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1,2,3-Triazole-Chalcone hybrids: Synthesis, in vitro cytotoxic activity and mechanistic investigation of apoptosis induction in multiple myeloma RPMI-8226.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.ejmech.2020.112062 Heba F Ashour 1 , Laila A Abou-Zeid 2 , Magda A-A El-Sayed 1 , Khalid B Selim 3
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.ejmech.2020.112062 Heba F Ashour 1 , Laila A Abou-Zeid 2 , Magda A-A El-Sayed 1 , Khalid B Selim 3
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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 IC50 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.
中文翻译：
1,2,3-三唑-查耳酮杂种：多发性骨髓瘤RPMI-8226的合成，体外细胞毒性活性和凋亡诱导机制的研究。
合成了一系列新的1,2,3-三唑-查耳酮杂种，并根据NCI（USA）方案在体外针对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（最有效的衍生物）的化合物4d在10μM时分别抑制RPMI-8226和SR白血病细胞系的生长99.73％和94.95％。同样，在相同测试浓度下，它抑制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显示六种类型的肿瘤细胞的IC50值小于1μM，MCF7的高选择性指数达到104倍。化合物4d对最敏感的白血病细胞株显示出比甲氨蝶呤和吉非替尼优越的活性，对其余敏感细胞株的活性更高或相当。RPMI-8226细胞的流式细胞仪分析表明，化合物4d导致细胞周期停滞在G2 / M期，并以剂量依赖性方式诱导细胞凋亡。机理评估认为这种凋亡诱导通过诱导ROS积累，增加Bax / Bcl-2比和激活胱天蛋白酶3、7和9来触发线粒体凋亡途径。
更新日期：2020-01-17
中文翻译：
1,2,3-三唑-查耳酮杂种：多发性骨髓瘤RPMI-8226的合成，体外细胞毒性活性和凋亡诱导机制的研究。
合成了一系列新的1,2,3-三唑-查耳酮杂种，并根据NCI（USA）方案在体外针对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（最有效的衍生物）的化合物4d在10μM时分别抑制RPMI-8226和SR白血病细胞系的生长99.73％和94.95％。同样，在相同测试浓度下，它抑制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显示六种类型的肿瘤细胞的IC50值小于1μM，MCF7的高选择性指数达到104倍。化合物4d对最敏感的白血病细胞株显示出比甲氨蝶呤和吉非替尼优越的活性，对其余敏感细胞株的活性更高或相当。RPMI-8226细胞的流式细胞仪分析表明，化合物4d导致细胞周期停滞在G2 / M期，并以剂量依赖性方式诱导细胞凋亡。机理评估认为这种凋亡诱导通过诱导ROS积累，增加Bax / Bcl-2比和激活胱天蛋白酶3、7和9来触发线粒体凋亡途径。
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