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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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.
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.
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.