Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors

Bioorg Med Chem. 2015 Sep 1;23(17):5566-73. doi: 10.1016/j.bmc.2015.07.027.

Zhen Wang ¹, Iris L K Wong ², Fu Xing Li ¹, Chao Yang ¹, Zhen Liu ¹, Tao Jiang ³, Ting Fu Jiang ³, Larry M C Chow ⁴, Sheng Biao Wan ⁵

Affiliations

1 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, China.
3 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
4 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China; State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, China. Electronic address: larry.chow@polyu.edu.hk.
5 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: biaowan@ouc.edu.cn.

PMID: 26233798 DOI: 10.1016/j.bmc.2015.07.027

Abstract

In the present study, a total of 9 novel permethyl ningalin B analogs have been synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast Cancer cell line LCC6MDR. Among these derivatives, compound 12 with dimethoxy groups at rings A and B and tri-substitution at ring C with ortho-methoxyethylmorpholine, meta-bromo and para-benzyloxy groups displays the most potent P-gp modulating activity with EC50 of 423 nM to reverse paclitaxel resistance. It is non-toxic towards L929 fibroblast with IC50 greater than 100 μM and with selective index greater than 236. Its mechanism to reverse P-gp mediated drug resistance is by virtue of inhibiting transport activity of P-gp, restoring intracellular drug accumulation and eventually chemosensitizing the Cancer cells to Anticancer drug again. Moreover, compound 12 showed better solubility (405 ng/mL) than hit compound 1 in phosphate buffer (pH 4.0). In summary, our study demonstrates that permethyl ningalin B derivative 12 is non-toxic and efficient P-gp inhibitor that is a potential candidate to be used clinically to reverse P-gp mediated Cancer Drug Resistance.

Keywords

ATP-binding cassette (ABC) transporter; Multidrug resistance (MDR); P-glycoprotein (P-gp); P-gp chemosensitizer; Permethyl ningalin B.

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