Pharmacological evaluation of resveratrol derivatives as dual bromodomain/PPARs inhibitors to treat dyslipidemia

• Grant number: 15/21271-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 12, 2016
• End date: February 09, 2017
• Field of knowledge: Health Sciences - Pharmacy - Medicines Analysis and Control
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Luiz Antonio Dutra
• Supervisor: Stefan Knapp
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Goethe University Frankfurt, Germany
• Associated to the scholarship: 14/03945-9 - Design, synthesis and pharmacological evaluation of new resveratrol derivatives useful for dyslipidemia treatment, BP.DR

Abstract

The dyslipidemia is a disease caused by increased levels of lipids levels into bloodstream widely prevalent worldwide. According to Brazilian Cardiology Society the disease is classified as Hypercolesterolemia (high levels of Low Density Lipoprotein-LDL), Hypertriglyceridemia (high levels of triglycerides-TG), Mixed Hyperlipidemia (high levels of both LDL and TG) and Low High Density Lipoprotein (HDL). Reduced levels of HDL and high level of LDL have been associated with atherosclerosis development. Currently, statins are the drugs of first choice for treatment of dyslipidemia. These drugs reduce LDL, however, it has low efficiency to decrease HDL. Strategies aiming to reduce lipid levels targeting different pathways during lipid biosynthesis. PPARs receptors, for example, are activated by fibrates, which raise HDL and reduce triglycerides levels. Bromodomain are epigenetic readers and its inhibition by RVX-208 increase apoA-1 and HDL levels in humans. Recently, it was described that inhibition of bromodomains, specifically BRD2, was the target for the dyslipidemic compound RVX-208. During our initial research we have synthesized new PPARs agonist based on resveratrol scaffold and we have identify the ability of these compounds to interact with BRD2. Therefore, in this proposal we will investigate the ability of these compounds to inhibit BRD2 in order to identify new dual hybrid compounds useful to treat dyslipidemia.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DUTRA, LUIZ A.; LACERDA, MARIELLA G.; INACIO, MAIARA DESTRO; MARTINS, JOHNNY W. L.; LOPES SILVA, ANA C.; DA SILVA, PATRICIA BENTO; CHORILLI, MARLUS; AMATO, ANGELICA A.; BAVIERA, AMANDA M.; PASSARELLI, MARISA; et al. Discovery of (E)-4-styrylphenoxy-propanamide: A dual PPAR alpha/gamma partial agonist that regulates high-density lipoprotein-cholesterol levels, modulates adipogenesis, and improves glucose tolerance in diet-induced obese mice. BIOORGANIC CHEMISTRY, v. 120, p. 12-pg., 2022-01-22. (14/03945-9, 13/07600-3, 15/21271-8)

DUTRA, LUIZ ANTONIO; GUANAES, JESSICA FRADE O.; JOHMANN, NADINE; LOPES PIRES, MARIA ELISA; CHIN, CHUNG MAN; MARCONDES, SISI; DOS SANTOS, JEAN LEANDRO. Synthesis, antiplatelet and antithrombotic activities of resveratrol derivatives with NO-donor properties. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 11, p. 2450-2453, JUN 1 2017. (15/19531-1, 11/15520-4, 15/21271-8, 14/03945-9)