Design and Synthesis of Human ABCB1 (P-glycoprotein) Inhibitors by Peptide Coupling of Diverse Chemical Scaffolds on Carboxyl and Amino Termini of (S)-valine-derived Thiazole Amino Acid

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Apr 30

PMID 24773054

Citations 12

Authors

Satyakam Singh

Nagarajan Rajendra Prasad

Eduardo E Chufan

Bhargav A Patel

Yi-Jun Wang

Zhe-Sheng Chen

Suresh V Ambudkar

Tanaji T Talele

Affiliations

Soon will be listed here.

Abstract

P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [(125)I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Compound 28 at 3 μM reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.

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