Synthesis and evaluation of stereoisomers of methylated catechin and epigallocatechin derivatives on modulating P-glycoprotein-mediated multidrug resistance in cancers

Eur J Med Chem. 2021 Dec 15:226:113795. doi: 10.1016/j.ejmech.2021.113795.

Iris L K Wong ¹, Xing-Kai Wang ², Zhen Liu ³, Wenqin Sun ¹, Fu-Xing Li ², Bao-Chao Wang ², Peng Li ², Sheng-Biao Wan ⁴, Larry M C Chow ⁵

Affiliations

1 Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China.
2 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
3 Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China; Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
4 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China. Electronic address: biaowan@ouc.edu.cn.
5 Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong, China. Electronic address: larry.chow@polyu.edu.hk.

PMID: 34597896 DOI: 10.1016/j.ejmech.2021.113795

Abstract

P-glycoprotein (P-gp; ABCB1)-mediated drug efflux causes multidrug resistance in Cancer. Previous synthetic methylated epigallocatechin (EGC) possessed promising P-gp modulating activity. In order to further improve the potency, we have synthesized some novel stereoisomers of methylated epigallocatechin (EGC) and gallocatechin (GC) as well as epicatechin (EC) and catechin (C). The (2R, 3S)-trans-methylated C derivative 25 and the (2R, 3R)-cis-methylated EC derivative 31, both containing dimethyoxylation at ring B, tri-methoxylation at ring D and oxycarbonylphenylcarbamoyl linker between ring D and C3, are the most potent in reversing P-gp mediated drug resistance with EC₅₀ ranged from 32 nM to 93 nM. They are non-toxic to fibroblast with IC₅₀ > 100 μM. They can inhibit the P-gp mediated drug efflux and restore the intracellular drug concentration to a cytotoxic level. They do not downregulate surface P-gp protein level to enhance drug retention. They are specific for P-gp with no or low modulating activity towards MRP1- or BCRP-mediated drug resistance. In summary, methylated C 25 and EC 31 derivatives represent a new class of potent, specific and non-toxic P-gp modulator.

Keywords

Catechin (C); Epicatechin (EC); Epigallocatechin (EGC); Gallocatechin (GC); P-glycoprotein (P-gp).

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