新型含氮杂环查耳酮衍生物的设计、合成及抗宫颈癌和逆转肿瘤多药耐药活性,Molecules

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新型含氮杂环查耳酮衍生物的设计、合成及抗宫颈癌和逆转肿瘤多药耐药活性
Molecules ( IF 4.2 ) Pub Date : 2023-06-03 , DOI: 10.3390/molecules28114537
Zheng Yang ₁ , Zheng-Ye Liu ₁ , Mourboul Ablise ₁ , Aikebaier Maimaiti ₁ , Zuohelaguli Mutalipu ₁ , Yusupuwajimu Alimujiang ₁ , Aizitiaili Aihaiti ₁

Affiliation

本研究以甘草查尔酮为先导化合物，利用活性亚结构剪接原理设计合成了21种新型含氮杂环查尔酮衍生物。这些衍生物的靶标是 VEGFR-2 和 P-gp，并评估了它们对宫颈癌的疗效。初步构象分析后，化合物 6f ((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) 对人宫颈癌细胞（HeLa 和 SiHa）表现出显着的抗增殖活性，与其他化合物和阳性对照药物。此外，该化合物对人类正常宫颈上皮细胞 (H8) 的毒性较低。随后的研究表明，6f 对 VEGFR-2 具有抑制作用，其在 HeLa 细胞中阻碍 p-VEGFR-2、p-PI3K 和 p-Akt 蛋白磷酸化的能力证明了这一点。反过来，这会以浓度依赖性方式抑制细胞增殖并诱导早期和晚期细胞凋亡。此外，6f 显着减少了 HeLa 细胞的侵袭和迁移。此外，6f 对人宫颈癌顺铂耐药的 HeLa/DDP 细胞的 IC50 为 7.74 ± 0.36 μM，耐药指数 (RI) 为 1.19，而顺铂 HeLa 细胞的耐药指数 (RI) 为 7.36。6f 和顺铂的组合导致 HeLa/DDP 细胞中的顺铂耐药性显着降低。分子对接分析显示 6f 的结合自由能为 -9.074 和 -9。823 kcal·mol−1 分别作用于 VEGFR-2 和 P-gp 靶标，并形成氢键合力。这些发现表明 6f 具有作为抗宫颈癌药物的潜力，并可能逆转宫颈癌中的顺铂耐药活性。4-羟基哌啶和 4-甲基哌啶环的引入可能有助于其疗效，其作用机制可能涉及对 VEGFR-2 和 P-gp 靶标的双重抑制。

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Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives

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 6f ((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 IC50 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 6f 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, 6f significantly curtails the invasion and migration of HeLa cells. In addition, 6f had an IC50 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 6f and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that 6f exhibited binding free energies of −9.074 and −9.823 kcal·mol−1 to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that 6f 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.

更新日期：2023-06-03

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