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

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.

Keywords: efflux transporters modulators; membrane proteins; molecular docking studies; multidrug resistance reversers; structure-activity relationships.