Publication: Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase
Authors
Sáez Ayala, Magalí ; Chazarra Parres, Soledad ; Cabezas Herrera, Juan ; Rodríguez López, José Neptuno ; Sánchez del Campo Ferrer, Luis
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Publisher
MDPI
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DOI
https://doi.org/10.3390/ijms10125398
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info:eu-repo/semantics/article
Description
This is a Published version of the following article, in International Journal of
Molecular Sciences. https://doi.org/10.3390/ijms10125398]. It is deposited under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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 (K-D) of 0.9 and 1.8 mu M, 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 mu M). 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 mu M. 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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Citation
International Journal of Molecular Sciences. Volumen 10. nº12. Páginas 5398-5410
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