Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors.,ACS Medicinal Chemistry Letters

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Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-11 , DOI: 10.1021/acsmedchemlett.9b00590
Debora Pratesi ₁ , Camilla Matassini ₁ , Andrea Goti _{1,

2} , Andrea Angeli ₃ , Fabrizio Carta ₃ , Claudiu T Supuran ₃ , Rolando Spanevello ₄ , Francesca Cardona _{1,

2}

Affiliation

The synthesis of selective inhibitors of human carbonic anhydrases (hCAs) is of paramount importance to avoid side effects derived from undesired interactions with isoforms not involved in the targeted pathology, and this was partially addressed with the introduction of a sugar moiety (the so-called "sugar approach"). Since glycomimetics are considered more selective than the parent sugars in inhibiting carbohydrate-processing enzyme, we explored the possibility of further tuning the selectivity of hCAs inhibitors by combining the sulfonamide moiety with a sugar analogue residue. In particular, we report the synthesis of two novel hCAs inhibitors 2 and 3 which feature the presence of a piperidine iminosugar and an additional carbohydrate moiety derived from levoglucosenone (1), a key intermediate derived from cellulose pyrolysis. Biological assays revealed that iminosugar 2 is a very strong inhibitor of the central nervous system (CNS) abundantly expressed hCA VII (K I of 7.4 nM) and showed a remarkable selectivity profile toward this isoform. Interestingly, the presence of levoglucosenone in glycomimetic 3 imparted a strong inhibitory activity toward the tumor associated hCA IX (K I of 35.9 nM).

中文翻译：

选择性碳酸酐酶抑制剂的基于拟模拟的方法。

避免人源碳酸酐酶（hCAs）选择性抑制剂的合成对于避免因与不涉及目标病理学的同工型的不良相互作用而产生的副作用至关重要，这可以通过引入糖部分来部分解决（所谓的糖基“糖法”）。由于模拟糖被认为在抑制碳水化合物加工酶方面比母体糖更具选择性，因此我们探索了通过将磺酰胺部分与糖类似物残基结合来进一步调节hCAs抑制剂选择性的可能性。特别是，我们报道了两种新颖的hCAs抑制剂2和3的合成，其特征是存在哌啶亚氨基糖和衍生自左旋糖原酮（1）的另一种碳水化合物部分，左旋葡糖酮是一种源自纤维素热解的关键中间体。生物学分析表明，亚氨基糖2是中枢神经系统（CNS）的一种非常强的抑制剂，可大量表达hCA VII（KI为7.4 nM），并显示出对该亚型的显着选择性。有趣的是，在糖模拟物3中存在左葡糖醛酮对与肿瘤相关的hCA IX具有强抑制活性（KI为35.9nM）。

更新日期：2020-03-11

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