Synthesis and Evaluation of Dihydropyrroloquinolines That Selectively Antagonize P-Glycoprotein

Brian D. Lee, Zhanjiang Li, Kevin J. French, Yan Zhuang, Zuping Xia, Charles D. Smith

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

In a search for improved multiple drug resistance (MDR) modulators, we identified a novel series of substituted pyrroloquinolines that selectively inhibits the function of P-glycoprotein (Pgp) without modulating multidrug resistance-related protein 1 (MRP1). These compounds were evaluated for their toxicity toward drug-sensitive tumor cells (i.e. MCF-7, T24) and for their ability to antagonize Pgp-mediated drug-resistant cells (i.e. NCI/ADR) and MRP1-mediated resistant cells (i.e. MCF-7/VP). Cytotoxicity and drug accumulation assays demonstrated that the dihydropyrroloquinolines inhibit Pgp to varying degrees, without any significant inhibition of MRP1. The compound termed PGP-4008 was the most effective at inhibiting Pgp in vitro and was further evaluated in vivo. PGP-4008 inhibited tumor growth in a murine syngeneic Pgp-mediated MDR solid tumor model when given in combination with doxorubicin. PGP-4008 was rapidly absorbed after intraperitoneal administration, with its plasma concentrations exceeding the in vitro effective dose for more than 2 h. PGP-4008 did not alter the plasma distribution of concomitantly administered anticancer drugs and did not cause systemic toxicity as was observed for cyclosporin A. Because of their enhanced selectivity toward Pgp, these substituted dihydropyrroloquinolines may be effective MDR modulators in a clinical setting.

Original languageEnglish (US)
Pages (from-to)1413-1422
Number of pages10
JournalJournal of Medicinal Chemistry
Volume47
Issue number6
DOIs
StatePublished - Mar 11 2004

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Synthesis and Evaluation of Dihydropyrroloquinolines That Selectively Antagonize P-Glycoprotein'. Together they form a unique fingerprint.

Cite this