Design, synthesis and evaluation of a novel series of inhibitors reversing P-glycoprotein-mediated multidrug resistance

Chem Biol Drug Des. 2018 Sep;92(3):1708-1716. doi: 10.1111/cbdd.13338. Epub 2018 Jun 14.

Abstract

Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells. Compound 19 also played an important role in the P-gp efflux function of intracellular Rh123 and doxorubicin (DOX) accumulation in K562/A02 cells. Moreover, compound 19 exhibited a long lifetime of approximately 24 hr. These results indicated that compound 19 is a potential lead compound for the design of new drugs to overcome cancer MDR.

Keywords: MDR; P-gp inhibitor; click chemistry; reversal activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Survival
  • Click Chemistry
  • Doxorubicin / chemistry
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology
  • Drug Design*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • K562 Cells
  • Microscopy, Confocal
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Rhodamines / chemistry
  • Rhodamines / metabolism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Rhodamines
  • Doxorubicin