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

Heidi L Perez; Patrizia Banfi; Jay Bertrand; Zhen-Wei Cai; James W Grebinski; Kyoung Kim; Jonathan Lippy; Michele Modugno; Joseph Naglich; Robert J Schmidt; Andrew Tebben; Paola Vianello; Donna D Wei; Liping Zhang; Arturo Galvani; Louis J Lombardo; Robert M Borzilleri

doi:10.1016/j.bmcl.2012.04.103

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

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3946-50. doi: 10.1016/j.bmcl.2012.04.103. Epub 2012 May 2.

Authors

Heidi L Perez¹, Patrizia Banfi, Jay Bertrand, Zhen-Wei Cai, James W Grebinski, Kyoung Kim, Jonathan Lippy, Michele Modugno, Joseph Naglich, Robert J Schmidt, Andrew Tebben, Paola Vianello, Donna D Wei, Liping Zhang, Arturo Galvani, Louis J Lombardo, Robert M Borzilleri

Affiliation

¹ Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543, USA. [email protected]

PMID: 22608961
DOI: 10.1016/j.bmcl.2012.04.103

Abstract

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.

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Crystallography, X-Ray
Cytochromes c / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Mitochondria / drug effects*
Mitochondria / metabolism
Models, Molecular
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology
bcl-2-Associated X Protein / antagonists & inhibitors*
bcl-2-Associated X Protein / chemistry
bcl-X Protein / antagonists & inhibitors*
bcl-X Protein / chemistry

Substances

Antineoplastic Agents
Sulfonamides
bcl-2-Associated X Protein
bcl-X Protein
Cytochromes c