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Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG)...

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Autores principales: Sánchez-del-Campo, Luís, Sáez-Ayala, Magalí, Chazarra, Soledad, Cabezas-Herrera, Juan, Rodríguez-López, José Neptuno
Formato: Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802001/
https://www.ncbi.nlm.nih.gov/pubmed/20054477
http://dx.doi.org/10.3390/ijms10125398
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author Sánchez-del-Campo, Luís
Sáez-Ayala, Magalí
Chazarra, Soledad
Cabezas-Herrera, Juan
Rodríguez-López, José Neptuno
author_facet Sánchez-del-Campo, Luís
Sáez-Ayala, Magalí
Chazarra, Soledad
Cabezas-Herrera, Juan
Rodríguez-López, José Neptuno
author_sort Sánchez-del-Campo, Luís
collection PubMed
description Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K(D))of 0.9 and 1.8 μM, respectively, while polyphenols lacking the ester bound gallate moiety [e.g., (-)-epigallocatechin (EGC) and (-)-epicatechin (EC)] did not bind to this enzyme. To avoid stability and bioavailability problems associated with tea catechins we synthesized a methylated derivative of ECG (3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin; TMECG), which effectively binds to DHFR (K(D) = 2.1 μM). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a K(D) of 8.2 nM. Quercetin glucuronides also bind to DHFR but its effective binding was highly dependent of the sugar residue, with quercetin-3-xyloside being the stronger inhibitor of the enzyme with a K(D) of 0.6 μM. The finding that natural polyphenols are good inhibitors of human DHFR could explain the epidemiological data on their prophylactic effects for certain forms of cancer and open a possibility for the use of natural and synthetic polyphenols in cancer chemotherapy.
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spelling pubmed-28020012010-01-06 Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase Sánchez-del-Campo, Luís Sáez-Ayala, Magalí Chazarra, Soledad Cabezas-Herrera, Juan Rodríguez-López, José Neptuno Int J Mol Sci Article Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K(D))of 0.9 and 1.8 μM, respectively, while polyphenols lacking the ester bound gallate moiety [e.g., (-)-epigallocatechin (EGC) and (-)-epicatechin (EC)] did not bind to this enzyme. To avoid stability and bioavailability problems associated with tea catechins we synthesized a methylated derivative of ECG (3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin; TMECG), which effectively binds to DHFR (K(D) = 2.1 μM). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a K(D) of 8.2 nM. Quercetin glucuronides also bind to DHFR but its effective binding was highly dependent of the sugar residue, with quercetin-3-xyloside being the stronger inhibitor of the enzyme with a K(D) of 0.6 μM. The finding that natural polyphenols are good inhibitors of human DHFR could explain the epidemiological data on their prophylactic effects for certain forms of cancer and open a possibility for the use of natural and synthetic polyphenols in cancer chemotherapy. Molecular Diversity Preservation International (MDPI) 2009-12-18 /pmc/articles/PMC2802001/ /pubmed/20054477 http://dx.doi.org/10.3390/ijms10125398 Text en © 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0 This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Sánchez-del-Campo, Luís
Sáez-Ayala, Magalí
Chazarra, Soledad
Cabezas-Herrera, Juan
Rodríguez-López, José Neptuno
Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title_full Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title_fullStr Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title_full_unstemmed Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title_short Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
title_sort binding of natural and synthetic polyphenols to human dihydrofolate reductase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802001/
https://www.ncbi.nlm.nih.gov/pubmed/20054477
http://dx.doi.org/10.3390/ijms10125398
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