Dissertation > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug

Design and Synthesis of Polyphenol Compounds as Multirug Resistence Reversal Agents

Author ZhangXiaoZuo
Tutor WanShengBiao
School Ocean University of China
Course Pharmaceutical Engineering
Keywords multi-drug resistence P-glycoprotein Ningalin B EGCG
Type Master's thesis
Year 2011
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Cancer has been one of the serious diseases threatening human health. Development of new effective antitumor drugs become the hot spot in the medicine research. Chemotherapy is one of the major means of tumor therapy. However, its clinical efficacy is frequently restricted by primary or clinically acquired resistance to drugs. The multi-drug resistance (MDR) is the most common cause of chemotherapy failure. The treatment of chemoresistant tumors represents an important challenge in the field of oncology.Primary or acquired overexpression of ATP-dependent transporters, including P-glycoprotein (Pgp, MDR1 protein), Multidrug resistance-associated protein(MRP), breast cancer resistance protein(BCRP), is a major cause of multidrug resistance. P-glycoprotein (Pgp; MDR1; ABCB1), which is best studied, is the first mammalian ABC protein to be identified. There are three generations of drugs for P-glycoprotein mediated multi-drug resistance. First-generation modulators of Pgp included compounds like verapamil (a calcium channel blocker) and cyclosporin which is already employed to treat other medical conditions. However, these molecules generally cause excessively high Adverse Drug Reactions yet show low effectiveness.Second-generation modulators are often derivatives of first-generation molecules, which displays better efficacy at low doses. However, significant increases in toxicity and decreased clearance of the chemotherapeutic drug were often observed. Third-generation modulators were developed to improve on the properties of the second generation compounds. Some highly selective and very potent inhibitors were produced, which are effective in the nanomolar concentration range. Searching for new P-glycoprotein mediated MDR reversal agents has become a hotspot. Recently multidrug resistance associated protein (MRP1) and breast cancer resistance protein, (BCRP) also appear to function as clinically relevant drug efflux pumps. So developing safe and efficient and specific MDR reversal agents for tumor is a great urgency.In our recent study, a series of permethyl ningalin B analogues were synthesized and evaluated as non-toxic MDR reversal agents of cancer cells. 1μM of two of compounds can sensitize LCC6MDR cells towards paclitaxel by 18.2-fold and 9.9-fold respectively. A synergy on modulating P-gp was noted when the two compounds were used together. Combination of 0.5μM of each of the two compounds resulted in a 66-fold sensitization of LCC6MDR cells towards paclitaxel. Meanwhile we synthesized and evaluated series of permethyl EGCG derivatives. 1μM of four compounds each can sensitize LCC6MDR cells towards paclitaxel by 18 to 53-fold.Based on the previous study, seven polyphenol compounds targeted to P-gp are designed and synthesized. All target compounds are novel and some of their structures are confirmed by 1HNMR, 13CNMR and HRMS.The in vitro bioactivity test of the synthetic compounds show that compounds 21 display significant P-gp mediated MDR reversal activity on reversing paclitaxel resistance of breast cancer cell lines (LCC6MDR ), which causes about 39.6-fold hyper-sensitization of LCC6MDR towards paclitaxel. However, all compounds in the in vitro bioactivity test towards BCRP and MRP1 show no obvious activity.In this article: based on the established reacting route, the parameters of reactions are altered to reduce the experimental difficulty and increase the production yield from 5.6% to 16.5%; Five Ningalin B analogues and two EGCG analogues are synthetized; The cell toxicity tests and in vitro bioactivity tests towards three targets is carried out to five of the compounds. The preliminary bioactivity is evaluated.

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