化疗毒性和肿瘤多药耐药仍然是宫颈癌临床治疗失败的主要原因。本研究以甘草查尔酮母核为先导化合物，以VEGFR-2和P-gp为作用靶点，利用活性子结构拼接原理设计合成了79种新型查耳酮衍生物，并探讨了它们的抗宫颈癌活性。进行了初步评估。结果显示，候选化合物B20对HeLa和HeLa/DDP细胞的IC50值分别为3.66±0.10和4.35±0.21μM，耐药指数（RI）为1.18，显着高于阳性药物顺铂（IC50：13.60±1.63，100.03±7.94μM，RI：7.36）。此外，B20 对 VEGFR-2 激酶和 P-gp 介导的罗丹明 123 外流表现出显着的抑制活性，并且能够抑制 VEGFR-2 和下游 PI3K/AKT 信号通路蛋白的磷酸化，诱导细胞凋亡，阻断细胞处于 S 期，并抑制 HUVEC 细胞的侵袭性迁移和小管生成。当 B20 为 200 毫克/千克时，急性毒性测试证明了可接受的安全性。在裸鼠HeLa/DDP细胞异种移植肿瘤模型中，B20在10和20 mg/kg时对移植肿瘤的抑制率分别为39.2%和79.2%。这些结果表明，B20 是一种有效的 VEGFR-2 和 P-gp 抑制剂，具有治疗顺铂耐药宫颈癌的积极潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Chemotherapy toxicity and tumor multidrug resistance remain the main reasons for clinical treatment failure in cervical cancer. In this study, 79 novel chalcone derivatives were designed and synthesized using the principle of active substructure splicing with the parent nucleus of licorice chalcone as the lead compound and VEGFR-2 and P-gp as the target of action and their potentials for anticervical cancer activity were preliminarily evaluated. The results showed that the IC50 values of candidate compound B20 against HeLa and HeLa/DDP cells were 3.66 ± 0.10 and 4.35 ± 0.21 μΜ, respectively, with a resistance index (RI) of 1.18, which was significantly higher than that of the positive drug cisplatin (IC50:13.60 ± 1.63, 100.03 ± 7.94 μΜ, RI:7.36). In addition, B20 showed significant inhibitory activity against VEGFR-2 kinase and P-gp-mediated rhodamine 123 efflux, as well as the ability to inhibit the phosphorylation of VEGFR-2 and downstream PI3K/AKT signaling pathway proteins, inducing apoptosis, blocking cells in the S-phase, and inhibiting invasive migration and tubule generation by HUVEC cells. Acceptable safety was demonstrated in acute toxicity tests when B20 was at 200 mg/kg. In the nude mouse HeLa/DDP cell xenograft tumor model, the inhibition rate of transplanted tumors was 39.2 % and 79.2 % when B20 was at 10 and 20 mg/kg, respectively. These results suggest that B20 is a potent VEGFR-2 and P-gp inhibitor with active potential for treating cisplatin-resistant cervical cancer.Copyright © 2024 Elsevier Inc. All rights reserved.