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Int. J. Mol. Sci. 2009, 10(12), 5398-5410; doi:10.3390/ijms10125398
Article

Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

1, 1, 1, 2 and 1,*
1 Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo, Murcia, Spain 2 Servicio de Análisis Clínicos, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
* Author to whom correspondence should be addressed.
Received: 5 November 2009 / Revised: 14 December 2009 / Accepted: 17 December 2009 / Published: 18 December 2009
(This article belongs to the Special Issue Phenolics and Polyphenolics)
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Abstract

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 (KD) 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 (KD = 2.1 μM). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a KD 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 KD 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.
Keywords: polyphenols; tea catechins; flavonoids; dihydrofolate reductase; antifolates; enzyme inhibition polyphenols; tea catechins; flavonoids; dihydrofolate reductase; antifolates; enzyme inhibition
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Sánchez-del-Campo, L.; Sáez-Ayala, M.; Chazarra, S.; Cabezas-Herrera, J.; Rodríguez-López, J.N. Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase. Int. J. Mol. Sci. 2009, 10, 5398-5410.

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