title: Azobenzene-based inhibitors of human carbonic anhydrase II.
abstract: 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.
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University Munich and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Leander Simon
authors.initials: LS
authors.lastname: Runtsch
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University Munich and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: David Michael
authors.initials: DM
authors.lastname: Barber
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University Munich and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
authors.affiliation: Department of Biochemistry, Technical University Munich and Munich Center for Integrated Protein Science, Lichtenbergstr. 4, 85748 Garching, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University Munich and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-University Munich and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
keywords: X-ray crystallography; azobenzene chemistry; enzyme inhibitors; human carbonic anhydrase II; sulfonamide