University of Florence, NEUROFARBA Department, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
Chem Commun (Camb). 2020 Apr 25;56(32):4444-4447. doi: 10.1039/d0cc00995d. Epub 2020 Mar 20.
Carbonic anhydrases (CAs, E.C. 4.2.1.1) are metalloenzymes expressed on a variety of cell types. Their overexpression leads to serious pathologies, including cancer. The discovery of a series of selenolesters with high structural diversity as novel CA inhibitors is reported here. These compounds show remarkable in vitro inhibition against a panel of human CA isoforms such as hCA I, II, IX and XII. We observed that they undergo a CA mediated hydrolysis, releasing different active selenol fragments, which act as CA inhibitors. Notably, to the best of our knowledge, this is the first example of an enzyme with selenolesterase activity. In addition, X-ray crystallographic data support the proposed mechanism, proving selenolesters as novel pro-drug inhibitors with potential pharmacological applications.
碳酸酐酶（CAs，EC 4.2.1.1）是在多种细胞类型上表达的金属酶。它们的过表达会导致严重的病理，包括癌症。本文报道了一系列具有高结构多样性的硒酯作为新型 CA 抑制剂的发现。这些化合物对一系列人 CA 同工酶（如 hCA I、II、IX 和 XII）表现出显著的体外抑制活性。我们观察到它们经历了 CA 介导的水解，释放出不同的活性硒醇片段，作为 CA 抑制剂发挥作用。值得注意的是，据我们所知，这是首例具有硒醇酯酶活性的酶的例子。此外，X 射线晶体学数据支持所提出的机制，证明硒酯是具有潜在药理应用的新型前药抑制剂。
