喹唑啉酮衍生物作为乳腺癌新潜在的CDK4/6抑制剂、诱导细胞凋亡剂和放射增敏剂。
Quinazolinone derivatives as new potential CDK4/6 inhibitors, apoptosis inducers and radiosensitizers for breast cancer.
发表日期：2023 Aug 02
作者：
Mostafa Gm El-Gazzar, Marwa G El-Gazzar, Mostafa M Ghorab
来源：
Cellular & Molecular Immunology
摘要：
背景：CDK4/6靶向已经推动了乳腺癌的治疗。本文中，采用乙酰胺连接剂合成了新的喹唑啉酮类化合物，作为潜在的抗乳腺癌药物。方法和结果：通过对人乳腺癌细胞系（MCF7和MDA-MB-231）进行体外细胞毒性评估，发现1,3-苯并二氧杂环（5d）具有最高的毒性。它对CDK4/6具有良好的抑制活性。化合物5d使细胞周期停留在G1期，通过Annexin V-FITC检测导致早期和晚期凋亡，导致caspase-3水平升高，并在MCF7细胞中上调了Bax表达并下调了Bcl-2表达。当与单剂量8-Gy γ-辐射联合使用时，化合物5d展示出良好的放射增敏活性。结论：本研究介绍了作为新的乳腺癌CDK4/6抑制剂的喹唑啉酮骨架。
Background: Targeting CDK4/6 has advanced breast cancer treatment. Herein, new quinazolinones were synthesized with acetamide linkers as potential anti-breast cancer agents. Methods & results: In vitro cytotoxic evaluation on human breast cancer cell lines (MCF7 and MDA-MB-231) identified 1,3-benzodioxole (5d) to be of the highest potency. It showed good inhibitory activity on CDK4/6. Compound 5d arrested the cell cycle at the G1-phase, caused induction of early and late apoptosis in an Annexin V-FITC assay, led to an increase in the level of caspase-3 and upregulated Bax expression and downregulated Bcl-2 in MCF7 cells. Compound 5d showed good radiosensitizing activity when combined with a single dose of 8-Gy γ-radiation. Conclusion: This study introduces quinazolinone scaffolds as new CDK4/6 inhibitors for breast cancer.