Evaluation of proteasome-inhibitory and apoptosis-inducing potencies of novel (-)-EGCG analogs and their prodrugs.
The anti-cancer and cancer-preventive effects of green tea and its main constituent (-)-epigallocatechin gallate [(-)-EGCG] are well documented by a variety of studies, including epidemiological, cell culture, animal, and clinical studies. While (-)-EGCG remains the most potent polyphenol in green tea, it is very unstable in neutral or alkaline conditions (i.e. physiologic pH). In an effort to discover more stable polyphenol proteasome inhibitors, we synthesized several novel (-)-EGCG analogs with -OH groups eliminated from the B- and/or D-rings. In addition, we also synthesized their putative prodrugs with -OH groups protected by peracetate that can be removed by cellular cytosolic esterases. We first examined the structure-activity relationship of these unprotected and protected compounds to their proteasome-inhibitory potentials. We found that decreasing -OH groups from either the B- or D-ring leads to diminished proteasome-inhibitory activity in vitro. However, in cultured tumor cells only the protected analogs were capable of potently inhibiting the proteasome activity. Furthermore, these protected analogs induced apoptotic cell death in a tumor cell-specific manner. The superior efficacy of the protected (-)-EGCG analogs indicates the formation of an entirely new compound(s) in intact tumor cells. These data suggest that the B-ring/D-ring peracetate-protected EGCG analogs have great potential to be developed into novel anti-cancer and cancer-preventive agents.
Landis-Piwowar
Kristin R
KR
The Prevention Program, Barbara Ann Karmanos Cancer Institute, Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA. doup@karmanos.org
Kuhn
Deborah J
DJ
Wan
Sheng Biao
SB
Chen
Di
D
Chan
Tak Hang
TH
Dou
Q Ping
QP
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D011355:Prodrugs / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D013662:Tea / Q000378:metabolism
D016588:Anticarcinogenic Agents; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D011355:Prodrugs; D061988:Proteasome Inhibitors; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate