Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Sinai University-Kantra Branch, Egypt.
Bioorg Chem. 2023 Jun;135:106496. doi: 10.1016/j.bioorg.2023.106496. Epub 2023 Mar 25.
Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC = 0.093 ± 0.006 μM and 0.143 ± 0.008 μM, respectively) to those of lapatinib and ribociclib (IC = 0.03 ± 0.002 μM and 0.067 ± 0.004 μM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.
新设计的 4-氨基喹唑啉衍生物（5a-f、6a、b、7、8、9、10a-c、11a、b、12a、b 和 13a、b）已经合成，并评估了它们作为潜在的多靶抗肿瘤活性、凋亡和抗增殖作用。因此，在美国国家癌症研究所（NCI）的 NCI 60 人癌细胞系（9 个亚系）中筛选了所有合成化合物的体外细胞毒性活性。成功地，2-吗啉基-N-（喹唑啉-4-基）乙酰胺 5e 因其对各种癌细胞系的显著效力和广谱活性而获得 NSC 代码；白血病 K-562、非小细胞肺癌 NCI-H522 细胞、结肠癌 SW-620、黑色素瘤 LOX IMVI、MALME-3M、肾癌细胞 RXF 393、ACHN 和乳腺癌 MDA-MB231/ATCC（GI%=99.6、161、126.03、90.22、174.47、139.7、191 和 97）。化合物 5e 对黑色素瘤 LOX IMVI 显示出最佳的抑制活性（GI=1.3µM），当在五个剂量下对 NCI 60 细胞系进行测试时。此外，化合物 5e 显示出与拉帕替尼和瑞博西利相当的 EGFR 和 CDK2 抑制活性结果（IC=0.093±0.006µM 和 0.143±0.008µM，分别）。化合物 5e 对黑色素瘤 LOX IMVI 的 Western 印迹分析显示，与拉帕替尼（31.18%）和瑞博西利（29.66%）相比，EGFR 和 CDK2 蛋白表达百分比显著降低，分别高达 32.97%和 34.09%。此外，化合物 5e 导致肾 UO-31 细胞的 S 期和乳腺癌 MCF7 和卵巢癌 IGROV1 的 G1 期明显的细胞周期阻滞，与对照物的 DNA 含量显著增加相关。相应地，它表现出有希望的抗增殖和凋亡活性，与未经处理的对照细胞相比，肾癌细胞 UO-31、乳腺癌 MCF7 和卵巢 IGROV1 癌细胞系的总凋亡百分比显著增加（分别为 1.79%至 46.72%、2.19%至 39.02%和 1.66%至 42.51%）。分子建模和动态模拟研究结果支持了本工作的主要目标。
