title: Optimization of permethyl ningalin B analogs as P-glycoprotein inhibitors.
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.
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Fu Xing
authors.initials: FX
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
authors.forename: Ting Fu
authors.initials: TF
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
authors.affiliation: 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.
authors.forename: Sheng Biao
authors.initials: SB
authors.lastname: Wan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D006575:Heterocyclic Compounds, 3-Ring; C409782:ningalin B
keywords: ATP-binding cassette (ABC) transporter; Multidrug resistance (MDR); P-glycoprotein (P-gp); P-gp chemosensitizer; Permethyl ningalin B