Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists

D. S. Lawrence, J. E. Copper, Charles Smith

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.

Original languageEnglish (US)
Pages (from-to)594-601
Number of pages8
JournalJournal of Medicinal Chemistry
Volume44
Issue number4
DOIs
StatePublished - Feb 15 2001

Fingerprint

Multiple Drug Resistance
P-Glycoprotein
Drug-Related Side Effects and Adverse Reactions
Drug Resistance
Pharmaceutical Preparations
Toxicity
Viral Structural Proteins
Quinoxalines
Membrane Transport Proteins
Cells
Phenols
Ketones
Amides
Antineoplastic Agents
Libraries
Neoplasms
Esters
Modulators
Pharmacology
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Lawrence, D. S. ; Copper, J. E. ; Smith, Charles. / Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 4. pp. 594-601.
@article{feee39e3b10d4df1974f0ceaf7628a9d,
title = "Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists",
abstract = "A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.",
author = "Lawrence, {D. S.} and Copper, {J. E.} and Charles Smith",
year = "2001",
month = "2",
day = "15",
doi = "10.1021/jm000282d",
language = "English (US)",
volume = "44",
pages = "594--601",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists. / Lawrence, D. S.; Copper, J. E.; Smith, Charles.

In: Journal of Medicinal Chemistry, Vol. 44, No. 4, 15.02.2001, p. 594-601.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists

AU - Lawrence, D. S.

AU - Copper, J. E.

AU - Smith, Charles

PY - 2001/2/15

Y1 - 2001/2/15

N2 - A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.

AB - A significant problem in the clinical treatment of cancer relates to the development of tumor resistance to many chemotherapeutic agents. Acquired drug resistance is often mediated through overexpression of membrane transport proteins that effectively efflux anticancer agents. Two of the best-studied transporters, P-glycoprotein (Pgp) and MRP1, have pharmacological properties that only partially overlap. In our search for improved drug-resistance antagonists, we have identified a family of substituted quinoxalines that selectively antagonizes Pgp over MRP1. Consequently, a focused library of congeners was designed and synthesized starting with a parent bromomethylquinoxalinone. This parent quinoxalinone was then condensed with a series of phenols to yield a family of substituted phenoxymethylquinoxalinones. These compounds were evaluated for their toxicity toward drug-sensitive MCF-7 breast carcinoma cells and for their abilities to antagonize Pgp and MRP1 in drug-resistant cell lines (NCI/ADR and MCF-7/VP, respectively). The results of this structure-activity study indicate that compounds with carbonyl substitutions of the phenoxy group (ester, amide, or ketone moieties) demonstrate excellent antagonism of Pgp while having relatively low toxicity toward drug-sensitive cells. Importantly, none of these compounds antagonized MRP1. Because of their transporter selectivity, we predict that substituted quinoxalinones may be more effective MDR modulators in vivo than are nonselective transporter antagonists.

UR - http://www.scopus.com/inward/record.url?scp=0035865923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035865923&partnerID=8YFLogxK

U2 - 10.1021/jm000282d

DO - 10.1021/jm000282d

M3 - Article

C2 - 11170649

AN - SCOPUS:0035865923

VL - 44

SP - 594

EP - 601

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -