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. 2014 Jun 7;5(8):927-30.
doi: 10.1021/ml500196t. eCollection 2014 Aug 14.

Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry

Nicolino Pala  1 , Laura Micheletto  1 , Mario Sechi  1 , Mayank Aggarwal  2 , Fabrizio Carta  3 , Robert McKenna  2 , Claudiu T Supuran  4
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Free PMC article

Carbonic Anhydrase Inhibition with Benzenesulfonamides and Tetrafluorobenzenesulfonamides Obtained via Click Chemistry

Nicolino Pala et al. ACS Med Chem Lett. .
Free PMC article

Abstract

A series of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized by using a click chemistry approach starting from azido-substituted sulfonamides and alkynes, incorporating aryl, alkyl, cycloalkyl, and amino-/hydroxy-/halogenoalkyl moieties. The new compounds were medium potency inhibitors of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms I and II and low nanomolar/subnanomolar inhibitors of the tumor-associated hCA IX and XII isoforms. The X-ray crystal structure of two such sulfonamides in adduct with hCA II allowed us to understand the factors governing inhibitory power.

Keywords: Carbonic anhydrase; benzenesulfonamide; click chemistry; human isoform I; human isoform II; human isoform IX; human isoform XII.

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Figures

Figure 1
Figure 1
Stick representation showing (A) compound 5c (green) and (B) compound 5h (pink) bound in the active site of hCA II. Residues are as labeled. The |2Fo – Fc| electron density is contoured at 1.2σ. Active site Zn is shown as a blue sphere. Figure was made using PyMOL.
Chart 1
Chart 1. Sulfonamides Obtained via Click Chemistry
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Figure 2
Figure 2
(A) Surface representation of hCA II in complex with 5c (green) and 5h (pink) extending out of the active site. Zn is shown as a blue sphere. (B) Zoomed active site details. Figure was made using PyMOL.
See this image and copyright information in PMC

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