Discovery of curcumin inspired sulfonamide derivatives as a new class of carbonic anhydrase isoforms I, II, IX, and XII inhibitors

P V Sri Ramya,Srinivas Angapelly,Andrea Angeli,Chander Singh Digwal,Mohammed Arifuddin,Bathini Nagendra Babu,Claudiu T Supuran,Ahmed Kamal

doi:10.1080/14756366.2017.1380638

Abstract

A series of curcumin inspired sulfonamide derivatives was prepared from various chalcones and 4-sulfamoyl benzaldehyde via Claisen–Schmidt condensation. All new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. Interesting inhibitory activities were observed against all these isoforms. hCA I, an isoform involved in several eye diseases was inhibited moderately with KIs in the range of 191.8–904.2 nM, hCA II, an antiglaucoma drug target was highly inhibited by the new sulfonamides, with KIs in the range of 0.75–8.8 nM. hCA IX, a tumor-associated isoform involved in cancer progression and metastatic spread was potently inhibited by the new sulfonamides, with KIs in the range of 2.3–87.3 nM, whereas hCA XII, and antiglaucoma and anticancer drug target, was inhibited with KIs in the range of 6.1–71.8 nM. It is noteworthy that one of the new compounds, 5d, was found to be almost 9 times more selective against hCA II (KI = 0.89 nM) over hCA IX and hCA XII, whereas 5e was 3 and 70 times more selective against hCA II (KI = 0.75 nM) over hCA IX and hCA XII, respectively.

Highlights

Carbonic anhydrase (CAs, EC 4.2.1.1) enzymes are ubiquitous metalloproteins present in prokaryotes and eukaryotes, and they catalyze the fundamental biochemical process of carbon dioxide hydration, being one of the principal regulators of cellular pH homeostasis[1]
The known carbonic anhydrase inhibitors (CAIs) can be divided into various classes: those that coordinate to the active site metal ion[9] and those that do not interact with it[16]
All the synthesized compounds were purified by recrystallization in hot ethanol and well characterized by spectroscopic techniques such as 1H, 13C NMR, FT-IR and HRMS etc., which were in full accordance with the depicted structures

Summary

Introduction

Carbonic anhydrase (CAs, EC 4.2.1.1) enzymes are ubiquitous metalloproteins present in prokaryotes and eukaryotes, and they catalyze the fundamental biochemical process of carbon dioxide hydration (a reversible reaction producing a bicarbonate anion and a proton), being one of the principal regulators of cellular pH homeostasis[1]. In mammals, 15 a-CA isozymes have been identified, that differ in subcellular localization, tissue distribution, and catalytic activity[1,2] Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII, and CA XIII), others are membrane bound (CA IV, CA IX, CA XII, and CA XIV), two are mitochondrial (CA VA and CA VB), and one is secreted in saliva and milk (CA VI)[2,9,10,11,12]. The sulfonamide functionality, denoted as a zinc-binding group (ZBG), coordinates in deprotonated form to the Zn(II) ion within the hCA active sites and establishes hydrogen bonds with a residues nearby (e.g. Thr[199] in a-CAs)[3,4] Such binding features are common among the active site architectures of all the 15 human isozymes, that all belong to the a-class[9,14].

Methods

Results

Conclusion