Ialongo Davide, Messore Antonella, Madia Valentina Noemi, Tudino Valeria, Nocentini Alessio, Gratteri Paola, Giovannuzzi Simone, Supuran Claudiu T, Nicolai Alice, Scarpa Susanna, Taurone Samanta, Camarda Michele, Artico Marco, Papa Veronica, Saccoliti Francesco, Scipione Luigi, Di Santo Roberto, Costi Roberta
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, p.le Aldo Moro 5, I-00185 Rome, Italy.
Laboratory of Molecular Modeling Cheminformatics & QSAR, NEUROFARBA Department, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Firenze, Italy.
Pharmaceuticals (Basel). 2023 Jan 27;16(2):188. doi: 10.3390/ph16020188.
Solid tumors are active tissues containing hypoxic regions and producing metabolic acids. By decreasing pH, cancer cells create a hostile environment for surrounding host cells and foster tumor growth and progression. By governing acid/base regulation, carbonic anhydrases (CAs) are involved in several physiological/pathological processes, including tumors. Indeed, CAs are clinically relevant in cancer therapy as among the fifteen human isoforms, two of them, namely CA IX (overexpressed in solid tumors and associated with increased metastasis and poor prognosis) and CA XII (overexpressed in some tumors) are involved in tumorigenesis. Targeting these two isoforms is considered as a pertinent approach to develop new cancer therapeutics. Several CA inhibitors (CAIs) have been described, even though they are unselective inhibitors of different isoforms. Thus, efforts are needed to find new selective CAIs. In this work, we described new diketo acid derivatives as CAIs, with the best acting compounds and as nanomolar inhibitors of CA IX and XII, being also two orders of magnitude selective over CAs I and II. Molecular modeling studies showed the different binding poses of the best acting CAIs within CA II and IX, highlighting the key structural features that could confer the ability to establish specific interactions within the enzymes. In different tumor cell lines overexpressing CA IX and XII, the tested compounds showed antiproliferative activity already at 24 h treatment, with no effects on somatic not transformed cells.
实体瘤是含有缺氧区域并产生代谢酸的活跃组织。癌细胞通过降低pH值，为周围的宿主细胞创造了一个不利的环境，并促进肿瘤的生长和进展。通过调节酸碱平衡，碳酸酐酶（CAs）参与了包括肿瘤在内的多种生理/病理过程。事实上，碳酸酐酶在癌症治疗中具有临床相关性，因为在15种人类同工酶中，其中两种，即CA IX（在实体瘤中过度表达，与转移增加和预后不良相关）和CA XII（在某些肿瘤中过度表达）参与了肿瘤发生。靶向这两种同工酶被认为是开发新型癌症治疗药物的一种相关方法。尽管已有几种碳酸酐酶抑制剂（CAIs）被描述，但它们是不同同工酶的非选择性抑制剂。因此，需要努力寻找新的选择性CAIs。在这项工作中，我们描述了新型二酮酸衍生物作为CAIs，其中活性最佳的化合物 和 作为CA IX和XII的纳摩尔抑制剂，对CA I和II的选择性也高出两个数量级。分子模拟研究显示了活性最佳的CAIs在CA II和IX中的不同结合模式，突出了能够在酶内建立特定相互作用的关键结构特征。在过表达CA IX和XII的不同肿瘤细胞系中，所测试的化合物在处理24小时时就显示出抗增殖活性，对未转化的体细胞没有影响。
