Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, 45110, Greece.
Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
Amino Acids. 2018 Feb;50(2):279-291. doi: 10.1007/s00726-017-2514-2. Epub 2017 Nov 28.
Quercetin is a flavonoid presenting cytotoxicity against different cancer cell lines. We hypothesized that its core could serve as a scaffold for generating more potent compounds. A quercetin-alanine bioconjugate was synthesized, its cellular internalization was monitored through confocal microscopy and its cytotoxic activity was explored against ten different cell lines. The bioconjugate consistently illustrated enhanced cytotoxic activity with respect to the parent compound. A threefold enhancement in its cytotoxicity was revealed for HeLa, A549, MCF-7 and LNCaP cells. In silico studies suggested that quercetin-alanine possesses enhanced binding affinity to human estrogen receptor alpha corroborating to its activity to MCF-7, overexpressing this receptor. Spectrofluorimetric, calorimetric and in silico studies revealed that quercetin-alanine binds primarily to Sudlow site I of serum albumin mainly through hydrogen bonding. Through this array of experiments we discovered that the specific compound bears a more refined pharmaceutical profile in contrast to quercetin in terms of cytotoxicity, while at the same time preserves its affinity to serum albumin. Natural products could thus offer a potent scaffold to develop bioconjugates with amplified therapeutic window.
槲皮素是一种具有细胞毒性的类黄酮，可针对不同的癌细胞系。我们假设它的核心可以作为生成更有效化合物的支架。合成了槲皮素-丙氨酸生物缀合物，通过共聚焦显微镜监测其细胞内化，并针对十种不同的细胞系探索其细胞毒性活性。与母体化合物相比，该生物缀合物始终表现出增强的细胞毒性活性。对于 HeLa、A549、MCF-7 和 LNCaP 细胞，其细胞毒性增强了三倍。计算机研究表明，槲皮素-丙氨酸与人雌激素受体α具有增强的结合亲和力，与其对过度表达该受体的 MCF-7 的活性相符。荧光分光光度法、量热法和计算机研究表明，槲皮素-丙氨酸主要通过氢键主要结合到血清白蛋白的 Sudlow 位点 I。通过一系列实验，我们发现与槲皮素相比，该特定化合物在细胞毒性方面具有更精细的药物特性，同时保留了与血清白蛋白的亲和力。天然产物因此可以为开发具有放大治疗窗口的生物缀合物提供有效的支架。
