Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo

被引：209

作者：

Carta, Fabrizio ^{[1
]}

Aggarwal, Mayank ^{[2
]}

Maresca, Alfonso ^{[1
]}

Scozzafava, Andrea ^{[1
]}

McKenna, Robert ^{[2
]}

Masin, Emanuela ^{[3
]}

Supuran, Claudiu T. ^{[1
]}

机构：

[1] Univ Firenze, Lab Chim Bioinorgan, I-350019 Florence, Italy

[2] Univ Florida, Dept Biochem & Mol Biol, Coll Med, Gainesville, FL 32610 USA

[3] Univ Firenze, Dept Preclin & Clin Pharmacol, I-350019 Florence, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 04期

关键词：

X-RAY-DIFFRACTION; CRYSTAL-STRUCTURE; IX EXPRESSION; ISOFORMS-I; ISOZYME-II; CA I; HYPOXIA; XII; GROWTH; SELECTIVITY;

D O I：

10.1021/jm300031j

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：1721 / 1730

页数：10

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