Síntesis de β-aminoalcoholes como potenciales inhibidores multidiana de la enfermedad de Alzheimer

Traballo Fin de Grao en Química. Curso 2017-2018O cambio demográfico asociado ao incremento da esperanza de vida reflíctese nun aumento das afeccións asociadas á idade como é a enfermidade de Alzheimer (EA). Esta enfermidade neurodexenerativa é irreversible pois non se dispón dun tratamento efectivo na actualidade. Unha hipótese aceptada para a orixe da EA está relacionada coa cascada amiloide, que postula que o aumento de péptidos β-amiloides dá lugar a todas as características patolóxicas da enfermidade, incluíndo a formación de placas senís e ovillos neurofibrilares, a disfunción sináptica e a morte neuronal. O obxectivo deste traballo é a síntese enantioespecífica dunha serie de β-aminoalcois 1-4 (Figura 1) que poidan actuar como posibles inhibidores multidiana da cascada amiloide: a enzima BACE-1, a enzima AChE e a agregación dos péptidos amiloides Aβ-42. A síntese converxente dos aminoalcois 1-4 realizouse en varios pasos. Sintetizáronse diferentes benciloxibenzaldehidos 10-12 que, a continuación, acopláronse mediante aminación redutora coas aminas quirais 8, sintetizadas previamente a partir da 3- metilhidantoína e os dous enantiómeros do epóxido quiral 14, para dar as dúas series de aminoalcois (S)-1-4 e (R)-1-4 enantioméricamente puros.El cambio demográfico asociado al incremento de la esperanza de vida se refleja en un aumento de las afecciones asociadas a la edad como es la enfermedad de Alzheimer (EA). Esta enfermedad neurodegenerativa es irreversible pues no se dispone de un tratamiento efectivo en la actualidad. Una hipótesis aceptada para el origen de la EA está relacionada con la cascada amiloide, que postula que el aumento de péptidos β-amiloides da lugar a todas las características patológicas de la enfermedad, incluyendo la formación de placas seniles y ovillos neurofibrilares, la disfunción sináptica y la muerte neuronal. El objetivo de este trabajo es la síntesis enantioespecífica de una serie de β- aminoalcoholes 1-4 (Figura 1) que puedan actuar como posibles inhibidores multidiana de la cascada amiloide: la enzima BACE-1, la enzima AChE y la agregación de los péptidos amiloides Aβ-42. La síntesis convergente de los aminoalcoholes 1-4 se realizó en varias etapas. Se sintetizaron diferentes benciloxibenzaldehídos 10-12 que, a continuación, se acoplaron mediante aminación reductora con las aminas quirales 8, sintetizadas previamente a partir de 3-metilhidantoína y los dos enantiómeros del epóxido quiral 14, para dar las dos series de aminoalcoholes (S)-1-4 y (R)-1-4 enantioméricamente puros.The demographic change associated with the increase in life expectancy is reflected by a rise in the aging-associated disorders, such as Alzheimer's disease (AD). This neurodegenerative disease is irreversible since there is at present no effective treatment available. An accepted hypothesis for the origin of the AD is related to the amyloid cascade, which postulates that the increase of β-amyloid peptides leads to all the pathological characteristics of the disease, including the formation of senile plaques and neurofibrillary tangles, the synaptic dysfunction and neuronal death. The objective of this work is the enantiospecific synthesis of a set of β-aminoalcohols 1- 4 (Figure 1) that can act as possible multitarget amyloid cascade inhibitors: BACE-1 and AChE enzymes and the Aβ-42 amyloid peptide aggregation. The convergent synthesis of aminoalcohols 1-4 was performed in several steps. Different benzyloxybenzaldehydes 10-12 were synthesized, which were then coupled by reductive amination with the chiral amines 8, previously synthesized from 3- methylhydantoin and the two enantiomers of the chiral epoxide 14, to give the enantiopure aminoalcohols (S)-1-4 and (R)-1-4

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases

The pleiotropic hormone relaxin-2 plays a pivotal role in the physiology and pathology of the cardiovascular system. Relaxin-2 exerts relevant regulatory functions in cardiovascular tissues through the specific receptor relaxin family peptide receptor 1 (RXFP1) in the regulation of cardiac metabolism; the induction of vasodilatation; the reversion of fibrosis and hypertrophy; the reduction of inflammation, oxidative stress, and apoptosis; and the stimulation of angiogenesis, with inotropic and chronotropic effects as well. Recent preclinical and clinical outcomes have encouraged the potential use of relaxin-2 (or its recombinant form, known as serelaxin) as a therapeutic strategy during cardiac injury and/or in patients suffering from different cardiovascular disarrangements, especially heart failure. Furthermore, relaxin-2 has been proposed as a promising biomarker of cardiovascular health and disease. In this review, we emphasize the relevance of the endogenous hormone relaxin-2 as a useful diagnostic biomarker in different backgrounds of cardiovascular pathology, such as heart failure, atrial fibrillation, myocardial infarction, ischemic heart disease, aortic valve disease, hypertension, and atherosclerosis, which could be relevant in daily clinical practice and could contribute to comprehending the specific role of relaxin-2 in cardiovascular diseases

Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Regulation of Inflammatory Processes in Animal Models

Sodium-glucose co-transporter 2 inhibitors, also known as gliflozins, were developed as a novel class of anti-diabetic agents that promote glycosuria through the prevention of glucose reabsorption in the proximal tubule by sodium-glucose co-transporter 2. Beyond the regulation of glucose homeostasis, they resulted as being effective in different clinical trials in patients with heart failure, showing a strong cardio-renal protective effect in diabetic, but also in non-diabetic patients, which highlights the possible existence of other mechanisms through which gliflozins could be exerting their action. So far, different gliflozins have been approved for their therapeutic use in T2DM, heart failure, and diabetic kidney disease in different countries, all of them being diseases that have in common a deregulation of the inflammatory process associated with the pathology, which perpetuates and worsens the disease. This inflammatory deregulation has been observed in many other diseases, which led the scientific community to have a growing interest in the understanding of the biological processes that lead to or control inflammation deregulation in order to be able to identify potential therapeutic targets that could revert this situation and contribute to the amelioration of the disease. In this line, recent studies showed that gliflozins also act as an anti-inflammatory drug, and have been proposed as a useful strategy to treat other diseases linked to inflammation in addition to cardio-renal diseases, such as diabetes, obesity, atherosclerosis, or non-alcoholic fatty liver disease. In this work, we will review recent studies regarding the role of the main sodium-glucose co-transporter 2 inhibitors in the control of inflammation

Circulating miR-499a and miR-125b as Potential Predictors of Left Ventricular Ejection Fraction Improvement after Cardiac Resynchronization Therapy

Cardiac resynchronization therapy represents a therapeutic option for heart failure drug-refractory patients. However, due to the lack of success in 30% of the cases, there is a demand for an in-depth analysis of individual heterogeneity. In this study, we aimed to evaluate the prognostic value of circulating miRNA differences. Responder patients were defined by a composite endpoint of the presence of left ventricular reverse remodelling (a reduction ≥15% in telesystolic volume and an increment ≥10% in left ventricular ejection fraction). Circulating miRNAs signature was analysed at the time of the procedure and at a 6-month follow-up. An expression analysis showed, both at baseline and at follow-up, differences between responders and non-responders. Responders presented lower baseline expressions of miR-499, and at follow-up, downregulation of miR-125b-5p, both associated with a significant improvement in left ventricular ejection fraction. The miRNA profile differences showed a marked sensitivity to distinguish between responders and non-responders. Our data suggest that miRNA differences might contribute to prognostic stratification of patients undergoing cardiac resynchronization therapy and suggest that preimplant cardiac context as well as remodelling response are key to therapeutic success

The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats

The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach. We found that empagliflozin increases the content of diglycerides and oxidized fatty acids (FA) in VAT, while in SAT, it decreases the levels of several lysophospholipids and increases 2 phosphatidylcholines. Empagliflozin also reduces the expression of the cytokines interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNFα), monocyte-chemotactic protein-1 (MCP-1) and IL-10, and of Cd86 and Cd163 M1 and M2 macrophage markers in VAT, with no changes in SAT, except for a decrease in IL-1β. Empagliflozin treatment also shows an effect on lipolysis increasing the expression of hormone-sensitive lipase (HSL) in SAT and VAT and of adipose triglyceride lipase (ATGL) in VAT, together with a decrease in the adipose content of the FA transporter cluster of differentiation 36 (CD36). In conclusion, our data highlighted differences in the VAT and SAT lipidomes, inflammatory profiles and lipolytic function, which suggest a distinct metabolism of these two white adipose tissue depots after the empagliflozin treatment