2. Academic Validation
  3. Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance

Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance

  • Eur J Med Chem. 2019 Jan 1;161:118-130. doi: 10.1016/j.ejmech.2018.10.038.
Qianwen Ren 1,  Gangqiang Yang 2,  Mengqi Guo 3,  Jingwen Guo 1,  Yang Li 1,  Jing Lu 1,  Qing Yang 1,  Hanhan Tang 1,  Yi Li 1,  Xiaojuan Fang 1,  Yixiao Sun 1,  Jia Grace Qi 1,  Jingwei Tian 1,  Hongbo Wang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
  • 2 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. Electronic address: oceanygq@ytu.edu.cn.
  • 3 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 4 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. Electronic address: hongbowangyt@gmail.com.
PMID: 30347326 DOI: 10.1016/j.ejmech.2018.10.038
Abstract

Multidrug resistance (MDR) is a major cause of failure in Cancer treatment, in which the overexpression of P-glycoprotein (Pgp) plays a crucial role. Herein, a novel class of ocotillol-type amide derivatives has been designed, synthesized, and evaluated for their ability to reverse MDR. The structure-activity relationship of the reversal activity was analyzed. Ten compounds showed promising chemo-reversal ability, among which the 24R-ocotillol-type amide derivative 6c with an N-Boc-hexanoyl unit exhibited the most potency in reversing paclitaxel resistance in KBV cells. Compound 6c could inhibit Pgp-mediated rhodamine123 efflux function via stimulating Pgp-ATPase activity and exhibited high binding affinity with Pgp in molecular docking studies. Importantly, compound 6c enhanced the efficacy of paclitaxel against KBV Cancer cell-derived xenograft tumors in nude mice after oral administration. These results indicate that ocotillol-type amide derivatives are promising lead compounds for overcoming MDR in Cancer.

Keywords

Molecular docking; Multidrug resistance reversal; Ocotillol; P-glycoprotein modulators; Structure-active relationship.

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