Overcoming Multidrug Resistance (MDR): Design,Biological Evaluation and Molecular Modelling Studies of 2,4-Substituted Quinazoline Derivatives |
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Authors: | Dr. Laura Braconi Prof. Elisabetta Teodori Dr. Marialessandra Contino Prof. Chiara Riganti Prof. Gianluca Bartolucci Dr. Dina Manetti Prof. Maria Novella Romanelli Dr. Maria Grazia Perrone Prof. Nicola Antonio Colabufo Prof. Stefano Guglielmo Prof. Silvia Dei |
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Affiliation: | 1. Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;2. Department of Pharmacy – Drug Sciences, University of Bari “A. Moro”, via Orabona 4, 70125 Bari, Italy;3. Department of Oncology, University of Turin, Via Santena 5/bis, 10126 Torino, Italy;4. Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Torino, Italy |
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Abstract: | Some 2,4-disubstituted quinazolines were synthesized and studied as multidrug resistance (MDR) reversers. The new derivatives carried the quinazoline-4-amine scaffold found in modulators of the ABC transporters involved in MDR, as the TKIs gefitinib and erlotinib. Their behaviour on the three ABC transporters, P-gp, MRP1 and BCRP, was investigated. Almost all compounds inhibited the P-gp activity in MDCK-MDR1 cells overexpressing P-gp, showing EC50 values in the nanomolar range ( 1 d , 1 e , 2 a , 2 c , 2 e ). Some compounds were active also towards MRP1 and/or BCRP. Docking results obtained by in silico studies on the P-gp crystal structure highlighted common features for the most potent compounds. The P-gp selective compound 1 e was able to increase the doxorubicin uptake in HT29/DX cells and to restore its antineoplastic activity in resistant cancer cells in the same extent of sensitive cells. Compound 2 a displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. |
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Keywords: | multidrug resistance reversers efflux transporters modulators molecular docking studies membrane proteins structure-activity relationships |
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