Dissertation > Medicine, health > Chinese Medicine > Of Pharmacy > Traditional Chinese medicine chemical

Design, Synthesis of (-)-EGCG Methylated Derivatives and Evaluation of Anti-MDR Activity

Author LiXueMin
Tutor WanShengBiao
School Ocean University of China
Course Pharmaceutical Engineering
Keywords multidrug resistance semi-synthesis (-)-EGCG methylated derivatives P-gp inhibitors bioactivity
CLC R284
Type Master's thesis
Year 2011
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Multidrug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. A major mechanism underlying this multidrug resistance is overexpression of P-glycoprotein (P-gp), which belongs to the superfamily of ATP binding cassette (ABC) transporter proteins and behaves as an energy-dependent efflux pump of anticancer agents such as phospholipids, sterols, bile salts, and amphipathic drugs. This effect lead to the decline of chemotherapeutic agent concentration within human cells.Great efforts have been made to discover effective and safe MDR inhibitors over the past two decades. So far, most of tumor MDR reversal agents all have some shortcomings, such as cardiovascular system toxic, kidney toxicity. The majority of P-gp inhibitors are passed directly with P-gp drug binding sites, competitive or noncompetitive inhibit the function of P-gp. However, their unacceptable toxicity, low selectivity and combining ability precluded them from clinical use.(–)-Epigallocatechin gallate ((-)-EGCG), a major component in green tea extracts, can tightly bound to the ATP-binding site of NBD2 of P-gp and reverse MDR. Study also show that (-)-EGCG methylated derivatives have good activity. However, its cheap, non-toxic, potent characteristics encourage us to optimize the structure of (-)-EGCG to get higher anti-MDR activity .In our recent study, several (-)-EGCG methylated derivatives have been synthesized and evaluated as non-toxic MDR reversal agents of cancer cells. compounds 14, 15 with a concentration of 1μM can sensitize LCC6MDR cells towards paclitaxel by 8.1-fold and 18.3-fold respectively. Based on these results, eight (-)- EGCG methylated derivatives are designed and synthesized.Two (-)-EGCG methylated derivatives with fluoro group, two (-)-EGCG analogs with, and different alkyl groups side substituted (-)-EGCG are designed and synthesized according to structure-activity relationship analysis of some present P-gp inhibitors. Among these (-)-EGCG methylated derivatives, 1μM of compounds 8, 12 have gave a significant higher RF 12.1and 9.8 value of P-gp, and the structure-activity relationship is discussed and these results reveale that our design is right.All of these six (-)-EGCG methylated derivatives are fist reported and synthesized. The semi-synthesis methods are optimized, and two compounds have a good P-gp inhibition activity. These results will improve the study of (-)-EGCG analogs as P-gp inhibitors and these tumor MDR reversal agents can directionally provide the basis of finding catechins with high-efficiency, low-toxic characters.

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