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Design, synthesis, X-ray structure and evaluation of functionalized hexacyclic carbazoles as new inhibitors of ABCG2 transporter
1 , 2 , 2, 3 , 1 , 1 , 4 , 1 , 5 , * 2 , * 1, 6
1  Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, 80210-170 Curitiba, PR, Brazil
2  Unité de Recherche de Chimie de l’Environnement et Moléculaire Structurale, Université des Frères Mentouri, Constantine 25000, Algeria
3  Département Sciences de la Matière, Université Oum El Bouaghi, 04000 Oum El Bouaghi, Algeria
4  EA 4446 Bioactive Molecules and Medicinal Chemistry, Faculté de Pharmacie - ISPB, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
5  Small Molecules for Biological Targets Team, Centre de recherche en cancérologie de Lyon, Centre Léon Bérard, CNRS 5286, INSERM 1052, Université Claude Bernard Lyon 1, Univ Lyon, Lyon, 69373, France
6  Department of Clinical Analysis, Federal University of Paraná, 80210-170 Curitiba, PR, Brazil

Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Cancer is one of the diseases with the highest mortality rates worldwide and the emergence of neoplasms presenting resistance to chemotherapy, also known as multidrug resistance (MDR), makes this conjuncture even worse. The overexpression of transmembrane proteins named ABC transporters is considered the main cause of this clinical condition [1]. These transporters (e.g. ABCB1, ABCC1, ABCG2) can recognize and promote the efflux of a broad spectrum of antineoplastic agents; thus, many studies have been carried out to develop compounds and evaluate their ability to inhibit this activity. Despite its pronounced relation with MDR, there are still no promising inhibitors of ABCG2 to be forwarded to clinical steps of drug development, which endorses the urgency to identify and characterize new selective inhibitors of this protein.

Carbazole skeleton is a key structural motif of many biologically active compounds including natural and synthetic products [2]. Starting from the tricyclic-carbazole motif to fused tetra-, penta-, hexa- and heptacyclic carbazoles, this skeleton could enable the design of new inhibitors of ABCG2 transporter.

In this study, a one-pot method for the synthesis of novel hexacyclic carbazole derivatives from readily available starting materials using a sequential multicomponent reaction/Fisher indolization strategy is described. Then five carbazole derivatives were tested to inhibit ABCG2 activity.

  1. O. Briz et al. Expert Opin Drug Metab Toxicol. 2019, 15(7):577-593.

2. S. Issa et al. J Enzyme Inhib. Med. Chem. 2019, 34(1):1321-1346.

Keywords: carbazoles; hexacyclic derivatives; multicomponent reaction; efflux pump; ABCG2; multidrug resistance