Benzophenone Sulfonamide Derivatives as Interaction Partners and Inhibitors of Human P-Glycoprotein

Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATPBinding Cassette (ABC) family of translocator proteins. Physiologically, it exports toxins outside the cell, however, its overexpression can lead to multidrug resistance (MDR) by exporting multiple structurally and chemically diverse compounds, creating barriers to treatment for various diseases including cancer. The current study aims to screen benzophenone sulfonamide derivatives as a class of inhibitors of P-gp and potential anticancer agents.

A total of 15 compounds were evaluated. These compounds were screened in a zooxanthellae efflux inhibition assay using a CCRF-CEM Vcr1000 cell line overexpressing human P-gp. Cytotoxicity assays were also performed for active compounds 11, 14 and 13. These scaffolds were then docked in a homology model (CEM) of human P-gp using mouse P-gp as a template (PDB ID: 4MIM) and recently published cryo-electron microscopy of human mouse chimeric P-gp structures to discover their interaction with specific residues in the binding pocket. Analysis was performed using Labview VI and Graph pad prism version 5.0.
 
The results showed the potency of all these compounds in the low nanomolar range, while compound 14 showed the highest activity with an IC50 value of 18.35 nM ± 4.90, followed by 11 and 13 with IC50 values of 30.66 nM ± 5.49 and 46.12 nM ± 3.06, respectively. Furthermore, the IC50 values calculated in the cytotoxicity assay were 22.97 μM±0.026, 583.1 μM±0.027 and 117.8 μM±0.062 for 14, 11 and 13, respectively. docking results revealed the interaction of these scaffolds in the transmembrane helix (TM), where Tyr307, Tyr310, Tyr953, Met986 and Gln946 were found to be the major interaction partners, and thus they may play an important role in the transport of these scaffolds.

Benzophenone sulfonamide derivatives have IC50 values in the low nanomolar range comparable to the standard inhibitor verapamil and are good P-gp inhibitors that can be used as anticancer agents. In addition, they showed interactions in the transmembrane region, which share the same binding region of verapamil and zosuquidar.