PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas

A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethylene glycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity in a detailed structure–activity relationship study. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment.

本研究以三种经典的氨基磺酰胺类碳酸酐酶（carbonic anhydrase, CA, EC 4.2.1.1）抑制剂药效团为母核，合成了一系列芳香族/杂环双磺酰胺类化合物；将其与乙二醇低聚或聚合二胺偶联，得到带有短或长（聚合型）连接臂的双磺酰胺衍生物。针对一组膜结合型碳酸酐酶同工型（包括肿瘤高表达的CA IX、XII以及胞质同工酶），研究团队对新型抑制剂及其前体开展了活性评测。详细的构效关系研究表明，部分化合物对两类同工酶均展现出纳摩尔级抑制活性，且多款化合物具备中等程度的同工酶选择性。此外，本研究在常氧与低氧条件下，采用二维及三维体外细胞模型，测试了碳酸酐酶抑制剂对高表达CA IX、XII的肿瘤细胞的杀伤效能。研究发现一款聚乙二醇化双磺酰胺类碳酸酐酶抑制剂（编号25），可显著降低结肠HT-29、乳腺MDA-MB231及卵巢SKOV-3癌细胞系的存活率，由此证实了聚合物偶联物在碳酸酐酶抑制与癌症治疗领域的应用潜力。