information about this subunit is currently available. Literature data and bioinformatics analysis assisted the identification of a stable DNA binding domain, encompassing residues from 721 to 860 of P150 within the full-length protein. This domain was recombinantly produced and in vitro investigated. An acidic region modulating its DNA binding ability was also identified and characterized. Results showed similarities and differences between the P150 and its yeast homologue, namely Cac-1, suggesting that, although sharing a common biological function, the two proteins may also possess different features.


Assuntos
Fator 1 de Modelagem da Cromatina/metabolismo , Cromatina/metabolismo , Domínios Proteicos/fisiologia , Proteínas Quinases/metabolismo , Subunidades Proteicas/metabolismo , Sequência de Aminoácidos , Proteínas Cromossômicas não Histona/metabolismo , Replicação do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Humanos , Ligação Proteica/fisiologia , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo
17.
Amino Acids ; 54(4): 543-558, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34436666

RESUMO

Human carbonic anhydrases IX (hCA IX) and XII (hCA XII) are two proteins associated with tumor formation and development. These enzymes have been largely investigated both from a biochemical and a functional point of view. However, limited data are currently available on the characterization of their post-translational modifications (PTMs) and the functional implication of these structural changes in the tumor environment. In this review, we summarize existing literature data on PTMs of hCA IX and hCA XII, such as disulphide bond formation, phosphorylation, O-/N-linked glycosylation, acetylation and ubiquitination, highlighting, when possible, their specific role in cancer pathological processes.


Assuntos
Anidrases Carbônicas , Neoplasias , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 227: 113956, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34731762

RESUMO

We report a series of compounds 1-17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Neuralgia/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Tiazinas/farmacologia , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxaliplatina/administração & dosagem , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química
19.
Soft Matter ; 17(29): 7047-7057, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34251388

RESUMO

In this study, galactose-grafted beads were prepared using the main design principle of the cluster effect. Galactose was chosen as the sugar for investigation because it acts as the main building block of long glycan chains and because a simple and fast protocol is still required for its immobilization. For the analysis, the lectin, ligand of the galactose, was immobilized on a gold plasmonic substrate. After preliminary characterization of the galactose-grafted beads, the investigation of the surface plasmon surface behavior of the system was carried out, for studying the affinity constant of the multivalent beads. The results of steady-state and of the kinetics analysis evidenced a higher affinity of the galactose-grafted beads over the beadless galactose solution. For the association kinetics analysis, a Langmuir isotherm was applied to the data. The analysis of the rate of dissociation evidenced the most important differences between the two samples, based on the more difficult release of the galactose-grafted beads during washing. To confirm the influence of the glycoside cluster effect, a low-density lectin substrate was tested, and the results evidenced that the characteristic size of the molecules determines a threshold for the cluster density. The calculated detection limit and dissociation constants were 3.5 µM and 40.2 µM, respectively. Considering those results, the evaluation of the affinities toward the receptors depends on the cluster density and then, it should be designed for mimicking the biological samples.


Assuntos
Ouro , Ressonância de Plasmônio de Superfície , Carboidratos , Cinética , Lectinas
20.
Bioorg Med Chem ; 44: 116279, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34216985

RESUMO

To tackle the challenge of isoform selectivity, we explored the entrance of the cavity for selected druggable human Carbonic Anhydrases (hCAs). Based on X-ray crystallographic studies on the 4-(4-(2-chlorobenzoyl)piperazine-1-carbonyl)benzenesulfonamide in complex with the brain expressed hCA VII (PDB code: 7NC4), a series of 4-(4(hetero)aroylpiperazine-1-carbonyl)benzene-1-sulfonamides has been developed. To evaluate their capability to fit the hCA VII catalytic cavity, the newer benzenesulfonamides were preliminary investigated by means of docking simulations. Then, this series of thirteen benzenesulfonamides was synthesized and tested against selected druggable hCAs. Among them, the 4-(4-(furan-2-carbonyl)piperazine-1-carbonyl)benzenesulfonamide showed remarkable affinity towards hCA VII (Ki: 4.3 nM) and good selectivity over the physiologically widespread hCA I when compared to Topiramate (TPM).


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Desenho de Fármacos , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Benzenossulfonamidas
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