Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Ha'il, Ha'il, Saudi Arabia.
Drug Dev Res. 2023 Jun;84(4):681-702. doi: 10.1002/ddr.22049. Epub 2023 Mar 5.
Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor-associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.
抑制特定的碳酸酐酶（CA）酶是开发靶向癌症的药物的一种经过验证的策略。CA 同工酶 IX 和 XII 在各种人类实体瘤中过度表达，它们在调节细胞外肿瘤酸化、增殖和进展方面起着关键作用。本研究设计、合成并表征了一系列基于香豆素骨架的新型磺酰胺类化合物，它们是有效的、选择性的 CA 抑制剂。所选化合物对 CA I 和 CA II 具有显著的活性和选择性，可针对肿瘤相关的 CA IX 和 CA XII 发挥作用，其抑制活性达到单个位数纳米摩尔水平。与对照药乙酰唑胺（AAZ）相比，有 12 种化合物对 CA IX 的抑制作用更强，而有一种化合物对 CA XII 的抑制作用也比 AAZ 更强。化合物 18f（对 CA I、II、IX 和 XII 的 Ki 值分别为 955 nM、515 nM、21 nM 和 5 nM）是一种新型的 CA IX 和 XII 抑制剂，可进一步开发。
