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Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists
D S Lawrence1, J E Copper, C D Smith
1Department of Pharmacology, Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
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.
Insights
Researchers developed novel quinoxalinone compounds that selectively block P-glycoprotein (Pgp), a key factor in multidrug resistance (MDR) in cancer. These compounds show promise for overcoming chemotherapy resistance with low toxicity to healthy cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Tumor resistance to chemotherapy is a major clinical challenge.
- Multidrug resistance (MDR) is often caused by efflux pumps like P-glycoprotein (Pgp) and MRP1.
- Existing MDR antagonists have overlapping properties, limiting their clinical utility.
Purpose of the Study:
- To identify novel MDR antagonists with selectivity for Pgp over MRP1.
- To synthesize and evaluate a library of substituted quinoxalinones for Pgp antagonism.
- To assess the structure-activity relationship of these compounds.
Main Methods:
- Synthesis of a focused library of substituted phenoxymethylquinoxalinones.
- Evaluation of compound toxicity against drug-sensitive MCF-7 breast carcinoma cells.
- Assessment of Pgp and MRP1 antagonism in drug-resistant cell lines (NCI/ADR and MCF-7/VP).
Main Results:
- Substituted quinoxalinones selectively antagonized Pgp.
- Compounds with carbonyl substitutions on the phenoxy group showed potent Pgp antagonism.
- These compounds exhibited low toxicity toward drug-sensitive cells.
- No antagonism of MRP1 was observed with the tested compounds.
Conclusions:
- Substituted quinoxalinones are potent and selective Pgp antagonists.
- These compounds represent promising candidates for MDR modulation in cancer therapy.
- The selectivity of these quinoxalinones may lead to improved in vivo efficacy compared to nonselective agents.