| 王宇,穆特娃尔·木合布力,木合布力·阿布力孜,杨争,鲁阔,晏通,邓欣怡,佐合拉古丽·木塔力甫.化学通报,2025,88(4):424-436. |
| 查尔酮衍生物的设计、合成及其抗多药耐药宫颈癌和抗血管生成活性的评价 |
| Design, Synthesis and Evaluation of Chalcone Derivatives for Anti-Multidrug Resistant Cervical Cancer and Anti-Angiogenic Activity |
| 投稿时间：2024-11-14 修订日期：2025-01-13 |
| DOI： |
| 中文关键词: 宫颈癌 查尔酮 血管生成 微管蛋白 |
| 英文关键词:Cervical cancer, Chalcone, Angiogenesis, Tubulin |
| 基金项目:国家自然科学基金项目(82160654)和新疆天然药物活性组分与释药技术重点实验室项目(XJDX1713)资助 |
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| 中文摘要: |
| 宫颈癌是一种最常见的妇科恶性肿瘤。靶向微管蛋白秋水仙碱结合位点的查尔酮类衍生物对宫颈癌细胞具有潜在的细胞毒性。本研究设计并合成了13个查尔酮衍生物作为秋水仙碱结合位点抑制剂(CBSIs)。评价5b对人宫颈癌细胞(SiHa、HeLa、HeLa/DDP和HeLa/DOX)和人正常宫颈上皮细胞(H8)的增殖抑制活性。发现5b具有显著的抗宫颈癌活性,IC50值为0.32 μM~2.78 μM,且对H8 细胞具有极低的毒性(IC50>100 μM)。进一步研究表明,5b在G2/M期阻滞HeLa细胞周期,诱导HeLa细胞凋亡,抑制HeLa细胞迁移和侵袭。免疫荧光实验、EBI竞争实验、体外微管蛋白聚合和分子对接实验表明,5b结合于秋水仙碱结合位点,抑制微管蛋白的聚合。在抗血管生成方面,5b不仅对HUVECs没有毒性,而且可以在体外有效的抑制HUVECs管的形成、迁移和侵袭。上述结果表面,5b是一种有效的CBSIs,具有显著的抗血管生成和抗宫颈癌特性。 |
| 英文摘要: |
| Cervical cancer is one of the most common gynecological malignancies. Chalcone derivatives targeting the colchicine binding site of microtubule proteins are potentially cytotoxic to cervical cancer cells. In this study, 13 chalcone derivatives were designed and synthesized as colchicine binding site inhibitors (CBSIs). The proliferation inhibitory activity of 5b was evaluated against human cervical cancer cells (SiHa, HeLa, HeLa/DDP and HeLa/DOX) and human normal cervical epithelial cells (H8). 5b was found to possess significant anti-cervical cancer activity with IC50 values ranging from 0.32 μM to 2.78 μM and very low toxicity (IC50>100 μM) against H8 cells. Further studies showed that 5b blocked the HeLa cell cycle in G2/M phase, induced HeLa cell apoptosis, and inhibited HeLa cell migration and invasion. Immunofluorescence assay, EBI competition assay, in vitro tubulin polymerization and molecular docking assay showed that 5b binds to colchicine binding site and inhibits tubulin polymerization. In terms of anti-angiogenesis, 5b was not only non-toxic to HUVECs, but also could effectively inhibit the formation, migration and invasion of HUVECs tubes in vitro. The above results suggest that 5b is an effective CBSIs with significant anti-angiogenic and anti-cervical cancer properties. |
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