4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki-Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies.

Benedetta Cornelio,Mariangela Ceruso,Andrei N Khlobystov,Claudiu T Supuran,Janos Sapi,Antonella Fontana,Graham A Rance,Marie Laronze-Cochard,Marta Ferraroni,Fabrizio Carta

doi:10.1021/acs.jmedchem.5b01771

Abstract

Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl-aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.

Highlights

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes present in most living organisms encoded by six genetically distinct families, the human α−, the β−, γ−, δ−, ζ− and the recently reported η−CAs.1 They catalyze the reversible hydration of carbon dioxide to the bicarbonate ion and a proton,2-3 a simple but essential reaction involved in respiration, electrolyte secretion, biosynthesis of several important molecules, pH homeostasis and tumorigenicity,4,5 and are targets for the design of activators and inhibitors
The benzenesulfonamide scaffold is known for its inhibitory potency against CAs and 2−substituted, 2,4−disubstituted and 3,4−disubstituted derivatives were shown in many cases to act as weaker inhibitors compared to 4−substituted derivatives
We prepared a library of twenty four new 4−arylbenzenesulfonamides (Figure 2) in which a high chemical diversity was guaranteed by a large spectrum of commercially available boronic acids or esters

Summary

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes present in most living organisms encoded by six genetically distinct families, the human α−, the β−, γ−, δ−, ζ− and the recently reported η−CAs. They catalyze the reversible hydration of carbon dioxide to the bicarbonate ion and a proton, a simple but essential reaction involved in respiration, electrolyte secretion, biosynthesis of several important molecules (urea, lipids, glucose, etc.), pH homeostasis and tumorigenicity, and are targets for the design of activators and inhibitors. We report the synthesis of new 4−arylbenzenesulfonamide derivatives by using the so−called “tail approach”, a drug design strategy based on appending scaffolds (tails) of different size, shape or nature to a ZBG containing pharmacophore, as opposed to the “ring approach” exploring several aromatic/heterocyclic fragments on which the ZBG is bound.. We report the synthesis of new 4−arylbenzenesulfonamide derivatives by using the so−called “tail approach”, a drug design strategy based on appending scaffolds (tails) of different size, shape or nature to a ZBG containing pharmacophore, as opposed to the “ring approach” exploring several aromatic/heterocyclic fragments on which the ZBG is bound.4,13,36,37 This modulation, based on the extension of benzenesulfonamide moiety by anchoring tails has been poorly investigated to date. To rationalize our drug design strategy, X−ray crystallography of several hCA II−sulfonamide adducts were investigated

Results and discussion

Conclusion 15

Experimental section