Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein

Abstract

A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [I]-IAAP, with IC values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.

The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter

“…012 software. Ligand preparations for VKNG-2 were done using Lig-prep [ 76 ]. A homology model of human ABBC1 was imported from the protein data bank.…”

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

“…In vivo study [67] showed TTT-28 enhanced intratumoral concentration of placitaxel, inhibiting the growth of ABCB1 overexpressing tumors. Additional extensive derivatizations of TTT-28 in terminal groups and central thiazole building block side chain helped to understand the drug/substrate interactions with P-gp [68]. Modifications on these sites led to divergent effects in ATPase efflux pump, from initial stimulation in TTT-28 to inhibition.…”

Evidence for the Interaction of A3 Adenosine Receptor Agonists at the Drug-Binding Site(s) of Human P-glycoprotein (ABCB1)

“…The structural basis for the distinction between these nucleosides in their interaction with P-gp is the presence of a 2-chlorine atom in compound 23, which is hydrogen in 22. These results could be due to the flexible nature of P-gp, which enables the protein to recognize various sizes and types of chemical structures (Patel et al, 2018); however, it should be noted that the affinity of both nucleosides at the target A 3 adenosine receptor is ∼1 nM, and selectivity for the clinically relevant pathway is unchanged.…”