Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Dammeitta, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University, Gamsaa, Egypt.
Eur J Med Chem. 2020 Mar 1;189:112062. doi: 10.1016/j.ejmech.2020.112062. Epub 2020 Jan 17.
A new series of 1,2,3-triazole-chalcone hybrids has been synthesized and screened in vitro against a panel of 60 human cancer cell lines according to NCI (USA) protocol. Compound 4d having 3, 4-dimethoxyphenyl chalcone moiety, the most potent derivative, inhibited the growth of RPMI-8226 and SR leukemia cell lines by 99.73% and 94.95% at 10 μM, respectively. Also, it inhibited the growth of M14 melanoma, K-562 leukemia, and MCF7 breast cancer cell lines by more than 80% at the same test concentration. 4d showed IC values less than 1 μM on six types of tumor cells and high selectivity index reached to 104 fold on MCF7. Compound 4d showed superior activity than methotrexate and gefitinib against the most sensitive leukemia cell lines in addition to higher or comparable activity against the rest sensitive cell lines. Flow cytometry analysis in RPMI-8226 cells revealed that compound 4d caused cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner. Mechanistic evaluation referred this apoptosis induction to triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9.
已合成了一系列新的 1,2,3-三唑查耳酮杂合体，并根据美国国家癌症研究所（NCI）的方案在体外对 60 个人类癌细胞系进行了筛选。具有 3,4-二甲氧基苯基查耳酮部分的化合物 4d 是最有效的衍生物，在 10 μM 时分别抑制 RPMI-8226 和 SR 白血病细胞系的生长达 99.73%和 94.95%。此外，它在相同的测试浓度下抑制 M14 黑色素瘤、K-562 白血病和 MCF7 乳腺癌细胞系的生长超过 80%。4d 在六种肿瘤细胞上的 IC 值小于 1 μM，对 MCF7 的选择性指数高达 104 倍。与甲氨蝶呤和吉非替尼相比，化合物 4d 对最敏感的白血病细胞系具有更高的活性，并且对其余敏感细胞系的活性也更高或相当。在 RPMI-8226 细胞中的流式细胞术分析表明，化合物 4d 以剂量依赖的方式导致细胞周期停滞在 G2/M 期并诱导细胞凋亡。机制评估表明，这种细胞凋亡的诱导是通过触发线粒体凋亡途径，通过诱导 ROS 积累、增加 Bax/Bcl-2 比值和激活 caspase 3、7 和 9 来实现的。
