Rupar Jelena, Popović-Nikolić Marija, Nikolić Katarina, Dobričić Vladimir, Čudina Olivera, Aleksić Mara M
University of Belgrade - Faculty of Pharmacy, Department of Physical Chemistry and Instrumental Methods, Vojvode Stepe 450, P.O.Box 146, Belgrade 11221, Serbia.
University of Belgrade - Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Vojvode Stepe 450, P.O.Box 146, Belgrade 11221, Serbia.
J Pharm Biomed Anal. 2025 Nov 15;265:117062. doi: 10.1016/j.jpba.2025.117062. Epub 2025 Jul 10.
Investigating and understanding the redox characteristics of potential anticancer agents is of great importance, as these properties are the key factor in the anticancer potential of drugs and can impact the mechanism of action, stability, metabolism, and selectivity of the drug toward cancer cells. Four compounds, previously confirmed to possess notable in vitro anticancer activity and the ability to interact with DNA, were subjected to a detailed electrochemical study. These are 9-acridinyl amino acid derivatives (9R-A), which were investigated in this study using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) with a glassy carbon electrode. The effects of pH (ranging from pH 2-9) and scan rate were thoroughly examined. The findings revealed that three independent oxidation and reduction processes occurred, all of which were diffusion-controlled. Two electroactive regions of the molecule contribute to these redox processes: the nitrogen (N10) of the acridine ring and the enamine nitrogen (N11) in the derivative's side chain. In 9R-A, the acridine ring undergoes a two-electron oxidation: first forming a monomeric radical cation that dimerizes, then undergoing a second electron transfer to yield a new radical cation. The reduction mechanism similarly involves a two-electron transfer, producing a monomeric radical that dimerizes and later forms a new radical. A significant factor in the redox behavior of 9-acridinyl amino acid derivatives is the presence of a secondary amine in the side-chain substituent. This amine undergoes oxidation via the loss of a single electron, resulting in the formation of a monomeric radical cation that is stabilized through deprotonation. While the oxidation mechanism appears to be consistent across all four 9R-A derivatives, differences in their oxidation affinity arise due to structural variations in the side-chain substituents. The experimental electrochemical findings were further supported by computational chemistry. Quantum chemical parameter evaluations provide deeper insights into the oxidation and reduction mechanisms, particularly in relation to the influence of substituents on these processes.
研究和了解潜在抗癌药物的氧化还原特性非常重要，因为这些特性是药物抗癌潜力的关键因素，并且会影响药物对癌细胞的作用机制、稳定性、代谢和选择性。四种先前已证实具有显著体外抗癌活性且能与DNA相互作用的化合物，接受了详细的电化学研究。这些是9-吖啶基氨基酸衍生物（9R-A），本研究使用循环伏安法（CV）和差分脉冲伏安法（DPV）以及玻碳电极对其进行了研究。全面考察了pH值（范围为pH 2 - 9）和扫描速率的影响。研究结果表明发生了三个独立的氧化和还原过程，所有这些过程均受扩散控制。分子的两个电活性区域促成了这些氧化还原过程：吖啶环的氮（N10）和衍生物侧链中的烯胺氮（N11）。在9R-A中，吖啶环经历双电子氧化：首先形成二聚的单体自由基阳离子，然后进行第二次电子转移以产生新的自由基阳离子。还原机制同样涉及双电子转移，产生二聚的单体自由基，随后形成新的自由基。9-吖啶基氨基酸衍生物氧化还原行为的一个重要因素是侧链取代基中存在仲胺。该胺通过失去单个电子进行氧化，导致形成通过去质子化稳定的单体自由基阳离子。虽然氧化机制在所有四种9R-A衍生物中似乎是一致的，但由于侧链取代基的结构变化，它们的氧化亲和力存在差异。计算化学进一步支持了实验电化学研究结果。量子化学参数评估为氧化和还原机制提供了更深入的见解，特别是关于取代基对这些过程的影响。
