Marques Tiago J S, Salvador Diana, Oliveira Helena, Serra Vanda V, Paradis Nicholas, Wu Chun, Silva Vera L M, Ramos Catarina I V
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro 3810-193 Aveiro Portugal
CESAM-Centre for Environmental and Marine Studies, Department of Biology, University of Aveiro 3810-193 Aveiro Portugal.
RSC Med Chem. 2025 Apr 17. doi: 10.1039/d4md00959b.
In this work, two new acridone derivatives, and , were synthesized, for the first time, aiming to evaluate their potential as quadruplex stabilizers and anticancer agents. was synthesized through a very straightforward one-pot sequential chemical reaction involving the Heck cross-coupling reaction of ()-3-iodo-2-(4-methoxystyryl)-1-methylquinolin-4(1)-one with a vinyl pyridine followed by electrocyclization and oxidation, while the synthesis of involved an additional -methylation of the pyridine ring. Their ability to stabilize G-quadruplex DNA structures, which are associated with the regulation of oncogenes, was assessed using biophysical methods. Both compounds demonstrated significant quadruplex stabilization properties, showing selectivity to G-quadruplexes over duplex DNA. Molecular dynamics simulation experiments supported the preferential binding of to MYC. The cytotoxicity of these derivatives was further evaluated in two distinct pancreatic tumor cell lines, PanC-1 and MIA PaCa-2, the lung tumor A549 cell line, the melanoma A375 cell line, and the immortalized human keratinocyte HaCaT cell line, through the evaluation of cell viability. For PanC-1 and MIA PaCa-2, the cell cycle dynamics and apoptotic cell death along with colocalization were also evaluated. The results revealed that exhibited anticancer activity, correlated with its quadruplex stabilization ability and, although not exclusive, nuclear co-localization was observed. These findings suggest that the newly synthesized cationic acridone is a promising candidate for the development of novel anticancer therapies targeting G-quadruplex structures.
在这项工作中，首次合成了两种新的吖啶酮衍生物， 和 ，旨在评估它们作为四链体稳定剂和抗癌剂的潜力。 通过一种非常直接的一锅法连续化学反应合成，该反应涉及()-3-碘-2-(4-甲氧基苯乙烯基)-1-甲基喹啉-4(1)-酮与乙烯基吡啶的Heck交叉偶联反应，随后进行电环化和氧化，而 的合成涉及吡啶环的额外甲基化。使用生物物理方法评估了它们稳定与癌基因调控相关的G-四链体DNA结构的能力。两种化合物都表现出显著的四链体稳定特性，对G-四链体的选择性高于双链DNA。分子动力学模拟实验支持 对MYC的优先结合。通过评估细胞活力，在两种不同的胰腺肿瘤细胞系PanC-1和MIA PaCa-2、肺肿瘤A549细胞系、黑色素瘤A375细胞系以及永生化人角质形成细胞HaCaT细胞系中进一步评估了这些衍生物的细胞毒性。对于PanC-1和MIA PaCa-2，还评估了细胞周期动力学、凋亡细胞死亡以及共定位情况。结果表明， 表现出抗癌活性，与其四链体稳定能力相关，并且虽然不是唯一的，但观察到了核共定位。这些发现表明，新合成的阳离子吖啶酮是开发针对G-四链体结构的新型抗癌疗法的有希望的候选物。
