Green tea polyphenols as proteasome inhibitors: implication in chemoprevention

Abstract

Next to water, tea is the most popular beverage in the world. The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate (EGCG), which is extensively studied for its cancer-preventive and anti-cancer activities as well as its cellular targets. One potential molecular target of EGCG is the proteasome. While molecular docking and structure-activity relationship (SAR) analysis suggests that the ester carbon of EGCG is important for mediating its proteasome-inhibitory activity, EGCG is very unstable under physiological conditions. Therefore, a series of analogs were synthesized aiming to improve stability and bioavailability of EGCG. Among them, peracetate-protected or the prodrug of EGCG was found to have increased bioavailability, stability, and proteasome-inhibitory activities against various human cancer cells and tumors compared to EGCG, suggesting its potential use for cancer prevention and treatment. Epidemiological studies have indicated that green tea consumption is associated with the reduced risk of cancers, especially associated with the reduced risk of late stage of cancers. This risk reduction may be attributed not only to proteasome inhibition, but also to numerous other intracellular molecules targeted by EGCG that are involved in cell cycle regulation, apoptosis, angiogenesis, and metastasis.

Fig. 1

Chemical structures of EGCG and its synthetic analogs and prodrugs.

Fig. 2. Docking of EGCG to the chymotrypsin site of the yeast 20S proteasome

A stick figure of EGCG with a transparent surface is used to show the proximity between EGCG and Thr 1, represented by a space-filling model (A). The dotted line represents a distance of 3.18 A from the hydroxyl of Thr 1 to the carbonyl carbon of EGCG. EGCG filled most of the binding cleft, which was seen by drawing a water-accessible mesh surface around EGCG (B) when docked into the binding site as depicted by a ribbon structure of the β5 subunit (C). The S1 pocket of the β5 subunit is defined by the hydrophobic residues, Ala 20, Val 31, Ile 35, Met 45, Ala 49, and Gln 53. The hydrophobic portion of A ring on EGCG is oriented in the middle of the S1 pocket between the side-chains of Ala 49, Ala 20, and Lys 33 (D). This conformation would allow the hydrophilic hydroxyls of the A ring to project out of the two sides of the S1 hydrophobic pocket and participate in H-bonding. In addition, the sidewalls of the S1 pocket that interact with EGCG are created by Met 45 and Val 31 (D). Reproduced with permission from Proteins: Structure, Function, and Bioinformatics.