用含有磺酰胺或生物素部分的香豆素合成并研究对人碳酸酐酶 IX、XII 的选择性抑制剂。
Synthesis and investigation of selective human carbonic anhydrase IX, XII inhibitors using coumarins bearing a sulfonamide or biotin moiety.
机构信息
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence, 50019, Italy; Department of Organic Chemistry, Faculty of Chemistry, University of Seville, Profesor García González 1, Seville, E-41012, Spain.
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Florence, 50019, Italy; NEUROFARBA Department, Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
出版信息
Chem Biol Interact. 2024 Dec 1;404:111284. doi: 10.1016/j.cbi.2024.111284. Epub 2024 Oct 21.
The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27, with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (K) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (K = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (K = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37-39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs.
碳酸酐酶同工型（CA）IX 和 XII 在多种实体肿瘤的发病机制和进展中的作用是众所周知的。在这种情况下，针对所述同工型的选择性碳酸酐酶抑制剂（CAI）是开发靶向癌症的药物的有效策略。为此，合成了基于芳基磺酰胺或生物素支架杂交的新型香豆素衍生物，并将其作为四种不同的人碳酸酐酶同工型（hCA I、II、IX 和 XII）的抑制剂进行了测试。具有硫脲部分和三唑作为连接子的香豆素-磺酰胺衍生的 27 对 hCA XII 表现出最高的抑制活性，其抑制常数（K）为 7.5 nM，对 hCA I 具有很好的选择性。化合物 32 是对 hCA IX（K = 6.3 nM）最强的抑制剂，比本文用作参比化合物的药物乙酰唑胺 AAZ（K = 25 nM）强 4 倍，对 hCA I 和 II 具有显著的选择性。香豆素-生物素衍生物 37-39 对靶标酶（hCA IX 和 XII）表现出出色的选择性，似乎是设计 CAI 的合理先导化合物。
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