Yang Chao, Wong Iris L K, Peng Kai, Liu Zhen, Wang Peng, Jiang Tingfu, Jiang Tao, Chow Larry M C, Wan Sheng Biao
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.
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.
Eur J Med Chem. 2017 Jan 5;125:795-806. doi: 10.1016/j.ejmech.2016.09.070. Epub 2016 Sep 22.
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 EC 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.
在本研究中，共合成了25种新型宁加林B类似物，并在过表达P-糖蛋白的乳腺癌细胞系LCC6MDR中评估了它们对P-糖蛋白的调节活性。初步构效关系研究表明，A环及其两个甲氧基是P-糖蛋白抑制活性的重要药效基团。在所有衍生物中，23是最有效的P-糖蛋白调节剂，在逆转紫杉醇、阿霉素、长春碱和长春新碱耐药性方面的半数效应浓度为120 - 165 nM。与维拉帕米相比，其使用相对安全，选择性指数至少大于606。机制研究表明，化合物23通过抑制P-糖蛋白的转运活性来逆转P-糖蛋白介导的耐药性，从而恢复细胞内药物蓄积。总之，我们的研究表明，宁加林B类似物23是一种无细胞毒性且有效的P-糖蛋白化学增敏剂，未来可用于逆转P-糖蛋白介导的临床癌症耐药性。
