Boraei Ahmed T A, Nafie Mohamed S, Barakat Assem, Tanaka Tomohiro, Kawano Koshu, Tojo Toshifumi, Aoki Shin, Sarhan Ahmed A M
Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt; Department of Chemistry, College of Sciences, University of Sharjah, Sharjah (P.O. Box 27272), United Arab Emirates.
Bioorg Chem. 2025 Mar;156:108154. doi: 10.1016/j.bioorg.2025.108154. Epub 2025 Jan 10.
The search for new anticancer compounds is a major focus for researchers in chemistry, biology, and medicine. Cancer affects people of all ages and regions, with rising incidence rates. It does not discriminate by age or gender, making it a significant threat to humanity. Therefore, discovering new treatments is essential. As a result, new 3-S-alkylated 4-amino-5-indolyl-triazoles 2a-e were synthesized by the alkylation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with the appropriate alkylating agent using KCO in EtOH/DMF. Hydrazinolysis of ester 2a afforded the hydrazide 3 which was converted into the substituted thiosemicarbazide 4 by reaction with 4-chlorophenyl isothiocyanate. The substituted thiosemicarbazide 4 was cyclized to triazole-3-thione 5 by reflux in 4.0 N aqueous KOH. The hit compound 6 obtained from triazole-3-thione 5 by alkylation with ethyl chloroacetate. For cytotoxicity, interestingly, compound 6 was exhibited potent cytotoxicity with IC values of 11 and 8.5 μM compared to Erlotinib (IC = 3.5 μM). At the same time, other compounds exhibited poor cytotoxicity with higher IC values. Compound 6 was investigated regarding the apoptosis activity in A549 and Jurkat cells. It induced total apoptosis in A549 cells by 38-fold, and it induced total apoptosis in Jurkat cells by 15.9-fold, arresting the cell cycle in both cell lines at the S-phase. Additionally, compound 6 exhibited potent EGFR/AKT/ERK/P38-MAPKα inhibition in both enzyme targeting and molecular docking studies. Accordingly, compound 6 can be further developed as kinase-targeted anti-lung cancer.
寻找新型抗癌化合物是化学、生物学和医学领域研究人员的主要关注点。癌症影响着各个年龄层和地区的人群，且发病率不断上升。它不受年龄或性别的限制，对人类构成重大威胁。因此，发现新的治疗方法至关重要。结果，通过在乙醇/二甲基甲酰胺中使用碳酸钾，使4-氨基-5-(1H-吲哚-2-基)-2,4-二氢-3H-1,2,4-三唑-3-硫酮1与合适的烷基化剂进行烷基化反应，合成了新型3-S-烷基化4-氨基-5-吲哚基-三唑2a-e。酯2a的肼解反应得到酰肼3，其通过与4-氯苯基异硫氰酸酯反应转化为取代的硫代氨基脲4。取代的硫代氨基脲4在4.0 N氢氧化钾水溶液中回流环化生成三唑-3-硫酮5。通过用氯乙酸乙酯烷基化从三唑-3-硫酮5得到活性化合物6。有趣的是，就细胞毒性而言，与厄洛替尼（IC = 3.5 μM）相比，化合物6表现出强效的细胞毒性，IC值分别为11和8.5 μM。同时，其他化合物表现出较差的细胞毒性，IC值更高。对化合物6在A549和Jurkat细胞中的凋亡活性进行了研究。它在A549细胞中诱导的总凋亡率为38倍，在Jurkat细胞中诱导的总凋亡率为15.9倍，使两种细胞系的细胞周期都停滞在S期。此外，在酶靶向和分子对接研究中，化合物6均表现出对表皮生长因子受体/蛋白激酶B/细胞外信号调节激酶/丝裂原活化蛋白激酶α的强效抑制作用。因此，化合物6可进一步开发为激酶靶向的抗肺癌药物。
