Structure-activity relationship of indomethacin analogues for MRP-1, COX-1 and COX-2 inhibition. identification of novel chemotherapeutic drug resistance modulators.
We report the screening of analogues of indomethacin to investigate the structure-activity relationship (SAR) of indomethacin-mediated multidrug resistance associated protein-1 (MRP-1) inhibition. By examining the activities of compounds with minor variations of the parent structure, we were able to separate MRP-1, glutathione-S-transferase (GST), cyclooxygenase (COX)-1 and COX-2 inhibitory activities. Combination cytotoxicity assays were utilised to identify agents which possess synergistic potential in MRP-1-expressing cell lines. MRP-1 Inside Out Vesicles (IOVs) were utilised to demonstrate the ability of the indomethacin analogues to inhibit the pump directly. Most of the indomethacin analogues active as MRP-1 inhibitors were poor GST inhibitors when compared with the GST-inhibitory activity of indomethacin. Two of the MRP-1 inhibitory analogues were found to have no COX-1 inhibitory activity and low COX-2 inhibitory activity, suggesting potentially reduced clinical toxicity. One MRP-1 inhibitory indomethacin analogue was also found to have low COX-1 inhibitory activity, but significant COX-2 inhibitory activity, making this analogue again interesting in terms of low potential toxicity, but with the possibility of direct inhibitory effects on tumour growth.
The National Cell and Tissue Culture Centre, Dublin City University, Glasneuin, 9, Dublin, Ireland.
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S
Touhey
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O'Connor
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Plunkett
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Maguire
M
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Clynes
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009369:Neoplasms / Q000188:drug therapy*; D011451:Prostaglandin-Endoperoxide Synthases; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007213:Indomethacin; D007527:Isoenzymes; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011451:Prostaglandin-Endoperoxide Synthases; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human