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Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-31 , DOI: 10.1016/j.ejmech.2020.112108 Chengcheng Fan 1 , Ting Zhong 2 , Huarong Yang 3 , Ying Yang 2 , Daoping Wang 2 , Xiaosheng Yang 2 , Yongnan Xu 4 , Yanhua Fan 2
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-31 , DOI: 10.1016/j.ejmech.2020.112108 Chengcheng Fan 1 , Ting Zhong 2 , Huarong Yang 3 , Ying Yang 2 , Daoping Wang 2 , Xiaosheng Yang 2 , Yongnan Xu 4 , Yanhua Fan 2
Affiliation
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Aurora A kinase, a member of the Aurora kinase family, is frequently overexpressed in various human cancers. In addition, Overexpression of Aurora A kinase is associated with drug resistance and poor prognosis in many cancers including breast cancer. Therefore, Aurora A kinase has been considered as an attractive anticancer target for the treatment of human cancers. Herein, A series of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives were designed, synthesized, and evaluated as Aurora A kinase inhibitors. The cell-based cytotoxicity assays showed that compound 16h was the most potent cytotoxic agent against all tested cancer cells and had a lower IC50 value than ENMD-2076 against MDA-MB-231 cells. Meanwhile, Aurora A kinase assay and Western blot analysis showed that 16h inhibited Aurora A kinase with an IC50 value of 21.94 nM and suppressed the phosphorylation of Histone H3 on Ser10 and Aurora A kinase on Thr288, which were consistent with the activation of Aurora A kinase. Accordingly, 16h caused aberrant mitotic phenotypes and obvious G2/M phase arrest in MDA-MB-231 cells and induced caspase-dependent apoptosis in MDA-MB-231 cells. These results demonstrated that 16h is a potential candidate for the development of anticancer agents targeting Aurora A kinase.
中文翻译：
设计，合成，生物评价6-（2-氨基-1H-苯并[d]咪唑-6-基）喹唑啉-4（3H）-一衍生物作为具有极光激酶抑制作用的新型抗癌药。
作为Aurora激酶家族成员的Aurora A激酶在各种人类癌症中经常过表达。此外，在包括乳腺癌在内的许多癌症中，Aurora A激酶的过度表达与耐药性和预后不良有关。因此，极光A激酶被认为是治疗人类癌症的有吸引力的抗癌靶标。在此，设计，合成了一系列6-（2-氨基-1H-苯并[d]咪唑-6-基）喹唑啉-4（3H）-衍生物，并将其评估为Aurora A激酶抑制剂。基于细胞的细胞毒性测定表明，化合物16h是对所有测试癌细胞的最有效的细胞毒性剂，并且对MDA-MB-231细胞的IC50值低于ENMD-2076。同时，Aurora A激酶测定和蛋白质印迹分析表明16h抑制Aurora A激酶，IC50值为21。94 nM并抑制了Ser10上的组蛋白H3和Thr288上的Aurora A激酶的磷酸化，这与Aurora A激酶的激活一致。因此，16h在MDA-MB-231细胞中引起异常的有丝分裂表型和明显的G2 / M期阻滞，并在MDA-MB-231细胞中诱导caspase依赖性凋亡。这些结果表明，16h是开发针对Aurora A激酶的抗癌药的潜在候选者。
更新日期：2020-02-03
中文翻译：
设计，合成，生物评价6-（2-氨基-1H-苯并[d]咪唑-6-基）喹唑啉-4（3H）-一衍生物作为具有极光激酶抑制作用的新型抗癌药。
作为Aurora激酶家族成员的Aurora A激酶在各种人类癌症中经常过表达。此外，在包括乳腺癌在内的许多癌症中，Aurora A激酶的过度表达与耐药性和预后不良有关。因此，极光A激酶被认为是治疗人类癌症的有吸引力的抗癌靶标。在此，设计，合成了一系列6-（2-氨基-1H-苯并[d]咪唑-6-基）喹唑啉-4（3H）-衍生物，并将其评估为Aurora A激酶抑制剂。基于细胞的细胞毒性测定表明，化合物16h是对所有测试癌细胞的最有效的细胞毒性剂，并且对MDA-MB-231细胞的IC50值低于ENMD-2076。同时，Aurora A激酶测定和蛋白质印迹分析表明16h抑制Aurora A激酶，IC50值为21。94 nM并抑制了Ser10上的组蛋白H3和Thr288上的Aurora A激酶的磷酸化，这与Aurora A激酶的激活一致。因此，16h在MDA-MB-231细胞中引起异常的有丝分裂表型和明显的G2 / M期阻滞，并在MDA-MB-231细胞中诱导caspase依赖性凋亡。这些结果表明，16h是开发针对Aurora A激酶的抗癌药的潜在候选者。
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