Polyphenol proteasome inhibitors, synthesis, and methods of use
Inventors
Dou, Q. Ping • Chan, Tak-Hang • Smith, David M.
Assignees
Hong Kong Polytechnic University HKPU • University of South Florida • University of South Florida St Petersburg
Publication Number
US-7358383-B2
Publication Date
2008-04-15
Expiration Date
2024-01-26
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Abstract
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.
Core Innovation
The invention provides synthetic green tea-derived polyphenolic compounds, specifically (−)-EGCG-amides, (+)-EGCG-amides, their pharmaceutically acceptable salts, analogs, and compounds represented by proprietary structural formulas. These synthetic polyphenols are shown to potently inhibit the chymotrypsin-like activity of the proteasome’s β5 subunit. Methods for synthesizing these compounds, allowing production of desired stereoisomers, are detailed within the disclosure.
The core problem addressed is the need for additional and improved options for inhibiting proteasome activity, particularly for anti-cancer therapy. While naturally occurring green tea polyphenols such as (−)-EGCG exhibit proteasome-inhibitory activity with selectivity for tumor cells, the mechanisms of their action and the scope of structurally effective analogs have remained unclear. In addition, issues of stability and potency in clinical contexts create a need for synthetic analogs with robust and selective activity.
This invention further provides pharmaceutical compositions comprising these synthetic polyphenolic compounds, which are formulated with pharmaceutically acceptable carriers for use in inhibiting proteasomal activity and treating cancers. Methods of use encompass administration routes such as oral, parenteral, topical, and inhalational delivery. The invention also covers methods for inhibiting chymotrypsin-like proteasome activity in vitro or in vivo and for treating various cancers by administering an effective amount of the disclosed compositions.
Claims Coverage
The independent claims of this patent cover three main inventive features related to synthetic green tea polyphenol compounds, their specific compound structures, and methods for their synthesis.
Synthetic green tea polyphenol compound compositions
A composition comprising at least one compound having the structure of a formula selected from the group consisting of specific green tea polyphenol analogs, including (−)-EGCG-amide, (+)-EGCG-amide, and related structures explicitly provided in the patent.
Specific optically pure or mixture polyphenol compounds
The composition wherein the compound may have less than 100% optical purity or may be optically pure, enabling coverage of both enantiomerically enriched and racemic mixtures of the polyphenolic inhibitor.
Synthesis method for EGCG amide analogs
A method for synthesizing a compound having the structure of formula B, involving coupling a specified precursor with an acid derivative (acyl halide, anhydride, or in the presence of a condensing agent) optionally followed by deprotection, including preferred reagents and methods as described for isolating fully protected gallate esters and subsequent deprotection steps, such as treatment with Pd(OH)2 and H2.
The independent claims encompass pharmaceutical compositions featuring defined synthetic green tea polyphenol analogs, coverage of different optical purities, and comprehensive synthetic methods for preparing these analogs.
Stated Advantages
The synthetic polyphenolic compounds are potent inhibitors of proteasomal chymotrypsin-like activity.
The compounds and methods allow for the production of stereoisomers as desired.
Pharmaceutical compositions can be easily formulated for various administration routes (oral, topical, parenteral, etc.).
Selectivity is demonstrated in targeting tumor and transformed cells over non-transformed or normal cells.
Amide analogs offer increased stability compared to natural ester bond-containing polyphenols.
Documented Applications
Inhibition of chymotrypsin-like and chymotrypsin activity of 20S and 26S proteasomes in vitro and in vivo.
Treatment of cancers, including prostate cancer, leukemia, hormone dependent cancers, breast cancer, colon cancer, lung cancer, epidermal cancer, liver cancer, esophageal cancer, stomach cancer, brain cancer, and kidney cancer.
Inhibition of cancer cell growth.
Increasing the proportion of G1 phase cells in a cell population.
Induction of apoptosis in cancer cells.
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