Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives
| Autor: | Andreia Palmeira, Sara Freitas, Carlos A. M. Afonso, Tiago Almeida, Carlos M. G. Azevedo, Madalena Pinto, Emília Sousa, Marta Correia-da-Silva, João Mendes Moreira, Vitor Vasconcelos, Ralph Urbatzka |
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| Přispěvatelé: | Centro Interdisciplinar de Investigação Marinha e Ambiental, CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
obesity Antioxidant antioxidant medicine.medical_treatment Drug Evaluation Preclinical Pre-adipocytes resveratrol 01 natural sciences Antioxidants chemistry.chemical_compound Mice antiobesity agent Drug Discovery lipid metabolism zebra fish Adipocytes animal Cytotoxicity polyphenol derivative Zebrafish messenger RNA drug effect 3T3-L1 cell line quantitative structure activity relation General Medicine 3. Good health unclassified drug EC50 Biochemistry Toxicity cytotoxicity Quantitative structure–activity relationship in vitro study animal experiment adipocyte chemistry Article in vivo study Small whole-animal model 03 medical and health sciences lipid preclinical study 3T3-L1 Cells medicine Animals controlled study drug screening Obesity protein expression mouse Pharmacology structure activity relation nonhuman Anti-obesity drugs Organic Chemistry Nile red Polyphenols Lipid metabolism surface area carbon nuclear magnetic resonance Lipid Metabolism 0104 chemical sciences Zebrafish nile red fluorescence fat metabolism assay 010404 medicinal & biomolecular chemistry polyphenol 030104 developmental biology dimethyl 2 2' [(9 oxo 9h xanthene 3 6 diyl) bis(oxy)]diacetate Lipid reducing capacity Polyphenol 1 2 bis[(3 methylbut 2 en 1 yl)oxy] 9h xanthen 9 one Anti-Obesity Agents metabolism proadipocyte |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP European Journal of Medicinal Chemistry |
| Popis: | Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 μM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo. To improve the safety profile, compounds were screened at 50 μM in murine preadipocytes in vitro for cytotoxicity. Obtained activity data were used to create a 2D-QSAR (quantitative structure activity relationship) model. 38 polyphenols showed strong lipid reducing activity. Toxicity analysis revealed that 18 of them did not show any toxicity in vitro or in vivo. QSAR analysis revealed the importance of the number of rings, fractional partial positively charged surface area, relative positive charge, relative number of oxygen atoms, and partial negative surface area for lipid-reducing activity. The five most potent compounds with EC50 values in the nanomolar range for lipid reducing activity and without any toxic effects are strong candidates for future research and development into anti-obesity drugs. Molecular profiling for fasn, sirt1, mtp and ppary revealed one compound that reduced significantly fasn mRNA expression. © 2018 Elsevier Masson This article is a result of the project INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035 , within the research line NOVELMAR, supported by North Portugal Regional Operational Program ( NORTE 2020 ), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This research was developed under the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790 ) and PTDC/DTPFTO/1981/2014 ( POCl-01-0145-FEDER-016581 ) supported through national funds provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF) through the COMPETE - Programa Operacional Factores de Competitividade (POFC) programme. Ralph Urbatzka and M. Correia-da-Silva were supported by FCT grants SFRH/BPD/112287/2015 and SFRH/BPD/81878/2011 , respectively. Appendix A |
| Databáze: | OpenAIRE |
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