5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells

Abstract

Multidrug resistance (MDR) is considered one of the major mechanisms responsible for the failure of numerous anticancer and antiviral chemotherapies. Various strategies to overcome the MDR phenomenon have been developed, and one of the most attractive research directions is focused on the inhibition of MDR transporters, membrane proteins that extrude cytotoxic drugs from living cells. Here, we report the results of our studies on a series newly synthesized of 5-arylidenerhodanines and their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. In the series, compounds possessing a triphenylamine moiety and the carboxyl group in their structure were of particular interest. These amphiphilic compounds showed over 17-fold stronger efflux pump inhibitory effects than verapamil. The cytotoxic and antiproliferative effects of target rhodanines on T-lymphoma cells were also investigated. A putative binding mode for 11, one of the most potent P-gp inhibitors tested here, was predicted by molecular docking studies and discussed with regard to the binding mode of verapamil.

Keywords: P-glycoprotein; T-lymphoma cancer cells; cancer multidrug resistance; crystal structure; efflux pump inhibition; molecular docking; rhodanine.

Scheme 1

Condensation of rhodanine and rhodanine-3-carboxyalkyl acids with benzaldehyde derivatives.

Figure 1

The molecular geometries of (a) 3 (molecule A), (b) 7 (molecule A), and (c) 11, with the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2

The overlap of the rhodanine rings of 3 (gray molecule A, light gray molecule B), 7 (green molecule A, light green molecule B), and 11 (purple).

Figure 3

Position of the top-ranked docking poses of 11 (black) and verapamil (blue) inside the hP-gp drug-binding pocket: (A) the homology model and (B) the cryo-EM structure 7O9W.

Figure 4

Binding modes and molecular interactions observed for the best docking poses of verapamil (reference poses). (A) Verapamil docked to the hP-gp homology model (XP GScore −9.387, IFD score −2651.60); (B) Verapamil docked to the cryo-EM structure 7O9W (XP GScore −10.974, IFD score −2243.60).

Figure 5

Binding modes and molecular interactions for 11 bound to hP-gp, predicted by IFD. (A) Two top-ranked docking poses of 11 in the homology model of hP-gp (pose Ia in cyan, pose Ib in pink); (B) the top-ranked docking pose of 11 in 7O9W (pose II, purple). Dashed lines represent hydrogen bonds and π-π interactions.