Carbonic anhydrase inhibitors.: Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors
Carbonic anhydrase inhibitors.: Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors
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DOI：
10.1021/jm0501073
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发表时间：
2005-07-28
影响因子：
7.3
通讯作者：
Supuran, CT
中科院分区：
文献类型：
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作者：
Cecchi, A;Hulikova, A;Supuran, CT
磺胺类药物可抑制碳酸酐酶（CA、EC 4.2.1.1）的催化活性，这些酶参与调节许多组织中的酸碱平衡和离子转运。碳酸酐酶 IX (CA IX) 是一种跨膜亚型，主要与肿瘤相关，在正常组织中分布有限，缺氧时会强烈过度表达。缺氧会增加 CA IX 的催化性能，导致微环境酸中毒，从而影响癌症进展和治疗结果。 CA IX 代表了缺氧肿瘤的检测和治疗的靶点。磺酰胺 CA IX 选择性抑制剂仅在含有 CA IX 的缺氧细胞中积聚，逆转由该酶介导的酸化。本文报道了优先抑制 CA IX 活性的荧光磺酰胺的设计，显示出通过质膜的渗透减少以及与表达 CA IX 的缺氧细胞的结合。这些抑制剂代表了开发基于肿瘤相关 CA 同工酶抑制的抗癌疗法的有前途的候选者，并为缺氧肿瘤的成像和进一步研究提供了有趣的工具。
Sulfonamides inhibit the catalytic activity of carbonic anhydrases (CAs, EC 4.2.1.1), enzymes participating in the regulation of acid-base balance and ion transport in many tissues. Carbonic anhydrase IX (CA IX), a transmembrane isoform with predominant association with tumors and limited distribution in normal tissues, is strongly overexpressed by hypoxia. Hypoxia increases the catalytic performance of CA IX contributing to microenvironmental acidosis, which influences cancer progression and treatment outcome. CA IX represents a target for detection and therapy of hypoxic tumors. Sulfonamide CA IX selective inhibitors accumulate only in hypoxic cells containing CA IX, reversing acidification mediated by this enzyme. The design of fluorescent sulfonamides that preferentially inhibit the activity of CA IX, showing reduced penetration through the plasma membranes and binding to hypoxic cells expressing CA IX, is reported here. These inhibitors represent promising candidates for developing anticancer therapies based on tumor-associated CA isozyme inhibition and offer interesting tools for imaging and further investigation of hypoxic tumors.