Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII.

Priya Hargunani,Mrunmayee P. Toraskar,Nikhil Tadge,Alessio Nocentini,Mariangela Ceruso,Paola Gratteri,Andris Kazaks,Kaspars Tars,Claudiu T. Supuran,Janis Leitans

doi:10.3390/ijms21072621

Abstract

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

Highlights

Carbon dioxide (CO2) plays a vital role in all life processes
As a response to regional hypoxia, cancer cells obtain their need for high levels of ATP synthesis by switching their metabolism from aerobic respiration to fermentative glycolysis [10]
4-ureidobenzenesulfonamide 2 was obtained from reaction of sulfanilamide with sodium cyanate in ethanol and water, which was further refluxed with hydrazine hydrate in ethanol to obtain 4-aminosulphonylphenyl semicarbazide 3

Summary

Introduction

Carbon dioxide (CO2) plays a vital role in all life processes. It exists in equilibrium with bicarbonate, but the interconversion is a slow process [1]. The membrane-bound CA IX and XII isoforms are known as the CAs associated with cancers, being expressed in a limited number of normal tissues [5,6,7,8,9]. The hypoxic conditions in solid tumors induce overexpression of CA IX and CA XII, which maintain the acidic tumor environment by catalyzing the reversible hydration of tumor cell-generated CO2 into a bicarbonate anion (HCO3−) and a proton (H+) and trap H+ extracellularly to lower the pH [5,6]. The overexpression of these isoforms contributes to the increased acidification of the extracellular hypoxic environment in contrast to normal tissues Expression of both membrane-associated CAs is induced by hypoxia in breast tumors and in several cancer cell lines [7,8]. CA expression in brain tumors is associated with poor prognosis [9,10]

Methods

Results

Conclusion