Benzenesulfonamides bearing pyrrolidinone moiety as inhibitors of carbonic anhydrase IX: synthesis and binding studies
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- 作者：Kęstutis Rutkauskas ; Asta Zubrienė ; Ingrida Tumosienė…
- 关键词：Benzenesulfonamide ; 5 ; oxopyrrolidine ; Hydrazone ; Oxadiazole ; Carbonic anhydrase ; Fluorescent thermal shift assay
- 刊名：Medicinal Chemistry Research
- 出版年：2017
- 出版时间：January 2017
- 年：2017
- 卷：26
- 期：1
- 页码：235-246
- 全文大小：
- 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
- 出版者：Springer US
- ISSN：1554-8120
- 卷排序：26
文摘
A series of novel compounds bearing substituted pyrrolidinone moieties at the para-position of benzenesulfonamide was synthesized as inhibitors of carbonic anhydrase (CA) isoform IX, known to be overexpressed in numerous human cancers. The inhibitors were tested towards all twelve catalytically active human CA isozymes to determine the affinity and selectivity towards CA IX over other isoforms. Compound affinity was determined by the fluorescence-based thermal shift assay and verified by isothermal titration calorimetry. Several compounds exhibited nanomolar binding affinity against CA IX while significantly weaker binding to the cytosolic off-target CA I was observed. The most effective CA IX binders reached the Kd of about 50 nM. This series of compounds can be used for further development of inhibitors with significant binding affinity and selectivity towards anticancer CA IX isozyme.