title: 3'-O, 4'-O-aromatic acyl substituted 7,8-pyranocoumarins: a new class of P-glycoprotein modulators.
abstract: OBJECTIVE
  P-glycoprotein (Pgp) overexpression in tumour cells leads to multidrug resistance (MDR) and causes failure in cancer chemotherapy. We have previously identified (±)-praeruptorin A (PA) as a potential lead compound for Pgp modulators. In this study we investigated the MDR-reversing activities of PA derivatives.
  
  
  METHODS
  Series 7,8-pyranocoumarins with various C-3' and C-4' side chains had been semi-synthesized and their MDR-reversing activity was investigated in Pgp-overexpressing MDR tumour cell line HepG2/Dox and in a KB V1 xenograft animal model.
  
  
  RESULTS
  All 7,8-pyranocoumarins exhibited equal or higher activity in modulating Pgp. DCK (12), DMDCK (15), 16, 21, 23 and 24 at 4 µm achieved 91%∼99% decrease in IC50 value (concentration inhibiting cell growth by 50%) of anticancer agents vinblastine, doxorubicin, puromycin and paclitaxel, and were more active than others. DMDCK also remarkably enhanced the growth inhibitory effect of paclitaxel on KB V1 xenografts (P < 0.05), showing a potency required for clinical usage. Mechanistic studies suggested that these 7,8-pyranocoumarins might reverse Pgp-MDR through directly binding to substrate binding site(s) or allosteric site(s) on Pgp therefore impairing Pgp-mediated drug transport.
  
  
  CONCLUSIONS
  Results from the study suggested that 3'-O, 4'-O-aromatic acyl substituted 7,8-pyranocoumarins could serve as a new class of Pgp modulator. Acyls play an important role in maintaining and enhancing the Pgp-modulating ability of pyranocoumarins. 3,4-Dimethoxyl substituted aromatic acyls, bearing a methoxy that might interact with Pgp as hydrogen bond accepter, were shown to be the most potent for reversing MDR.
authors.affiliation: Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Shen
authors.forename: Guangying
authors.initials: G
authors.lastname: Chen
authors.forename: Guoyuan
authors.initials: G
authors.lastname: Zhu
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Cai
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Hu
authors.forename: Wang-Fun
authors.initials: WF
authors.lastname: Fong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023421:Models, Animal; D015394:Molecular Structure; D039681:Pyranocoumarins / Q000494:pharmacology*; D013223:Statistics as Topic; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003374:Coumarins; D039681:Pyranocoumarins; C441070:praeruptorin A