title: Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance.
abstract: BACKGROUND
  We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group.
  
  
  OBJECTIVE
  Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates.
  
  
  METHODS
  MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates.
  
  
  RESULTS
  The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1-1.3 µM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time.
  
  
  CONCLUSIONS
  The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Kwang-su
authors.initials: KS
authors.lastname: Park
authors.affiliation: Neuro-Medicine Center, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Seoungbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: hchoo@kist.re.kr.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address: chongy@konkuk.ac.kr.
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: C555218:7-O-pivaloxymethylquercertin; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011794:Quercetin; D014700:Verapamil
keywords: Modulator; Multidrug resistance (MDR); P-glycoprotein (Pgp); Pivaloxymethyl; Quercetin