Cecchi Alessandro, Hulikova Alzbeta, Pastorek Jaromír, Pastoreková Silvia, Scozzafava Andrea, Winum Jean-Yves, Montero Jean-Louis, Supuran Claudiu T
Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
J Med Chem. 2005 Jul 28;48(15):4834-41. doi: 10.1021/jm0501073.
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.
磺胺类药物可抑制碳酸酐酶（CAs，EC 4.2.1.1）的催化活性，碳酸酐酶是参与许多组织酸碱平衡调节和离子转运的酶。碳酸酐酶IX（CA IX）是一种跨膜异构体，主要与肿瘤相关，在正常组织中分布有限，在缺氧状态下会强烈过表达。缺氧会增加CA IX的催化性能，导致微环境酸中毒，进而影响癌症进展和治疗效果。CA IX是缺氧肿瘤检测和治疗的一个靶点。磺胺类CA IX选择性抑制剂仅在含有CA IX的缺氧细胞中积累，可逆转该酶介导的酸化作用。本文报道了一种荧光磺胺类药物的设计，该药物优先抑制CA IX的活性，显示出降低穿过质膜的穿透性并与表达CA IX的缺氧细胞结合。这些抑制剂是基于肿瘤相关CA同工酶抑制开发抗癌疗法的有前景的候选药物，并为缺氧肿瘤的成像和进一步研究提供了有趣的工具。
