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The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

ABSTRACT: Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

SUBMITTER: Toure BB

PROVIDER: S-EPMC4027142 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

Touré B Barry BB Miller-Moslin Karen K Yusuff Naeem N Perez Lawrence L Doré Michael M Joud Carol C Michael Walter W DiPietro Lucian L van der Plas Simon S McEwan Michael M Lenoir Francois F Hoe Madelene M Karki Rajesh R Springer Clayton C Sullivan John J Levine Kymberly K Fiorilla Catherine C Xie Xiaoling X Kulathila Raviraj R Herlihy Kara K Porter Dale D Visser Michael M

ACS medicinal chemistry letters 20130104 2

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the ...[more]

PMID: 24900652

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