University of South Florida

The Hong Kong Polytechnic University

Mcgill University

David M Smith

Q Ping Dou

Tak-Hang Chan

Edward Turos

Sangkil Nam

The present invention relates to synthetic green tea derived polyphenolic compounds, their modes of syntheses, and their use in inhibiting proteasomal activity and in treating cancers. The present invention is also directed to pharmaceutical compositions useful in methods of inhibiting proteasomes and of treating cancers.

Polyphenol proteasome inhibitors, synthesis, and methods of use

The subject invention concerns N-thiolated &#x3b2;-lactam compounds of formula A, wherein Ris a hydrocarbon group having 1-8 carbon atoms; Ris an organothio group; and Ris alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, and analogs and pharmaceutically acceptable salts, esters and amides thereof. The subject invention also concerns methods for inducing tumor cell death or inhibiting tumor cell proliferation, and methods for inducing DNA damage, inhibiting DNA replication, activating p38 MAP kinase, or activating caspase cascade activation, or releasing cytochrome C from mitochondria into the cytoplasm in a tumor cell. Methods for treating cancer using N-thiolated &#x3b2;-lactam compounds, as well as pharmaceutical compositions comprising the same are further disclosed.

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The subject invention concerns N-thiolated &#x3b2;-lactam compounds of formula A,wherein Ris a hydrocarbon group having 1&#x2013;8 carbon atoms; Ris an organothio group; and Ris alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, and analogs and pharmaceutically acceptable salts, esters and amides thereof. The subject invention also concerns methods for inducing tumor cell death or inhibiting tumor cell proliferation, and methods for inducing DNA damage, inhibiting DNA replication, activating p38 MAP kinase, or activating caspase cascade activation, or releasing cytochrome C from mitochondria into the cytoplasm in a tumor cell. Methods for treating cancer using N-thiolated &#x3b2;-lactam compounds, as well as pharmaceutical compositions comprising the same are further disclosed.

Methods for preventing and treating cancer using N-thiolated &#x3b2;-lactam compounds and analogs thereof

Disclosed herein are ester-bond containing tea polyphenols that has a susceptibility to nucleophilic attack, their analogs and pharmaceutically acceptable salts, method for inhibiting proteasomal chymotrypsin-like activity in vivo and in vitro, methods for cancer treatment with tea-derived polyphenols, such as EGCG, ECG, GCG, or CG, as well as pharmaceutical compositions comprising the same.

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Boston, MA, United States of America

David M Smith