Isosteric exchange of the acylsulfonamide moiety in Abbott's Bcl-XL protein interaction antagonist.
A multi-component reaction strategy was used for the fast and efficient synthesis of amide isosteres of known Bcl-2 inhibitors capable of disrupting protein-protein interactions. Ugi reaction and a subsequent nucleophilic aromatic substitution reaction provide a versatile path to libraries of compounds similar to Abbott's acylsulfonamides. Modeling arguments are used to explain the inferior activity of the amide as opposed to the sulfonamide series.
Dömling
Alexander
A
Department of Pharmaceutical Sciences, University of Pittsburgh, PA 15261, USA. asd30@pitt.edu
Antuch
Walfrido
W
Beck
Barbara
B
Schauer-Vukasinović
Vesna
V
D000577:Amides / Q000737:chemistry; D017209:Apoptosis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003486:Cyanides / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009369:Neoplasms / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000577:Amides; D003486:Cyanides; D010455:Peptides; D011506:Proteins; D013449:Sulfonamides; D051020:bcl-X Protein