Design, synthesis, X-ray structure and evaluation of functionalized hexacyclic carbazoles as new inhibitors of ABCG2 transporter

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.