Abstract:
Objectives Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. Methods Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1-200 μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 μm) assays. Key fndings Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. Conclusions Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment. © 2016 Royal Pharmaceutical Society.
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Documento: |
Artículo
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Título: | Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates |
Autor: | Martínez, M.D.; Luna, L.; Tesio, A.Y.; Feresin, G.E.; Durán, F.J.; Burton, G. |
Filiación: | Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellõn 2, Buenos Aires, C1428EGA, Argentina Instituto de Biotecnología, Facultad de Ingeniería, Universidad Nacional de San Juan, San Juan, Argentina INQUIMAE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
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Palabras clave: | antioxidant activity; bioisosteres; difluoromethyl group; hydroxycinnamic acids; lipid peroxidation; 1,1 diphenyl 2 picrylhydrazyl; antioxidant; beta carotene; caffeic acid; methyl 3 [3 acetyloxy 4 [(difluoromethyl)phenyl]]propenoate; methyl 3 [4 acetyloxy [3 (difluoromethyl)phenyl]]propenoate; methyl 3 [[3 (difluoromethyl) 4 hydroxyphenyl]]propenoate; methyl 3 [[3 (difluoromethyl) 4 methoxyphenyl]]propenoate; methyl 3 [[4 (difluoromethyl) 3 hydroxyphenyl]]propenoate; methyl 3 [[4 (difluoromethyl) 3 methoxyphenyl]]propenoate; unclassified drug; 1,1-diphenyl-2-picrylhydrazyl; antioxidant; biphenyl derivative; coumaric acid; ferricyanide; fluorinated hydrocarbon; free radical; picric acid; antioxidant activity; Article; bleaching; cell assay; controlled study; cyclic potentiometry; differential pulse voltammetry; drug structure; electrochemical analysis; erythrocyte; fluorescence recovery after photobleaching; human; human cell; hydrogen bond; lipid peroxidation; lipophilicity; oxidation reduction potential; cell culture; chemical structure; chemistry; drug effects; electrochemistry; metabolism; oxidation reduction reaction; synthesis; Antioxidants; beta Carotene; Biphenyl Compounds; Cells, Cultured; Coumaric Acids; Electrochemistry; Erythrocytes; Ferricyanides; Free Radicals; Humans; Hydrocarbons, Fluorinated; Lipid Peroxidation; Molecular Structure; Oxidation-Reduction; Picrates |
Año: | 2016
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Volumen: | 68
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Número: | 2
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Página de inicio: | 233
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Página de fin: | 244
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DOI: |
http://dx.doi.org/10.1111/jphp.12507 |
Título revista: | Journal of Pharmacy and Pharmacology
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Título revista abreviado: | J. Pharm. Pharmacol.
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ISSN: | 00223573
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CODEN: | JPPMA
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CAS: | 1,1 diphenyl 2 picrylhydrazyl, 1898-66-4; beta carotene, 7235-40-7; caffeic acid, 27323-69-9, 331-39-5; coumaric acid, 25429-38-3; ferricyanide, 13408-62-3, 5683-74-9; picric acid, 14798-26-6, 88-89-1; 1,1-diphenyl-2-picrylhydrazyl; Antioxidants; beta Carotene; Biphenyl Compounds; Coumaric Acids; Ferricyanides; Free Radicals; hexacyanoferrate III; Hydrocarbons, Fluorinated; Picrates
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00223573_v68_n2_p233_Martinez |
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Citas:
---------- APA ----------
Martínez, M.D., Luna, L., Tesio, A.Y., Feresin, G.E., Durán, F.J. & Burton, G.
(2016)
. Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates. Journal of Pharmacy and Pharmacology, 68(2), 233-244.
http://dx.doi.org/10.1111/jphp.12507---------- CHICAGO ----------
Martínez, M.D., Luna, L., Tesio, A.Y., Feresin, G.E., Durán, F.J., Burton, G.
"Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates"
. Journal of Pharmacy and Pharmacology 68, no. 2
(2016) : 233-244.
http://dx.doi.org/10.1111/jphp.12507---------- MLA ----------
Martínez, M.D., Luna, L., Tesio, A.Y., Feresin, G.E., Durán, F.J., Burton, G.
"Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates"
. Journal of Pharmacy and Pharmacology, vol. 68, no. 2, 2016, pp. 233-244.
http://dx.doi.org/10.1111/jphp.12507---------- VANCOUVER ----------
Martínez, M.D., Luna, L., Tesio, A.Y., Feresin, G.E., Durán, F.J., Burton, G. Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates. J. Pharm. Pharmacol. 2016;68(2):233-244.
http://dx.doi.org/10.1111/jphp.12507