Maniewska Jadwiga, Czyżnikowska Żaneta, Szczęśniak-Sięga Berenika M, Michalak Krystyna
Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
Department of Inorganic Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland.
Membranes (Basel). 2022 Aug 17;12(8):791. doi: 10.3390/membranes12080791.
The modified 1,2-benzothiazine analogues designed as new drug candidates and discussed in this paper are oxicam derivatives. Oxicams are a class of non-steroidal anti-inflammatory drugs (NSAIDs). Their biological target is cyclooxygenase (COX), a membrane protein associated with the phospholipid bilayer. In recent decades, it has been proven that the biological effect of NSAIDs may be closely related to their interaction at the level of the biological membrane. These processes are often complicated and the biological membranes themselves are very complex. Therefore, to study these mechanisms, simplified models of biological membranes are used. To characterize the interaction of six oxicam derivatives with DPPC, DMPC and EYPC, artificial models of biological membranes (multi-bilayers or liposomes), differential scanning calorimetry (DSC) and fluorescence spectroscopy techniques were applied. In spectroscopic measurements, two fluorescent probes (Laurdan and Prodan) localized in different membrane segments were used. All tested oxicam derivatives interacted with the lipid bilayers and may penetrate the artificial models of biological membranes. They intercalated into the lipid bilayers and were located in the vicinity of the polar/apolar membrane interface. Moreover, a good drug candidate should not only have high efficiency against a molecular target but also exhibit strictly defined ADMET parameters, therefore these activities of the studied compounds were also estimated.
本文中设计为新药候选物并进行讨论的修饰1,2 - 苯并噻嗪类似物是昔康衍生物。昔康是一类非甾体抗炎药（NSAIDs）。它们的生物学靶点是环氧化酶（COX），一种与磷脂双分子层相关的膜蛋白。近几十年来，已证实NSAIDs的生物学效应可能与其在生物膜水平的相互作用密切相关。这些过程通常很复杂，而且生物膜本身也非常复杂。因此，为了研究这些机制，人们使用了生物膜的简化模型。为了表征六种昔康衍生物与二棕榈酰磷脂酰胆碱（DPPC）、二肉豆蔻酰磷脂酰胆碱（DMPC）和蛋黄卵磷脂（EYPC）的相互作用，应用了生物膜的人工模型（多层膜或脂质体）、差示扫描量热法（DSC）和荧光光谱技术。在光谱测量中，使用了位于不同膜段的两种荧光探针（劳丹和普罗丹）。所有测试的昔康衍生物都与脂质双层相互作用，并可能穿透生物膜的人工模型。它们插入脂质双层中，并位于极性/非极性膜界面附近。此外，一个好的药物候选物不仅应该对分子靶点具有高效性，还应该表现出严格定义的药物代谢动力学和药物安全性参数，因此还对所研究化合物的这些活性进行了评估。
