Synthesis of some quinazolinones inspired from the natural alkaloid L<i>-</i>norephedrine as EGFR inhibitors and radiosensitizers

A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds <b>5</b> and <b>6</b> were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for <b>5</b> and <b>6</b> revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound <b>5</b> was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of <b>5</b> and <b>6</b> in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.本研究通过L-去甲麻黄碱（L-norephedrine）辅助合成一系列喹唑啉酮类化合物，以构建新型类似物，作为潜在的抗癌与放射增敏剂。随后对该系列新化合物开展细胞毒性活性与表皮生长因子受体（EGFR）抑制活性评估，测试其对MDA-MB-231、MCF-7、HepG-2、HCT-116癌细胞系的细胞毒性作用。活性最优的化合物5与6，针对MCF-10A正常细胞系进行筛选后显示出较低的毒性；二者对MDA-MB-231乳腺癌细胞系展现出较高的选择性，证实具备相对安全的特性。对化合物5与6的放射增敏活性检测结果表明，在接受单次8 Gy γ射线辐照后，二者可对肿瘤细胞产生增敏作用。化合物5可诱导细胞凋亡，并将细胞周期阻滞于G2-M期。通过对化合物5与6在EGFR活性位点的分子对接模拟，深入解析了其与关键氨基酸的结合相互作用模式。