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Synthetic epigallocatechin gallafe (EGGG) analogs

A technology of analogs and compounds, applied in the field of synthetic epigallocatechin gallate (EGCG) analogs, can solve the problems of reduced biological activity, short half-life, limited clinical use of green tea polyphenols, etc.

Inactive Publication Date: 2014-09-03
THE HONG KONG POLYTECHNIC UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the low absorption rate, instability, and short half-life of EGCG due to metabolic transformations reduce its bioavailability, thereby limiting the clinical use of green tea polyphenols
The hydroxyl groups of (-)-EGCG are modified through biotransformation reactions including methylation, glucuronidation, and sulfation, resulting in reduced bioactivity in vivo

Method used

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  • Synthetic epigallocatechin gallafe (EGGG) analogs
  • Synthetic epigallocatechin gallafe (EGGG) analogs
  • Synthetic epigallocatechin gallafe (EGGG) analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] Preparation of cis-1,2,3,4-tetrahydronaphthalene-2,3-diol (12)

[0247] Acetone / H to 1,4-dihydronaphthalene (500mg, 3.84mmol) 2 Add NMO H to O (3.0 / 1.0mL) solution 2 O solution (1.43mL, 50%wt, 6.90mmol) and OsO 4 2-methyl-2-propanol solution (313 μL, 2.5% wt., 25 μmol). The mixture was stirred at room temperature for 16 hours. Add saturated Na 2 SO 3 aqueous solution (10 mL), and stirred for an additional 15 minutes. Join H 2 O (10 mL) and EtOAc (30 mL) and stirred for 5 minutes. The aqueous phase was extracted with EtOAc (4 x 30 mL). The combined organic phases were washed with brine (20 mL), and washed with anhydrous Na 2 SO 4 dry. The solution was concentrated by rotary evaporator and dried in vacuo to give the crude product which was chromatographed on silica gel (Hexane / EtOAc / CH 2 Cl 2 =5 / 1 / 1) to afford 521.7 mg (83%) of the title compound as a white solid. 1 H NMR (acetone-d 6 ,300MHz)δ7.13(m,2H),7.09(m,2H),4.11(t,J=5.4,2H),3.01(m,4H),2.36(s,2H); 1...

Embodiment 2

[0378] Inhibition of the chymotrypsin-like activity of purified 20S proteasomes

[0379] refer to figure 2 , EGCG effectively inhibited proteasomal chymotrypsin activity, which was consistent with our previous observations. Compound 5 is a substituted tetralin, which can be regarded as an analog of EGCG, which inhibits the chymotrypsin-like activity of the proteasome, IC 50 The value is 19 μM. Compound 16 lacking the gallate moiety did not inhibit proteasomal chymotrypsin activity even at a concentration of 50 μΜ. On the other hand, compound 7 (IC 50 =29 μM) was only slightly less active than EGCG or 5 despite the lack of gallate. Not surprisingly, compound 21 has no proteasome inhibitory activity even at 50 μM. When acetylated, the resulting derivatives 4, 6, 8, 17 and 22 showed no proteasome inhibition under these conditions.

Embodiment 3

[0381] COMT affects the proteasome inhibitory activity of derivatives 5 and 7

[0382] Lysates of human breast cancer MDA-MB-231 cells containing high COMT activity were treated with different concentrations of compound 5 or 7. image 3 It was shown that compound 7 at concentrations in the range of 1-10 μM inhibited between 18-51% of proteasome activity, while compound 5 only inhibited 10-16% of proteasome activity under the same conditions. Compound 7 was not expected to be more active than compound 5 in inhibiting the proteasomal activity of MDA-MB-231 cell lysates based on the data in Example 2. These results suggest that compound 5 may be more sensitive to biotransformation by COMT than compound 7. In contrast, 10 μM EGCG only inhibited the chymotrypsin-like activity of these cells by about 22%. Thus, consistent with previous reports, EGCG is also sensitive to methylation by COMT (H., Lu, X. Meng, C.S. Yang, Drug Metabolism and Disposition; 31; 572, 2003).

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Abstract

Synthetic polyphenolic compounds of formula (I), their modes of synthesis, and pharmaceutical compositions thereof are provided herein. Use of the compounds and compositions described herein for treating cancer and for treating metabolic disorders is also provided.

Description

technical field [0001] The present invention relates to novel compounds and compositions comprising epigallocatechin gallate analogs, in particular for use as proteasome inhibitors and / or AMPK activators and for the treatment of cancer. Background technique [0002] The ubiquitin-proteasome system (UPS) is responsible for the highly regulated degradation of intracellular proteins that play important roles in cellular functions (Hershko A (2005) Cell Death Differ. 12, 1191 ). One compound targeting UPS is the proteasome inhibitor bortezomib (Velcade TM (Velcade TM )), which is clinically used in the treatment of patients with multiple myeloma or mantle cell lymphoma. Velcade TM is an N-substituted dipeptidylboronic acid. Another proteasome inhibitor is salinosporamide, a marine natural product characterized by functionalized beta lactones (Feling RH et al., (2003) Angew.Chem.Int.Ed.Engl .42, 355). Another proteasome inhibitor is epigallocatechin gallate (EGCG) and its a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/84A61P3/00A61P3/08A61P35/00C07C229/60C07C233/55C07C271/28
CPCC07C271/28C07C69/84C12N9/12C07C233/11A61K45/06A61K31/245A61K31/24C07C69/92C12Y207/11031C07C2102/10C07C229/60A61K31/235C07C69/76C07C233/54C07C69/86C07C2602/10A61P3/00A61P3/04A61P3/06A61P3/08A61P3/10A61P5/50A61P35/00A61P35/02A61P43/00
Inventor 德恒·陈斯里达尔·帕穆庆平·窦迪·陈
Owner THE HONG KONG POLYTECHNIC UNIV
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