Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with EMATE, a dual inhibitor of carbonic anhydrases and steroid sulfatase

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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Carborane-Based Carbonic Anhydrase Inhibitors: Insight into CAII/CAIX Specificity from a High-Resolution Crystal Structure, Modeling, and Quantum Chemical Calculations

BioMed Research International ◽

10.1155/2014/389869 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Pavel Mader ◽

Adam Pecina ◽

Petr Cígler ◽

Martin Lepšík ◽

Václav Šícha ◽

...

Keyword(s):

Crystal Structure ◽

High Resolution ◽

Carbonic Anhydrase ◽

Quantum Chemical Calculations ◽

Quantum Chemical ◽

Computational Analysis ◽

Structure Modeling ◽

Carbonic Anhydrases ◽

Carbonic Anhydrase Inhibitors ◽

Insight Into

Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

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Carbonic anhydrase inhibitors: The X-ray crystal structure of ethoxzolamide complexed to human isoform II reveals the importance of thr200 and gln92 for obtaining tight-binding inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2008.03.023 ◽

2008 ◽

Vol 18 (8) ◽

pp. 2669-2674 ◽

Cited By ~ 23

Author(s):

Anna Di Fiore ◽

Carlo Pedone ◽

Jochen Antel ◽

Harald Waldeck ◽

Andreas Witte ◽

...

Keyword(s):

Crystal Structure ◽

Carbonic Anhydrase ◽

Tight Binding ◽

Carbonic Anhydrase Inhibitors ◽

X Ray ◽

Binding Inhibitors

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Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

International Journal of Molecular Sciences ◽

10.3390/ijms21072560 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2560 ◽

Cited By ~ 2

Author(s):

Majid Ali ◽

Murat Bozdag ◽

Umar Farooq ◽

Andrea Angeli ◽

Fabrizio Carta ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Design Strategy ◽

Binding Mode ◽

Crystallographic Analysis ◽

Carbonic Anhydrases ◽

Detailed Structure ◽

Design Synthesis ◽

X Ray ◽

Structure Activity ◽

New Compounds

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

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