PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas
PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas
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DOI：
10.1021/acs.jmedchem.6b00492
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发表时间：
2016-05-26
影响因子：
7.3
通讯作者：
Hies, Marc A.
中科院分区：
文献类型：
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作者：
Akocak, Suleyman;Alam, M. Raqibul;Hies, Marc A.
从三种已建立的氨基磺酰胺碳酸酐酶（CA，EC 4.2.1.1）抑制剂药效团合成一系列芳族/杂环双磺酰胺，其与乙二醇低聚或聚合二胺偶联以产生具有短或长（聚合）接头的双磺酰胺。针对一组膜结合CA同工酶（包括肿瘤过表达的CA IX和XII以及胞质同工酶）测试新型抑制剂及其前体，在详细的结构中鉴定了针对这两类和几种具有中等同工酶选择性的化合物的纳摩尔强效抑制剂-活性关系研究。CA抑制剂杀死过表达CA IX和XII的肿瘤细胞的能力在常氧和缺氧条件下使用2D和3D体外细胞模型进行测试。该研究确定了一种纳摩尔级有效的PEG化双磺酰胺CA抑制剂（25），能够显著降低结肠HT-29、乳腺MDA-MB 231和卵巢SKOV-3癌细胞系的活力，从而揭示了聚合物缀合物在CA抑制和癌症治疗中的潜力。
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.