A potential prodrug for a green tea polyphenol proteasome inhibitor: evaluation of the peracetate ester of (-)-epigallocatechin gallate [(-)-EGCG].
Green tea has been shown to have many biological effects, including effects on metabolism, angiogenesis, oxidation, and cell proliferation. Unfortunately, the most abundant green tea polyphenol (-)-epigallocatechin gallate or (-)-EGCG is very unstable in neutral or alkaline medium. This instability leads to a low bioavailability. In an attempt to enhance the stability of (-)-EGCG, we introduced peracetate protection groups on the reactive hydroxyls of (-)-EGCG (noted in text as 1). HPLC analysis shows that the protected (-)-EGCG analog is six times more stable than natural (-)-EGCG under slightly alkaline conditions. A series of bioassays show that 1 has no inhibitory activity against a purified 20S proteasome in vitro, but exhibits increased proteasome-inhibitory activity in intact leukemic cells over natural (-)-EGCG, indicating an intercellular conversion. Inhibition of cellular proteasome activity by 1 is associated with induction of cell death. Therefore, our results indicate that the protected analog 1 may function as a prodrug of the green tea polyphenol proteasome inhibitor (-)-EGCG.
Department of Applied Biology and Chemical Technology and the Open Laboratory for Chiral Technology, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong SAR, China.
Wai Har
WH
Lam
Aslamuzzaman
A
Kazi
Deborah J
DJ
Kuhn
Larry M C
LM
Chow
Albert S C
AS
Chan
Q Ping
QP
Dou
Tak Hang
TH
Chan
D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004952:Esters; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D010463:Peracetic Acid / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013662:Tea
D004952:Esters; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D011355:Prodrugs; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D046988:Proteasome Endopeptidase Complex; D010463:Peracetic Acid