Synthesis and biological evaluation of novel quinoline analogs of ketoprofen as multidrug resistance protein 2 (MRP2) inhibitors | ||
| Iranian Journal of Basic Medical Sciences | ||
| مقاله 13، دوره 24، شماره 6، شهریور 2021، صفحه 815-824 اصل مقاله (865.53 K) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22038/ijbms.2021.54554.12265 | ||
| نویسندگان | ||
| Fatemeh Mosafa1؛ Farzin Hadizadeh1، 2؛ Faezeh Fathi1؛ Zahra Eslami Nasab1؛ Tahereh Pourzahed1؛ Sayyed Mohammad Aboutorabzade2؛ Razieh Ghodsi* 1، 2 | ||
| 1Biotechnology Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran | ||
| 2Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran | ||
| چکیده | ||
| Objective(s): A new series of quinoline analogs of ketoprofen was designed and synthesized as multidrug resistance protein 2 (MRP2) inhibitors using ketoprofen as the lead compounds. Materials and Methods: The cytotoxic activity of the compounds was evaluated againt two cancer cell lines including A2780/RCIS (MRP2-overexpressing ovarian carcinoma), A2780, drug-sensitive ovarian carcinoma using MTT assay. Compounds showing low toxicity in MTT test were selected to investigate their MRP inhibition activity. MRP2 inhibitory potency was evaluated by determination of the uptake amount of fluorescent 5-carboxy fluorescein diacetate (5-CFDA) substrate, by A2780/RCIS in the presence of the selected compounds. Mode of interaction between synthesized ligands and homology modeled MRP2 was investigated by MOE software. Results: Compound 6d, a 4-carboxy quinoline possessing dimethoxy phenyl in position 2 of quinoline ring, showed the most MRP2 inhibition activity among all the quinolines and more than the reference drug ketoprofen. MRP2 inhibition activity of compound 7d was less in comparison to that of compound 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2. Docking studies showed that compound 7d methyl ester of 6d, interacted less compared to its parent 6d, which is consistent with biological results. Conclusion: This study indicates that 6- or 8-benzoyl-2-arylquinoline is a suitable scaffold to design MRP2 inhibitors. The position of benzoyl in quinoline ring is important in inhibition of MRP2. Generally, MRP2 inhibition activity of compound 7d was less in comparison to that of 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2. | ||
| کلیدواژهها | ||
| Anticancer؛ (ATP)-binding cassette؛ Multi-drug resistance protein؛ Multi-drug resistance protein inhibitor؛ Molecular docking؛ Quinoline؛ Synthesis | ||
| مراجع | ||
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