Overcoming Multidrug Resistance (MDR): Design, Biological Evaluation and Molecular Modelling Studies of 2,4‐Substituted Quinazoline Derivatives

• Published in: ChemMedChem Vol. 17; no. 12; pp. e202200027 - n/a
• Main Authors: Braconi, Laura, Teodori, Elisabetta, Contino, Marialessandra, Riganti, Chiara, Bartolucci, Gianluca, Manetti, Dina, Romanelli, Maria Novella, Perrone, Maria Grazia, Colabufo, Nicola Antonio, Guglielmo, Stefano, Dei, Silvia
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.06.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Chemistry, Medicinal; Crystal structure; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; efflux transporters modulators; Gefitinib; Life Sciences & Biomedicine; MDR1 protein; membrane proteins; Modulators; molecular docking studies; Molecular modelling; Multidrug resistance; multidrug resistance reversers; Multidrug resistant organisms; Neoplasm Proteins - metabolism; P-Glycoprotein; Pharmacology & Pharmacy; Quinazolines - pharmacology; Science & Technology; structure-activity relationships; molecular docking studies; membrane proteins; structure-activity relationships; multidrug resistance reversers; efflux transporters modulators; ABC TRANSPORTERS; INHIBITORS; CANCER; ATP
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200027

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. 2,4‐disubstituted quinazoline derivatives as MDR reversers: Derivatives carrying the quinazoline‐4‐amine scaffold were studied for their activity on ABC transporters, P‐gp, MRP1 and BCRP, involved in multidrug resistance (MDR). Potent P‐gp inhibitors with activity in the nanomolar range were identified. The results allowed us to propose structural requirements for defining P‐gp, MRP1 and BCRP activity and selectivity.