Alsehli Mosa, Sheikh Ali Adeeb Al, Nafie Mohamed S, Bardaweel Sanaa, Aljuhani Ateyatallah, Darwish Khaled M, Alraqa Shaya Yahya, Rezki Nadjet, Aouad Mohamed Reda
Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002 Saudi Arabia.
Chemistry Department, Kuwait University, Sabah Al Salem University City, Kuwait.
Bioorg Chem. 2025 Feb;155:108131. doi: 10.1016/j.bioorg.2025.108131. Epub 2025 Jan 7.
The discovery of novel anti-cancer drugs motivated us to synthesize a new series of triple 1,2,3-triazole-based arm scaffolds featuring distinct un functionalized alkyl and/or aryl side chains with possible anti-cancer action using the click chemistry approach under both conventional and green microwave irradiation (MWI) methods. The Cu(I) catalyzed cycloaddition reaction of targeted tris-alkyne with un functionalized aliphatic and aromatic azides has been adopted as an efficient approach for synthesizing the desired click adducts. Microwave irradiation improved the synthetic processes, resulting in higher yields and faster reaction times. Spectroscopic techniques (FT-IR, H, C NMR andCHN analysis) were used for the elucidation of the resulting click structures. The newly synthesized tris-1,2,3-triazoles exhibited promising cytotoxicity, particularly compounds 26 and 28, with IC values of 22.18 µM and 20.3 µM against A549 and CaCo-2 cells, respectively. While they had IC values of 23.06 µM and 21.91 µM against T-47D and CaCo-2 cells, respectively. Both compounds exhibited promising anti-proliferative activity through the wound healing assay. Additionally, both compounds induced total apoptotic cell death by 68.3 % and 58.5 %, respectively, compared to untreated cells (7.7 %). Furthermore, they induced necrotic cell death by 1.4 % and 10.5 %, respectively, compared to 0.1 % in the untreated cells. For the molecular target, compounds 26 and 28 exhibited potent VEGFR2 inhibition with IC values of 35.5 nM and 27.8 nM, respectively, and this was highlighted through the molecular docking findings. Tris-1,2,3-triazoles (26 and 28) exhibited promising cytotoxicity and anti-proliferative against T-47D breast cancer cells through apoptosis and VEGFR2 inhibition using both enzyme kit and western blotting protein expression assays. Molecular docking study highlighted the binding affinity of tested compounds towards the VEGFR2 protein. Accordingly, tris-1,2,3-triazoles (26 and 28) can be further developed as more potent anti-cancer agents.
新型抗癌药物的发现促使我们使用点击化学方法，在传统和绿色微波辐射（MWI）方法下，合成一系列新的基于1,2,3-三唑的三联臂支架，其具有不同的未官能化烷基和/或芳基侧链，可能具有抗癌作用。已采用铜（I）催化的靶向三炔与未官能化脂肪族和芳香族叠氮化物的环加成反应作为合成所需点击加合物的有效方法。微波辐射改善了合成过程，提高了产率并缩短了反应时间。光谱技术（傅里叶变换红外光谱、氢谱、碳谱和元素分析）用于阐明所得点击结构。新合成的三-1,2,3-三唑表现出有前景的细胞毒性，特别是化合物26和28，对A549和CaCo-2细胞的IC值分别为22.18 μM和20.3 μM。而它们对T-47D和CaCo-2细胞的IC值分别为23.06 μM和21.91 μM。通过伤口愈合试验，这两种化合物均表现出有前景的抗增殖活性。此外，与未处理的细胞（7.7%）相比，这两种化合物分别诱导68.3%和58.5%的细胞发生完全凋亡性死亡。此外，与未处理细胞中的0.1%相比，它们分别诱导1.4%和10.5%的细胞发生坏死性死亡。对于分子靶点，化合物26和28表现出对血管内皮生长因子受体2（VEGFR2）的强效抑制作用，IC值分别为35.5 nM和27.8 nM，这在分子对接研究结果中得到了突出体现。三-1,2,3-三唑（26和28）通过使用酶试剂盒和蛋白质免疫印迹法检测蛋白表达，表现出通过诱导凋亡和抑制VEGFR2对T-47D乳腺癌细胞有前景的细胞毒性和抗增殖作用。分子对接研究突出了测试化合物与VEGFR2蛋白的结合亲和力。因此，三-1,2,3-三唑（26和28）可进一步开发为更有效的抗癌药物。
