以二甲基吡啶-1,2,4-三唑混合物为基础，设计、合成了新的席夫碱，在靶向胃肠道癌细胞治疗方面发挥细胞毒作用。并进行了生物评估和分子对接研究。
New Schiff bases derived from dimethylpyridine-1,2,4-triazole hybrid as cytotoxic agents targeting gastrointestinal cancers: Design, synthesis, biological evaluation and molecular docking studies.
发表日期：2023 Jul 31
作者：
Małgorzata Strzelecka, Benita Wiatrak, Paulina Jawień, Żaneta Czyżnikowska, Piotr Świątek
来源：
BIOORGANIC CHEMISTRY
摘要：
在这项研究中，设计合成了一系列新型二甲基吡啶-1,2,4-三唑席夫碱的杂化结构，并对其在几种人类胃肠道癌细胞（EPG，Caco-2，LoVo，LoVo/Dx，HT29）和正常结肠上皮细胞（CCD 841 CoN）中的体外细胞毒力进行了评估。席夫碱4h是针对胃癌EPG细胞最强的化合物（CC50 = 12.10 ± 3.10μM），其细胞毒性比5-FU和顺铂分别高9倍和21倍。此外，它对正常细胞不具有毒性。在对结直肠癌细胞的细胞毒性中，化合物4d和4l对HT29细胞表现出良好的活性（CC50 = 52.80 ± 2.80μM和61.40 ± 10.70μM），其细胞毒性与顺铂和5-FU相当或更强。而且，它们对正常细胞的毒性较低，具有较高的选择性指数（SI，CCD 841 CoN/HT29 = 4.20和2.85），而参考药物的选择性指数较低（SI，CCD 841 CoN/HT29 < 1）。选择性席夫碱被用于 P- 糖蛋白抑制试验。席夫碱4d、4e和4l影响 P- 糖蛋白外排功能，显著增加了结肠癌细胞系中罗丹明123的积累。进一步的机制研究显示，化合物4l通过caspase依赖的机制和调节p53-MDM2信号通路诱导HT29细胞的凋亡细胞死亡。此外，对化合物4d、4e、4h和4i进行了体外物理化学性质的预测。结果显示这些化合物具有有前景的药物样性质。2023年版权所有© 作者。由Elsevier Inc.出版。保留所有权利。
In this research, a series of novel hybrid structures of dimethylpyridine-1,2,4-triazole Schiff bases were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, HT29) and normal colonic epithelial cells (CCD 841 CoN). Schiff base 4h was the most potent compound against gastric EPG cancer cells (CC50 = 12.10 ± 3.10 μM), being 9- and 21-fold more cytotoxic than 5-FU and cisplatin, respectively. Moreover, it was not toxic to normal cells. Regarding the cytotoxicity against colorectal cancer cells, compounds 4d and 4l exhibited good activity against HT29 cells (CC50 = 52.80 ± 2.80 μM and 61.40 ± 10.70 μM, respectively), and were comparable to or more potent than cisplatin and 5-FU. Also, they were less toxic to normal cells with a higher selectivity index (SI, CCD 841 CoN/HT29 = 4.20 and 2.85, respectively) than reference drugs (SI, CCD 841 CoN/HT29 < 1). Selected Schiff bases were subjected to the P-glycoprotein inhibition assay. Schiff bases 4d, 4e, and 4l influenced P-gp efflux function, significantly increasing the accumulation of rhodamine 123 in colon cancer cell lines. Further mechanistic studies showed that compound 4l induced apoptotic cell death through a caspase-dependent mechanism and by regulating the p53-MDM2 signaling pathway in HT29 cells. Also, physicochemical predictions of compounds 4d, 4e, 4h, and 4i were examined in silico. The results revealed that the compounds possessed promising drug-likeness profiles.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.