Liška Tomáš Ján, Janovec Ladislav, Michalková Radka, Potočňák Ivan, Samolova Erika, Tvrdoňová Monika, Bekešová Slávka, Gramblička Michal, Kudličková Zuzana, Trizna Lukáš, Sabolová Danica, Mojžiš Ján, Vilková Mária
NMR Laboratory, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01 Košice, Slovak Republic.
Department of Organic Chemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01 Košice, Slovak Republic.
ACS Omega. 2025 Sep 30;10(40):47007-47021. doi: 10.1021/acsomega.5c05347. eCollection 2025 Oct 14.
A new series of acridin-4-yl-based thiazolidinone derivatives was synthesized and structurally characterized using NMR, IR, HRMS, and single-crystal X-ray diffraction. NMR analysis in solution revealed signal multiplicity suggestive of isomeric or conformational heterogeneity. To investigate this behavior, we employed GFN2-xTB, DFT (PBE0-D4 and revDSD-PBEP86-D4), and ab initio molecular dynamics simulations. Theoretical results indicated a preference for nonplanar conformers due to steric hindrance and internal rotations, in agreement with experimental NMR and crystallographic data. Conformational searches and NMR prediction further supported the predominance of and isomers in solutions. Biological evaluation revealed selective cytotoxicity of compound against HeLa and A549 cell lines (IC = 14.75 and 17.75 μM, respectively). Mechanistic studies in HeLa cells demonstrated dose-dependent apoptosis induction, mitochondrial membrane hyperpolarization, cytochrome c release, S-phase cell cycle arrest, and elevated intracellular ROS. Co-treatment with the antioxidant -acetylcysteine (NAC) significantly mitigated these effects, suggesting a ROS-mediated mitochondrial apoptotic pathway. This integrated experimental-theoretical study highlights the importance of conformational dynamics in modulating biological activity and provides valuable insights into the structure-activity relationship of acridine-thiazolidinone hybrids. The results support their potential as modular scaffolds for further development of anticancer agents.
合成了一系列基于吖啶-4-基的噻唑烷酮衍生物，并通过核磁共振（NMR）、红外光谱（IR）、高分辨质谱（HRMS）和单晶X射线衍射对其结构进行了表征。溶液中的NMR分析显示信号多重性，表明存在异构体或构象异质性。为了研究这种行为，我们采用了GFN2-xTB、密度泛函理论（DFT，PBE0-D4和revDSD-PBEP86-D4）以及从头算分子动力学模拟。理论结果表明，由于空间位阻和内旋转，非平面构象体更受青睐，这与实验NMR和晶体学数据一致。构象搜索和NMR预测进一步支持了溶液中 和 异构体的优势。生物学评估显示化合物对HeLa和A549细胞系具有选择性细胞毒性（IC分别为14.75和17.75 μM）。对HeLa细胞的机制研究表明，其具有剂量依赖性的凋亡诱导、线粒体膜超极化、细胞色素c释放、S期细胞周期停滞以及细胞内活性氧升高。与抗氧化剂N-乙酰半胱氨酸（NAC）共同处理可显著减轻这些影响，表明存在活性氧介导的线粒体凋亡途径。这项综合的实验-理论研究突出了构象动力学在调节生物活性中的重要性，并为吖啶-噻唑烷酮杂化物的构效关系提供了有价值的见解。结果支持了它们作为进一步开发抗癌药物的模块化支架的潜力。
