Abstract：
BACKGROUND: 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.
OBJECTIVE: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：耐药性一直是癌症化疗中的一个问题，这通常会导致短期有效性。Further,文献表明，端粒G-四链体可能是一个有希望的抗癌靶点。
目的：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。
方法：新型非阳离子和阳离子嘧啶衍生物的相互作用（3a，b）通过圆二色谱（CD），紫外可见光谱和聚丙烯酰胺凝胶电泳（PAGE）方法探索了G-四链体DNA（1k8p和3qsc）。通过MTT测定法评价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凋亡诱导。对1k8p和3qsc与化合物的配合物进行了计算分子建模(CMM)和分子动力学模拟(MD)研究。范德华夫妇,静电,极性溶剂化，溶剂可接触表面积(SASA)，并对结合能进行了计算和分析。
结果：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。在配体的存在下，氢键的数量和RMSD值增加，表明更强的结合，并暗示增加的结构动力学。阳离子嘧啶3b对结合能的静电贡献较高，表明更多的负结合能。
结论：实验和MD结果均证实，3b更容易与DNAG-四链体（1k8p和3qsc）形成复合物，抑制细胞生长，并诱导细胞凋亡，与非阳离子嘧啶3a相比。
目的：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。
方法：新型非阳离子和阳离子嘧啶衍生物的相互作用（3a，b）通过圆二色谱（CD），紫外可见光谱和聚丙烯酰胺凝胶电泳（PAGE）方法探索了G-四链体DNA（1k8p和3qsc）。通过MTT测定法评价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凋亡诱导。对1k8p和3qsc与化合物的配合物进行了计算分子建模(CMM)和分子动力学模拟(MD)研究。范德华夫妇,静电,极性溶剂化，溶剂可接触表面积(SASA)，并对结合能进行了计算和分析。
结果：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。在配体的存在下，氢键的数量和RMSD值增加，表明更强的结合，并暗示增加的结构动力学。阳离子嘧啶3b对结合能的静电贡献较高，表明更多的负结合能。
结论：实验和MD结果均证实，3b更容易与DNAG-四链体（1k8p和3qsc）形成复合物，抑制细胞生长，并诱导细胞凋亡，与非阳离子嘧啶3a相比。
