Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pharmaceutics, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Anticancer Agents Med Chem. 2024;24(15):1126-1141. doi: 10.2174/0118715206291797240523112439.
Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target.
We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA.
The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed.
The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies.
Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.
耐药性一直是癌症化疗中的一个问题，这常常导致短期疗效。此外，文献表明，端粒 G-四链体可能是一个有前途的抗癌靶点。
我们合成并表征了两种新的嘧啶衍生物作为 G-四链体 DNA 的配体。
通过圆二色性（CD）和紫外-可见光谱以及聚丙烯酰胺凝胶电泳（PAGE）方法研究了新型非阳离子和阳离子嘧啶衍生物（3a，b）与 G-四链体 DNA（1k8p 和 3qsc）的相互作用。通过 MTT 测定评估了所需化合物的抗增殖活性。通过碘化丙啶（P.I.）染色和流式细胞术评估细胞凋亡诱导。对复合物 1k8p 和 3qsc 与化合物的计算分子建模（CMM）和分子动力学模拟（MD）进行了研究。计算并分析了范德华力、静电、极性溶剂化、溶剂可及表面积（SASA）和结合能。
实验结果证实，化合物 3a 和 3b 均与 1k8p 和 3qsc 相互作用，并对癌细胞产生细胞毒性和促凋亡作用。在配体存在的情况下，氢键的数量和 RMSD 值增加，表明结合更强，并表明结构动态增加。阳离子嘧啶 3b 的静电对结合能的贡献更高，表明结合能更负。
实验和 MD 结果均证实，与非阳离子嘧啶 3a 相比，3b 更倾向于与 DNA G-四链体（1k8p 和 3qsc）形成复合物，抑制细胞生长并诱导细胞凋亡。
