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Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance

文献类型：期刊论文

作者Liu, Bo3; Yu, Xueni1,2; Liu, Liping1,2; Wang, Lei1,2; Wang, Jie3; Huang, Qianqian3; Xu, Zhongliang1,2; Luo, Cheng1,2,3; Lou, Liguang1,2; Huang, Wei1,2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-02-23
卷号66期号:4页码:2550-2565
DOI10.1021/acs.jmedchem.2c01424
文献子类Article
英文摘要Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (D)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 mu M, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.
WOS关键词DIVERSITY-ORIENTED SYNTHESIS ; JATROPHANE DITERPENOIDS ; VINCRISTINE RESISTANCE ; CYCLOSPORINE-A ; IN-VIVO ; CANCER ; REVERSAL ; CHEMOTHERAPY ; COMBINATION ; MECHANISMS
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000930529700001
源URL[http://119.78.100.183/handle/2S10ELR8/309706]  
专题新药研究国家重点实验室
通讯作者Lou, Liguang; Huang, Wei; Yang, Weibo
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China;
推荐引用方式
GB/T 7714		 Liu, Bo,Yu, Xueni,Liu, Liping,et al. Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(4):2550-2565.
APA Liu, Bo.,Yu, Xueni.,Liu, Liping.,Wang, Lei.,Wang, Jie.,...&Yang, Weibo.(2023).Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.JOURNAL OF MEDICINAL CHEMISTRY,66(4),2550-2565.
MLA Liu, Bo,et al."Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance".JOURNAL OF MEDICINAL CHEMISTRY 66.4(2023):2550-2565.

入库方式： OAI收割

来源：上海药物研究所

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