University of Ain Shams, Faculty of Science, Department of Chemistry, Abbassia 11566, Cairo, Egypt.
Hormonal Evaluation Department, National Organization for Drug Control & Research (NODCAR), Cairo, Egypt.
Anticancer Agents Med Chem. 2019;19(4):538-545. doi: 10.2174/1871520619666190201145221.
The genetic heterogeneity of tumor cells and the development of therapy-resistant cancer cells in addition to the high cost necessitate the continuous development of novel targeted therapies.
In this regard, 14 novel benzoxazinone derivatives were synthesized and examined for anticancer activity against two human epithelial cancer cell lines; breast MCF-7 and liver HepG2 cells. 6,8-Dibromo-2- ethyl-4H-benzo[d][1,3]oxazin-4-one was subjected to react with nitrogen nucleophiles to afford quinazolinone derivatives and other related moieties (3-12). Benzoxazinone 2 responds to attack with oxygen nucleophile such as ethanol to give ethyl benzoate derivative 13. The reaction of benzoxazinone 2 with carbon electrophile such as benzaldehyde derivatives afforded benzoxazinone derivatives 14a and 14b.The structure of the prepared compounds was confirmed with spectroscopic tools including IR, 1H-NMR, and 13C-NMR.
Derivatives 3, 9, 12, 13, and 14b exhibited high antiproliferative activity and were selective against cancer cells showing no toxicity in normal fibroblasts. Derivative 3 with NH-CO group in quinazolinone ring was effective only against breast cells, while derivative 12 with NH-CO group in imidazole moiety was only effective against liver cells probably through arresting cell cycle and enabling repair mechanisms. The other derivatives (9, 13, and 14b) had broader antiproliferative activity against both cell lines. These derivatives enhance the expression of the p53 and caspases 9 and 3 to varying degrees in both cell lines. Derivative 14b caused the highest induction in the investigated genes and was the only derivative to inhibit the EGFR activity.
The unique features about derivative 14b could be attributed to its high lipophilicity, high carbon content, or its extended conjugation through planar aromatic system. More investigations are required to identify the lead compound(s) in animal models.
肿瘤细胞的遗传异质性和治疗耐药癌细胞的发展，以及高昂的成本，都需要不断开发新的靶向治疗方法。
在这方面，合成了 14 种新型苯并恶嗪酮衍生物，并对其进行了抗癌活性测试，针对两种人上皮癌细胞系；乳腺癌 MCF-7 和肝癌 HepG2 细胞。6,8-二溴-2-乙基-4H-苯并[d][1,3]恶嗪-4-酮与氮亲核试剂反应，得到喹唑啉酮衍生物和其他相关部分（3-12）。苯并恶嗪酮 2 与氧亲核试剂如乙醇反应，得到苯甲酸乙酯衍生物 13。苯并恶嗪酮 2 与碳亲电试剂如苯甲醛衍生物反应，得到苯并恶嗪酮衍生物 14a 和 14b。通过包括 IR、1H-NMR 和 13C-NMR 在内的光谱工具确认了所制备化合物的结构。
衍生物 3、9、12、13 和 14b 表现出高的增殖抑制活性，对癌细胞具有选择性，对正常成纤维细胞没有毒性。在喹唑啉酮环中具有 NH-CO 基团的衍生物 3 仅对乳腺癌细胞有效，而在咪唑部分具有 NH-CO 基团的衍生物 12 仅对肝癌细胞有效，可能通过阻断细胞周期并使修复机制能够起作用。其他衍生物（9、13 和 14b）对两种细胞系均具有更广泛的增殖抑制活性。这些衍生物在两种细胞系中不同程度地增强了 p53 和 caspase 9 和 3 的表达。衍生物 14b 引起了所研究基因的最高诱导，并且是唯一抑制 EGFR 活性的衍生物。
衍生物 14b 的独特之处可能归因于其高亲脂性、高碳含量或通过平面芳香系统的扩展共轭。需要进一步的研究来确定动物模型中的先导化合物。
