Carbonic anhydrase inhibitors. X-ray crystal studies of the carbonic anhydrase II–trithiocarbonate adduct—An inhibitor mimicking the sulfonamide and urea binding to the enzyme

The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns.

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Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with a bis-sulfonamide—two heads are better than one?

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(03)00508-0 ◽

2003 ◽

Vol 13 (16) ◽

pp. 2759-2763 ◽

Cited By ~ 27

Author(s):

Angela Casini ◽

Francesco Abbate ◽

Andrea Scozzafava ◽

Claudiu T Supuran

Keyword(s):

Carbonic Anhydrase ◽

Crystallographic Structure ◽

Carbonic Anhydrase Inhibitors ◽

X Ray ◽

Better Than

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Azobenzene-based inhibitors of human carbonic anhydrase II

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.11.127 ◽

2015 ◽

Vol 11 ◽

pp. 1129-1135 ◽

Cited By ~ 7

Author(s):

Leander Simon Runtsch ◽

David Michael Barber ◽

Peter Mayer ◽

Michael Groll ◽

Dirk Trauner ◽

...

Keyword(s):

Crystal Structure ◽

Catalytic Activity ◽

Carbonic Anhydrase ◽

Drug Class ◽

Carbonic Anhydrase Ii ◽

Carbonic Anhydrases ◽

X Ray ◽

X Ray Crystallography ◽

Human Carbonic Anhydrase

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

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Out of the active site binding pocket for carbonic anhydrase inhibitors

Chemical Communications ◽

10.1039/c4cc07320g ◽

2015 ◽

Vol 51 (2) ◽

pp. 302-305 ◽

Cited By ~ 71

Author(s):

Katia D'Ambrosio ◽

Simone Carradori ◽

Simona M. Monti ◽

Martina Buonanno ◽

Daniela Secci ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Active Site ◽

Binding Pocket ◽

Carbonic Anhydrase Ii ◽

Carbonic Anhydrase Inhibitors ◽

Human Carbonic Anhydrase ◽

Site Binding

2-Benzylsulfinylbenzoic acid binds to human carbonic anhydrase II in a mode completely different from any other class of carbonic anhydrase inhibitors investigated so far.

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