Structure-activity relationships of synthetic analogs of (-)-epigallocatechin-3-gallate as proteasome inhibitors.
BACKGROUND
Cancer-related molecular targets of green tea polyphenols, such as (-)-epigallocatechin-3-gallate [(-)-EGCG], remain unknown. We previously showed that (-)-EGCG is a potent and specific inhibitor of the proteasomal chymotrypsin-like activity in vitro and in vivo.


METHODS
EGCG amides and five simple analogs were prepared by enantioselective synthesis. Proteasome inhibition in vitro was measured by fluorogenic substrate assay and in vivo by accumulation of proteasome target proteins (p27, IkappaB-alpha and Bax). Inhibition of tumor cell proliferation was determined by G1 arrest, DNA fragmentation and colony formation inhibition.


RESULTS
EGCG analogs with modifications in the A-ring, C-ring or ester bond inhibit the chymotrypsin-like activity of purified 20S proteasome with altered potencies. However, these compounds were able to potently inhibit the proteasome activity in vivo and also suppress colony formation of prostate cancer LNCaP cells. Some compounds caused G1 arrest and DNA fragmentation in leukemia Jurkat T cells. However, these EGCG analogs caused no or little proteasome inhibition in normal or nontransformed cells.


CONCLUSIONS
The A-ring and gallate ester/amide bond are essential for the proteasome-inhibitory function of (-)-EGCG.
Kazi
Aslamuzzaman
A
Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida 33612, USA.
Wang
Zhigang
Z
Kumar
Naveen
N
Falsetti
Samuel C
SC
Chan
Tak-Hang
TH
Dou
Q Ping
QP
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D000972:Antineoplastic Agents, Phytogenic; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009097:Multienzyme Complexes; D013662:Tea; C107792:UBQLN1 protein, human; D002392:Catechin; C045651:epigallocatechin gallate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex