3′-O, 4′-O-aromatic acyl substituted 7,8-pyranocoumarins: A new class of P-glycoprotein modulators

Xiaoling Shen, Guangying Chen, Guoyuan Zhu, Jiazhong Cai, Lu Wang, Yingjie Hu, David W F FONG*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Objectives 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. Key findings 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.

Original languageEnglish
Pages (from-to)90-100
Number of pages11
JournalJournal of Pharmacy and Pharmacology
Volume64
Issue number1
DOIs
Publication statusPublished - Jan 2012

Scopus Subject Areas

  • Pharmacology
  • Pharmaceutical Science

User-Defined Keywords

  • (±)-Praeruptorin A
  • 7, 8-pyranocoumarin
  • multidrug resistance
  • P-glycoprotein

Fingerprint

Dive into the research topics of '3′-O, 4′-O-aromatic acyl substituted 7,8-pyranocoumarins: A new class of P-glycoprotein modulators'. Together they form a unique fingerprint.

Cite this