设计、合成喹唑啉-4-酮/查尔酮杂合体及其对 EGFR 抑制途径的抗增殖活性。
Design, Synthesis, and Antiproliferative Activity of Quinazolin-4-One/Chalcone Hybrids the EGFR Inhibition Pathway.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519, Minia, Egypt.
出版信息
Anticancer Agents Med Chem. 2023;23(17):1932-1943. doi: 10.2174/1871520623666230727104933.
BACKGROUND
Quinazolinone scaffolds have drawn international attention due to their potent anticancer activity and therapeutic applications. Furthermore, Chalcone and Oxime are special chemical templates with a wide range of biological activities, including anti-cancer activity. As a result, the purpose of this research is to synthesize and develop a new series of 2-thioxo-3-substituted quinazolin-4-one/chalcone analogues and 2-thioxo-3-substituted quinazolin-4-one/oximes analogues in order to obtain a new cytotoxic agent that can target epidermal growth factor (EGFR) and/or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) oncogene.
OBJECTIVE
All synthesised compounds were tested for anticancer activity against four human cancer cell lines. The new hybrids' potential anti-cancer mechanism was evaluated using EGFR and BRAF enzymatic tests. The most active molecules within the target enzyme's active site were studied using molecular docking. Apoptosis and cell cycle analysis were also investigated.
METHODS
The target compounds 7a-j (series I) are obtained in high yields by alkylation of 2-mercapto-3-ethyl-(3H)- quinazolin-4-one 3a with acylated chalcones 6a-j. Alkylation of compounds 3b-c with N-(4-acetylphenyl)-2- bromoacetamide 8, the corresponding ketones intermediates 9b-c was produced in high yields. Compounds 7a-j, 9b-c, and 10b-c were tested for their antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as a control drug. The EGFR and BRAF assay tests were used to assess the inhibitory potency against EGFR and BRAF.
RESULTS
Compounds 7c, 7d, 7f and 10c exhibited high proliferative activity and inhibited EGFR, which could serve as a potential target for antiproliferative activity. The most active hybrid, 7c, primarily caused cell cycle arrest in G0/G1 phase and S phase as well as cell apoptosis. Finally, the most active hybrids were docked well to the EGFR active site.
CONCLUSION
2-thioxo-3-substituted quinazolin-4-one/chalcone derivatives have significant apoptotic and antiproliferative properties.
背景
由于其强大的抗癌活性和治疗应用，喹唑酮支架引起了国际关注。此外，查尔酮和肟是具有广泛生物活性的特殊化学模板，包括抗癌活性。因此，本研究的目的是合成和开发一系列新型 2-硫代-3-取代喹唑啉-4-酮/查尔酮类似物和 2-硫代-3-取代喹唑啉-4-酮/肟类似物，以获得一种新的细胞毒性剂，可针对表皮生长因子 (EGFR) 和/或 V-Raf 鼠肉瘤病毒致癌基因同源物 B (BRAF) 癌基因。
目的
所有合成的化合物均针对四种人癌细胞系进行了抗癌活性测试。使用 EGFR 和 BRAF 酶测试评估新杂合体的潜在抗癌机制。使用分子对接研究靶酶活性部位内最活跃的分子。还研究了细胞凋亡和细胞周期分析。
方法
通过 2-巯基-3-乙基-(3H)-喹唑啉-4-酮 3a 与酰化查尔酮 6a-j 的烷基化，以高产率获得目标化合物 7a-j（系列 I）。用 N-(4-乙酰基苯基)-2-溴乙酰胺 8 烷基化化合物 3b-c，得到相应的酮中间体 9b-c，产率高。用 MTT 法测定化合物 7a-j、9b-c 和 10b-c 对四种人癌细胞系的增殖活性，并以多柔比星为对照药物。使用 EGFR 和 BRAF 测定试验评估对 EGFR 和 BRAF 的抑制效力。
结果
化合物 7c、7d、7f 和 10c 表现出高增殖活性并抑制 EGFR，可作为抗增殖活性的潜在靶点。最活跃的杂种 7c 主要导致细胞周期停滞在 G0/G1 期和 S 期以及细胞凋亡。最后，最活跃的杂种与 EGFR 活性部位结合良好。
结论
2-硫代-3-取代喹唑啉-4-酮/查尔酮衍生物具有显著的凋亡和抗增殖特性。
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