Menicatti Marta, Pallecchi Marco, Bua Silvia, Vullo Daniela, Di Cesare Mannelli Lorenzo, Ghelardini Carla, Carta Fabrizio, Supuran Claudiu T, Bartolucci Gianluca
a NEUROFARBA Department , Sezione di Scienze Farmaceutiche, University of Florence , Florence , Italy.
b Polo Scientifico , Laboratorio di Chimica Bioinorganica, University of Florence , Florence , Italy.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):671-679. doi: 10.1080/14756366.2018.1445737.
Rheumatoid arthritis (RA) is a chronic inflammatory disease caused by a faulty autoimmune response. Recently, it was reported that some human carbonic anhydrases (CAs) isoforms are overexpressed in inflamed synovium of RA patients. New CA inhibitors (CAIs) incorporating CA-binding moiety and the cyclooxygenase inhibitor tail (nonsteroidal anti-inflammatory drug [NSAID] type) were studied. The aim of this work is the evaluation of the chemical stability of NSAID - CAI hybrids towards spontaneous or enzymatic hydrolysis by LC-MS/MS. The analytes are isomer pairs of 6- or 7-hydroxycoumarin, their different fragment ions abundances allowed the development of a mathematical tool (LEDA) to distinguish them. LEDA reliability at ng mL level was checked (>90%), being proved the effectiveness in the correct assignment of the isomer present in the sample. The hybrids resulted stable in all tested matrices allowing us to conclude that these compounds reach the target tissues unmodified, opening perspectives for their development in the treatment of inflammation.
类风湿性关节炎（RA）是一种由错误的自身免疫反应引起的慢性炎症性疾病。最近，有报道称一些人类碳酸酐酶（CAs）同工型在RA患者发炎的滑膜中过度表达。研究了结合CA结合部分和环氧化酶抑制剂尾部（非甾体抗炎药[NSAID]类型）的新型CA抑制剂（CAIs）。这项工作的目的是通过LC-MS/MS评估NSAID-CAI杂合物对自发或酶促水解的化学稳定性。分析物是6-或7-羟基香豆素的异构体对，它们不同的碎片离子丰度使得能够开发一种数学工具（LEDA）来区分它们。检查了LEDA在纳克/毫升水平的可靠性（>90%），证明其在正确鉴定样品中存在的异构体方面是有效的。杂合物在所有测试基质中均表现出稳定性，这使我们能够得出结论，这些化合物未被修饰地到达靶组织，为其在炎症治疗中的开发开辟了前景。
