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

  • J Med Chem. 2023 Feb 23;66(4):2550-2565. doi: 10.1021/acs.jmedchem.2c01424.
Bo Liu  1 ,  Xueni Yu  2  3 ,  Liping Liu  2  3 ,  Lei Wang  2  3 ,  Jie Wang  1 ,  Qianqian Huang  1 ,  Zhongliang Xu  2  3 ,  Cheng Luo  1  2  3 ,  Liguang Lou  2  3 ,  Wei Huang  1  2  3 ,  Weibo Yang  1  2  3
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 2. State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 36728755 DOI: 10.1021/acs.jmedchem.2c01424
Abstract

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 μM, 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.