黄酮类衍生物靶向 BCR-ABL 激酶：半合成、分子动力学模拟和酶抑制。
Flavonoid Derivatives Targeting BCR-ABL Kinase: Semisynthesis, Molecular Dynamic Simulations and Enzymatic Inhibition.
机构信息
Programa de Pos-Graduacao em Agroquimica, Universidade Federal do Espirito Santo, 29500000, Alegre - ES, Brazil.
Programa de Pos-Graduacao em Quimica, Universidade Federal do Espirito Santo, 29075910, Vitoria- ES, Brazil.
出版信息
Curr Top Med Chem. 2021;21(22):1999-2017. doi: 10.2174/1568026621666210705170047.
BACKGROUND
Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics.
OBJECTIVE
This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors.
METHODS
Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase.
RESULTS
Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k).
CONCLUSION
6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.
背景
天然产物一直是新趋势研究的热点，有助于深入了解生命科学的基本途径，并可作为药物治疗的策略。
目的
本工作专注于对 6-羟基黄酮母核进行进一步修饰，以获得改进的 BCR-ABL 激酶抑制剂。
方法
通过Williamson 合成得到醚衍生物，通过微波辅助点击反应得到三唑。通过 IR、1H 和 13C NMR 以及高分辨率质谱对化学结构进行了精细表征。测试了它们对 BCR-ABL 激酶的抑制活性。
结果
两个含有三唑环作为药效团桥的抑制剂在 IC50 值为 364 nM（化合物 3j）和 275 nM（化合物 3k）时表现出最强的激酶抑制作用。
结论
6-羟基黄酮骨架可被视为 BCR-ABL 激酶抑制剂的有前途的核心。
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