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

Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

Received: 5 November 2009; in revised form: 14 December 2009 / Accepted: 17 December 2009 / Published: 18 December 2009
(This article belongs to the Special Issue Phenolics and Polyphenolics)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, 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 (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
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MDPI and ACS Style

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.

AMA Style

Sánchez-del-Campo L, Sáez-Ayala M, Chazarra S, Cabezas-Herrera J, Rodríguez-López JN. Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase. International Journal of Molecular Sciences. 2009; 10(12):5398-5410.

Chicago/Turabian Style

Sánchez-del-Campo, Luís; Sáez-Ayala, Magalí; Chazarra, Soledad; Cabezas-Herrera, Juan; Rodríguez-López, José Neptuno. 2009. "Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase." Int. J. Mol. Sci. 10, no. 12: 5398-5410.

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