Ureido-Substituted Benzenesulfonamides Potently Inhibit Carbonic Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer Metastasis

被引：444

作者：

Pacchiano, Fabio ^{[3
]}

Carta, Fabrizio ^{[3
]}

McDonald, Paul C. ^{[1
,2
]}

Lou, Yuanmei ^{[1
,2
]}

Vullo, Daniela ^{[3
]}

Scozzafava, Andrea ^{[3
]}

Dedhar, Shoukat ^{[1
,2
,4
]}

Supuran, Claudiu T. ^{[3
]}

机构：

[1] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada

[2] BC Canc Agcy, Vancouver, BC V5Z 1L3, Canada

[3] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy

[4] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 06期

关键词：

CRYSTAL-STRUCTURE; CA-IX; HYPOXIA; EXPRESSION; SULFONAMIDES; MARKER; PH;

D O I：

10.1021/jm101541x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of ureido-substituted benzenesulfonamides was prepared that showed a very interesting profile for the inhibition of several human carbonic anhydrases (hCAs, EC 4.2.1.1), such as hCAs land II (cytosolic: isoforms) and hCAs IX and XII (transmembrane, tumor-associated enzymes). Excellent inhibition of all these isoforms has been observed with various members of the series, depending on the substitution pattern of the urea moiety. Several low nanomolar CA DC/XII inhibitors also showing good selectivity for the transmembrane over the cytosolic isoforms have been discovered. One of them, 4-{[(3'-nitrophenyl)carbamoyl] amino}benzene sulfonamide, significantly inhibited the formation of inetastases by the highly aggressive 4T1 mammary tumor cells at pharmacologic concentrations of 45 mg/kg constituting an interesting candidate for the development of conceptually novel antimetastatic drugs.

引用

页码：1896 / 1902

页数：7

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