Synthesis and biological evaluation of a new family of anti-benzylanilinosulfonamides as CA IX inhibitors.
We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors prepared regio- and stereoselectively by reacting sulfanilamide with ethyl trans-phenylglycidate in the presence of cobalt(II) chloride. Various derivatizations of the ester moiety in the parent compound led to a small library of derivatives (2R,3R and 2S,3S) which displayed interesting inhibitory activities towards the human tumor-associated isoform CA IX. One of the new compounds shows high selectivity in inhibiting hCA IX compared to the two physiologically relevant, cytosolic isozymes hCA I and hCA II. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active sites of hCA IX and hCA II.
Thiry
Anne
A
Drug Design and Discovery Center, FUNDP, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. anne.thiry@fundp.ac.be
Delayen
Aurélie
A
Goossens
Laurence
L
Houssin
Raymond
R
Ledecq
Marie
M
Frankart
Aurélie
A
Dogné
Jean-Michel
JM
Wouters
Johan
J
Supuran
Claudiu T
CT
Hénichart
Jean-Pierre
JP
Masereel
Bernard
B
D000951:Antigens, Neoplasm / Q000187:drug effects*; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship; D000077145:Sulfanilamide; D013424:Sulfanilamides; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D013424:Sulfanilamides; D013449:Sulfonamides; D000077145:Sulfanilamide; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases