The crystallization and X-ray investigation of one form of human carbonic anhydrase

1962 ◽  
Vol 5 (5) ◽  
pp. IN8-584 ◽  
Author(s):  
B. Strandberg ◽  
B. Tilander ◽  
K. Fridborg ◽  
S. Lindskog ◽  
P.O. Nyman
Keyword(s):  
Carbonic Anhydrase ◽  
X Ray ◽  
Human Carbonic Anhydrase

scholarly journals The Influence of Varying Fluorination Patterns on the Thermodynamics and Kinetics of Benzenesulfonamide Binding to Human Carbonic Anhydrase II

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 509 ◽  
Author(s):  
Steffen Glöckner ◽  
Khang Ngo ◽  
Björn Wagner ◽  
Andreas Heine ◽  
Gerhard Klebe
Keyword(s):  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ii ◽  
The Novel ◽  
Binding Modes ◽  
X Ray ◽  
Structure Activity ◽  
Small Set ◽  
Novel Method ◽  
Human Carbonic Anhydrase ◽  
Kinetics Of

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.

scholarly journals Azobenzene-based inhibitors of human carbonic anhydrase II

2015 ◽  
Vol 11 ◽  
pp. 1129-1135 ◽  
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.

Dual Human Carbonic Anhydrase/Cyclooxygenase-2 Inhibitors: A Promising Approach for Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Mohammad Mahboubi-Rabbani ◽  
Afshin Zarghi
Keyword(s):  
Carbonic Anhydrase ◽  
Combination Therapy ◽  
Active Site ◽  
Inhibitory Action ◽  
Cyclooxygenase 2 ◽  
X Ray ◽  
Cox 2 ◽  
Human Carbonic Anhydrase ◽  
Cancer Chemoresistance ◽  
Cyclooxygenase 2 Inhibitors

: Human carbonic anhydrase (hCA) and cyclooxygenase-2 (COX-2) have been known for a long to be chiefly involved in both the pathogenesis and progression of cancer and cancer chemoresistance. Interestingly, there is emerging evidence that the sulfonamide-type COX-2 selective inhibitors (coxibs) demonstrate inhibitory action against the cancer-related hCA isoforms, confirmed by X-ray crystal structures for celecoxib and valdecoxib complexes with the hCA active site. Consequently, the antineoplastic activity of the sulfonamide coxibs may be justified by the contribution of hCA inhibition to such processes in addition to COX-2 inhibition. Accordingly, these compounds' anti-tumoral activity should be further explored for their possible use in cancer prevention and combination therapy; however, few papers deal with this issue. Beginning with a brief description of the main molecular and catalytic features of both enzymes and their roles in tumor physiology, this review covers a survey of the most recent evidence regarding the molecules targeting one or both of hCA and COX-2, also providing insights into their mechanism of action and efficacy in preventing cancer.

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