Design, synthesis and biological evaluation of tyrosine derivatives as Mcl-1 inhibitors.,European Journal of Medicinal Chemistry

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Design, synthesis and biological evaluation of tyrosine derivatives as Mcl-1 inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-14 , DOI: 10.1016/j.ejmech.2020.112142
Lulu Liu ₁ , Renshuai Liu ₁ , Xinying Yang ₁ , Xuben Hou ₁ , Hao Fang ₁

Affiliation

The upregulation of the protein myeloid cell leukemia-1 (Mcl-1) is closely associated with various human cancers, which can result in the evasion of apoptosis and a low survival rate. Therefore, developing Mcl-1 inhibitors has become a promising paradigm for cancer therapy. Herein, we designed and synthesized a novel series of tyrosine derivatives, among which compounds 5g, 6l and 6c exhibited very high binding affinity to Mcl-1 with Ki values of 0.18, 0.27 and 0.23 μM, respectively. Interestingly, compound 6l showed not only potent activity against Mcl-1 but also considerable selectivity over Bcl-2 and Bcl-xL, which was rationalized by molecular docking and fragment-centric topographical mapping (FCTM). It is worth noting that compounds 5g, 6l and 6c displayed potent antiproliferative activity against several cancer cell lines and could induce apoptosis of KM3 and HepG2 cells in a dose-dependent manner.

中文翻译：

设计，合成和生物学评估酪氨酸衍生物作为Mcl-1抑制剂。

蛋白质髓样细胞白血病1（Mcl-1）的上调与各种人类癌症密切相关，这可能导致规避凋亡和低存活率。因此，开发Mcl-1抑制剂已成为癌症治疗的有希望的范例。本文中，我们设计并合成了一系列新型的酪氨酸衍生物，其中化合物5g，6l和6c对Mcl-1的结合亲和力很高，Ki值分别为0.18、0.27和0.23μM。有趣的是，化合物6l不仅显示出对Mcl-1的有效活性，而且还显示出超过Bcl-2和Bcl-xL的选择性，这通过分子对接和以片段为中心的地形图（FCTM）得以合理化。值得注意的是，化合物5g

更新日期：2020-02-20

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