College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China.
Molecules. 2023 Jun 3;28(11):4537. doi: 10.3390/molecules28114537.
This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, significantly curtails the invasion and migration of HeLa cells. In addition, had an IC of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that exhibited binding free energies of -9.074 and -9.823 kcal·mol to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets.
本研究利用活性亚结构拼接原理设计并合成了 21 种新型含氮杂环查尔酮衍生物，以甘草查尔酮为先导化合物。这些衍生物的靶点是 VEGFR-2 和 P-gp，并评估了它们对宫颈癌的疗效。经过初步构象分析，化合物 ((E)-1-(2-羟基-5-((4-羟基哌啶-1-基)甲基)-4-甲氧基苯基)-3-(4-((4-甲基哌啶-1-基)甲基)苯基)丙-2-烯-1-酮)对人宫颈癌细胞 (HeLa 和 SiHa) 的增殖具有显著的抑制活性，IC 值分别为 6.52±0.42 和 7.88±0.52μM，与其他化合物和阳性对照药物相比。此外，该化合物对人正常宫颈上皮细胞 (H8) 的毒性较低。后续研究表明，化合物 抑制 VEGFR-2 的磷酸化，抑制 HeLa 细胞中 p-VEGFR-2、p-PI3K 和 p-Akt 蛋白的磷酸化，从而抑制细胞增殖，并呈浓度依赖性诱导细胞早期和晚期凋亡。此外，化合物 显著抑制 HeLa 细胞的侵袭和迁移。此外，化合物 对人宫颈癌顺铂耐药 HeLa/DDP 细胞的 IC 为 7.74±0.36μM，耐药指数 (RI) 为 1.19，而顺铂 HeLa 细胞的 IC 为 7.36。 与顺铂联合使用可显著降低 HeLa/DDP 细胞的顺铂耐药性。分子对接分析表明，化合物 与 VEGFR-2 和 P-gp 靶点的结合自由能分别为-9.074 和-9.823 kcal·mol，形成氢键。这些发现表明，化合物 具有作为抗宫颈癌药物的潜力，并可能逆转宫颈癌的顺铂耐药活性。引入 4-羟基哌啶和 4-甲基哌啶环可能有助于其疗效，其作用机制可能涉及双重抑制 VEGFR-2 和 P-gp 靶点。
