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Extending the structure-activity relationship study of marine natural ningalin B analogues as P-glycoprotein
Chao Yang1, Iris L K Wong2, Kai Peng1
1Key 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.
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.