Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors.

Moataz Shaldam,Tamer M Ibrahim,Claudiu T Supuran,Clemente Capasso,Ramadan A El-Domany,Wagdy M Eldehna,Alessio Nocentini,Zainab M Elsayed,Rofaida Salem

doi:10.3390/ijms222011119

Abstract

A new series of quinoline-based benzenesulfonamides (QBS) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group (QBS 13a–c); thereafter, the sulphonamide group was switched to ortho- and meta-positions to afford regioisomers 9a–d and 11a–g. Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS 16. All the described QBS have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII. In general, para-sulphonamide derivatives 13a–c displayed the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 11c (KI = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS.

Highlights

Carbonic anhydrases (CA) are metalloenzymes that catalyze the reversable interconversion between carbon dioxide and bicarbonate ion reaction [1]
Resuming the efforts to create effective Human carbon anhydrases (hCAs) IX and hCA XII inhibitors, here we describe the design and synthesis of novel 4-aminoquinoline-based sulfonamides (Figure 2)
Reaction courses and product mixtures were routinely monitored using thin layer chromatography (TLC) that was carried out using aluminum sheets pre-coated with silica gel 60 F254 purchased from Merk (Merck Group, Darmstadt, Germany) Compounds 5–7 and 15 were prepared according to the reported methods [27,34,35]

Summary

Introduction

Carbonic anhydrases (CA) are metalloenzymes that catalyze the reversable interconversion between carbon dioxide and bicarbonate ion reaction [1]. Human carbon anhydrases (hCAs) belong to the α-CA family, one of the eight discovered families of carbon anhydrases [2]. Twelve hCAs (hCAs I–VII, hCA IX and hCAs XII–XIV) out of the sixteen isozymes discovered exhibit catalytic action [3]. CAs are involved in both biological and pathological processes such as homeostasis of pH, respiration, bone resorption, epilepsy, tumorigenicity and obesity [4,5]. The role of CAs in various diseases has been confirmed and several hCAs isoforms are, valuable targets for designing inhibitors with clinical applications, such as anti-glaucoma, antiepileptic, anti-obesity, anticancer, etc.

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Results

Conclusion