» Articles » PMID: 24773054

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
Specialty Chemistry
Date 2014 Apr 30
PMID 24773054
Citations 12
Authors
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.

Citing Articles

Structural insights into binding-site access and ligand recognition by human ABCB1.

Kurre D, Dang P, Le L, Gadkari V, Alam A EMBO J. 2025; 44(4):991-1006.

PMID: 39806099 PMC: 11833089. DOI: 10.1038/s44318-025-00361-z.


Soloxolone -3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function.

Moralev A, Salomatina O, Salakhutdinov N, Zenkova M, Markov A Molecules. 2024; 29(20).

PMID: 39459307 PMC: 11510211. DOI: 10.3390/molecules29204939.


A Novel 3--Pyridine-1,2,4-oxadiazole Derivative of Glycyrrhetinic Acid as a Safe and Promising Candidate for Overcoming P-Glycoprotein-Mediated Multidrug Resistance in Tumor Cells.

Moralev A, Salomatina O, Chernikov I, Salakhutdinov N, Zenkova M, Markov A ACS Omega. 2024; 8(51):48813-48824.

PMID: 38162726 PMC: 10753724. DOI: 10.1021/acsomega.3c06202.


Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance.

Wang C, Zhang J, Wei X, Yang M, Ma W, Yu R Mar Drugs. 2023; 21(5).

PMID: 37233508 PMC: 10220702. DOI: 10.3390/md21050314.


A ciprofloxacin derivative with four mechanisms of action overcomes paclitaxel resistance in p53-mutant and MDR1 gene-expressing type II human endometrial cancer.

Alhaj-Suliman S, Naguib Y, Wafa E, Saha S, Ebeid K, Meng X Biomaterials. 2023; 296:122093.

PMID: 36965280 PMC: 10092294. DOI: 10.1016/j.biomaterials.2023.122093.


References
1.
Robert J, Jarry C . Multidrug resistance reversal agents. J Med Chem. 2003; 46(23):4805-17. DOI: 10.1021/jm030183a. View

2.
Robey R, Steadman K, Polgar O, Morisaki K, Blayney M, Mistry P . Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res. 2004; 64(4):1242-6. DOI: 10.1158/0008-5472.can-03-3298. View

3.
Orlowski S, Mir L, BELEHRADEK Jr J, Garrigos M . Effects of steroids and verapamil on P-glycoprotein ATPase activity: progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators. Biochem J. 1996; 317 ( Pt 2):515-22. PMC: 1217517. DOI: 10.1042/bj3170515. View

4.
Bohme M, Buchler M, Muller M, Keppler D . Differential inhibition by cyclosporins of primary-active ATP-dependent transporters in the hepatocyte canalicular membrane. FEBS Lett. 1993; 333(1-2):193-6. DOI: 10.1016/0014-5793(93)80403-h. View

5.
Ambudkar S . Drug-stimulatable ATPase activity in crude membranes of human MDR1-transfected mammalian cells. Methods Enzymol. 1998; 292:504-14. DOI: 10.1016/s0076-6879(98)92039-0. View