The Role of the Acidity of N-Heteroaryl Sulfonamides as Inhibitors of Bcl-2 Family Protein鈥揚rotein Interactions

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• 作者：B. Barry Tour茅 ; Karen Miller-Moslin ; Naeem Yusuff ; Lawrence Perez ; Michael Dor茅 ; Carol Joud ; Walter Michael ; Lucian DiPietro ; Simon van der Plas ; Michael McEwan ; Francois Lenoir ; Madelene Hoe ; Rajesh Karki ; Clayton Springer ; John Sullivan ; Kymberly Levine ; Catherine Fiorilla ; Xiaoling Xie ; Raviraj Kulathila ; Kara Herlihy ; Dale Porter ; Michael Visser
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：4
• 期：2
• 页码：186-190
• 全文大小：306K
• 年卷期：v.4,no.2(February 14, 2013)
• ISSN：1948-5875

文摘

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.

Keywords:

B cell lymphoma; Bcl-2 family; protein鈭抪rotein interaction; apoptosis; cancer