4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki–Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies
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- 作者：Benedetta Cornelio ; Marie Laronze-Cochard ; Mariangela Ceruso ; Marta Ferraroni ; Graham A. Rance ; Fabrizio Carta ; Andrei N. Khlobystov ; Antonella Fontana ; Claudiu T. Supuran ; Janos Sapi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 28, 2016
- 年：2016
- 卷：59
- 期：2
- 页码：721-732
- 全文大小：601K
- ISSN：1520-4804
文摘
Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para-position were prepared by palladium nanoparticle-catalyzed Suzuki–Miyaura cross-coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl–aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides.