Identification of a phenylacylsulfonamide series of dual Bcl-2/Bcl-xL antagonists

• Published in: Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (12), p.3946-3950
• Main Authors: Perez, Heidi L., Banfi, Patrizia, Bertrand, Jay, Cai, Zhen-Wei, Grebinski, James W., Kim, Kyoung, Lippy, Jonathan, Modugno, Michele, Naglich, Joseph, Schmidt, Robert J., Tebben, Andrew, Vianello, Paola, Wei, Donna D., Zhang, Liping, Galvani, Arturo, Lombardo, Louis J., Borzilleri, Robert M.
• Format: Article
• Language: English
• Subjects: Antagonists; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bcl-2; Bcl-2 protein; bcl-2-Associated X Protein - antagonists & inhibitors; bcl-2-Associated X Protein - chemistry; Bcl-x protein; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - chemistry; Bcl-xL; Biological and medical sciences; Cell Line, Tumor; chemistry; Crystallography, X-Ray; Cytochromes c - metabolism; Humans; Hydrophobic and Hydrophilic Interactions; Isolated mitochondria; Medical sciences; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Models, Molecular; Pharmacology. Drug treatments; Protein–protein interaction; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.04.103

A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity.