Vučkovski Marija, Filipović Ana, Jadranin Milka, Korićanac Lela, Žakula Jelena, Bondžić Bojan P, Bondžić Aleksandra M
Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000 Belgrade, Serbia.
University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Serbia.
Int J Mol Sci. 2024 Dec 5;25(23):13076. doi: 10.3390/ijms252313076.
Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, and P-glycoprotein substrate affinity, were assessed theoretically using the SwissADME software. The metal-chelating ability of the new compounds was evaluated on metal ions Fe, Zn, and Cu, whose homeostasis disruption is linked to the development of Alzheimer's disease. Inhibition potential was tested on the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase, as well as Na, K-ATPase, an enzyme commonly overexpressed in tumours. Antioxidant potential was assessed using the DPPH assay. Cytotoxicity studies were conducted on healthy MRC-5 cells and three cancer cell lines: HeLa, MDA-231, and MDA-468. The results indicated that derivatization of quercetin with THIQ yielded compounds with lower toxicity, preserved chelating ability, improved antioxidant potential, increased selectivity toward the cholinergic enzyme butyrylcholinesterase, and enhanced inhibition potential toward Na, K-ATPase and butyrylcholinesterase compared to quercetin alone. Therefore, the synthesized derivatives represent compounds with an improved profile and could be promising candidates for further optimization in developing drugs for neurodegenerative and cancer diseases.
槲皮素是一种具有显著药用潜力的著名黄酮类化合物，在其C8位用四氢异喹啉（THIQ）部分进行衍生化，并对新化合物的物理化学和药理学性质、抑制潜力、抗氧化活性和细胞毒性进行了评估。使用SwissADME软件从理论上评估了包括亲脂性、膜通透性和P-糖蛋白底物亲和力在内的物理化学和药理学性质。在金属离子铁、锌和铜上评估了新化合物的金属螯合能力，这些金属离子的体内稳态破坏与阿尔茨海默病的发展有关。对胆碱能酶乙酰胆碱酯酶和丁酰胆碱酯酶以及钠钾ATP酶（一种在肿瘤中通常过度表达的酶）测试了抑制潜力。使用DPPH测定法评估抗氧化潜力。对健康的MRC-5细胞和三种癌细胞系：HeLa、MDA-231和MDA-468进行了细胞毒性研究。结果表明，与单独的槲皮素相比，用THIQ对槲皮素进行衍生化得到的化合物具有更低的毒性、保留的螯合能力、提高的抗氧化潜力、对胆碱能酶丁酰胆碱酯酶的选择性增加，以及对钠钾ATP酶和丁酰胆碱酯酶的抑制潜力增强。因此，合成的衍生物代表了具有改进特性的化合物，可能是用于开发神经退行性疾病和癌症疾病药物的进一步优化的有前途的候选物。
