5,7-Bis(benzyloxy)-2-[3,4,5-tris(benzyloxy)phenyl]chroman-3-yl 3-(benzyloxy)benzoate; antiproliferative, antitumor agent; reducing tumor cell growth; more potent, better bioavailability than catechin
Inventors
Chan, Tak-Hang • Lam, Wai-Har • Chow, Larry Ming-Cheung • DOU, QING PING • Kuhn, Deborah Joyce • Kazi, Aslamuzzaman
Assignees
McGill University • Hong Kong Polytechnic University HKPU • Wayne State University • University of South Florida • University of South Florida St Petersburg
Publication Number
US-7544816-B2
Publication Date
2009-06-09
Expiration Date
2024-08-19
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Abstract
(−)-EGCG, the most abundant catechin, was found to be chemopreventive and anticancer agent. However, (−)-EGCG has at least one limitation: it gives poor bioavailability. This invention provides compounds of generally formula 10, wherein R1 is selected from the group of —H and C1 to C6 acyl group; R2, R3, and R4 are each independently selected from the group of —H, —OH, and C1 to C6 acyloxyl group; and at least one of R2, R3, or R4 is —H. The derivatives of (−)-EGCG that is at least as potent as (−)-EGCG. The carboxylate protected forms of (−)-EGCG and its derivatives are found to be more stable than the unprotected forms, which can be used as proteasome inhibitors to reduce tumor cell growth.
Core Innovation
(−)-Epigallocatechin gallate (EGCG), a polyphenol found in green tea, is known for its chemopreventive and anticancer properties but exhibits poor bioavailability in vivo due to instability in neutral or alkaline environments. This instability leads to low absorption in the body, limiting the clinical potential of (−)-EGCG as an anticancer agent through proteasome inhibition.
The invention provides novel derivatives of (−)-EGCG described by a specific general formula, where R1, R2, R3, and R4 are selectively hydrogen, hydroxyl, or acyl (C1 to C6 acyl or acyloxyl) groups, with at least one substituent as hydrogen. These derivatives, especially in their carboxylate-protected forms (peracetate or other acyl-protected groups), are demonstrated to be more chemically stable under physiological conditions and have improved bioavailability compared to unprotected (−)-EGCG.
The protected forms of these derivatives function as proteasome inhibitors and are able to reduce tumor cell growth. In vitro and in vivo studies described in the patent show these compounds have improved stability and are at least as potent as (−)-EGCG in inhibiting proteasome activity, decreasing cellular proliferation, and inducing apoptosis in tumor cells.
Claims Coverage
There are multiple independent inventive features claimed, focusing on new compound structures, methods of use for treating tumor growth, and methods of proteasome inhibition.
Compounds for inhibiting proteasome with specific substituents
A compound having a formula where: - R1 is selected from —H and C1 to C6 acyl group. - R2, R3, and R4 are each independently —H, —OH, or C1 to C6 acyloxyl group. - At least one of R2, R3, R4 is —H. - If R1 is H and R2 = R3 = R4, then R2 is not —OH. The claims cover specific variants where substituents R1, R2, and R3 are precisely defined (such as R1 being —(CO)—CH3 and R2 being —O—(CO)—CH3).
Method of reducing tumor cell growth by administering the claimed compounds
A method comprising administering an effective amount of a compound of the defined formula (as above) to reduce tumor cell growth. This includes specified combinations for R1, R2, and R3 as detailed in the claims.
Method of inhibiting proteasome by administering the claimed compounds
A method comprising administering an effective amount of a compound with the specified formula to inhibit proteasome activity. Specific substituent options for R1, R2, R3, and R4 are further delineated.
Protected forms of (−)-EGCG and its derivatives for proteasome inhibition
The invention covers carboxylate-protected (e.g., acetate-protected) derivatives of (−)-EGCG and its structural analogs, which exhibit stability and proteasome-inhibitory properties, as well as their use in reducing tumor cell growth.
The inventive features provide new, chemically defined derivatives of (−)-EGCG with improved stability and bioavailability, and explicitly claim their use for proteasome inhibition and reducing tumor cell growth.
Stated Advantages
Protected derivatives are more stable in physiological (neutral/alkaline) conditions than unprotected EGCG.
The compounds are at least as potent as (−)-EGCG in inhibiting proteasome activity and reducing tumor cell growth.
The derivatives exhibit improved bioavailability compared to (−)-EGCG.
Protected forms (prodrugs) remain inactive until hydrolyzed in vivo, reducing systemic toxicity.
The compounds are more potent apoptosis inducers in tumor cells than unprotected analogs.
Selective induction of apoptosis in tumor and transformed cells, with minimal effect on normal cells.
Documented Applications
Use as proteasome inhibitors to reduce tumor cell growth.
Method for inhibiting proteasome activity in vivo.
Method for reducing proliferation and inducing apoptosis in tumor cells, including leukemia, breast cancer, and prostate cancer cells.
Use in the manufacture of medicaments for reducing tumor cell growth.
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