Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein inhibitors

Eur J Med Chem. 2017 Jan 5:125:795-806. doi: 10.1016/j.ejmech.2016.09.070.

Chao Yang ¹, Iris L K Wong ², Kai Peng ¹, Zhen Liu ¹, Peng Wang ¹, Tingfu Jiang ¹, Tao Jiang ¹, Larry M C Chow ³, Sheng Biao Wan ⁴

Affiliations

1 Key Laboratory of Marine Drugs, Ministry of Education, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, 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 SAR, China; State Key Laboratory for Chirosciences, The Hong Kong Polytechnic University, Hong Kong SAR, China.
3 Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China; State Key Laboratory for Chirosciences, The Hong Kong Polytechnic University, Hong Kong SAR, China. Electronic address: larry.chow@polyu.edu.hk.
4 Key Laboratory of Marine Drugs, Ministry of Education, Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, 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: 27750197 DOI: 10.1016/j.ejmech.2016.09.070

Abstract

In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast Cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC₅₀ of 120-165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil. Mechanistic study demonstrates that compound 23 reverses P-gp mediated drug resistance by inhibiting transport activity of P-gp, thereby restoring intracellular drug accumulation. In summary, our study demonstrates that ningalin B analogue 23 is a non-cytotoxic and effective P-gp chemosensitizer that can be used in the future for reversing P-gp mediated clinical Cancer Drug Resistance.

Keywords

ATP-Binding cassette (ABC) transporter; Multidrug resistance (MDR); Ningalin B; P-glycoprotein (P-gp); P-gp chemosensitizer.

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