Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo

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• 作者：Fabrizio Carta ; Mayank Aggarwal ; Alfonso Maresca ; Andrea Scozzafava ; Robert McKenna ; Emanuela Masini ; Claudiu T. Supuran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1721-1730
• 全文大小：369K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glucoma.