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Design, synthesis, stereochemical determination, molecular docking study, in silico pre-ADMET prediction and anti-proliferative activities of indole-pyrimidine derivatives as Mcl-1 inhibitors
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.bioorg.2021.105335
Phoebe F Lamie 1 , John N Philoppes 1
Affiliation  

In this study, fourteen novel indole-pyrimidine hybrids were designed and synthesized. Their chemical structures were confirmed using different spectroscopic techniques (1H NMR, 13C NMR, IR and mass). Their (E) stereochemical configuration was determined theoretically (MM2 property) and experimentally using 2D NMR technique (NOESY experiment). The prepared compounds were subjected to preliminary biological studies as Mcl-1 inhibitors. Most of the compounds exhibited good abilities for targeting Mcl-1 protein, especially, 7d, 7e, 7i and 7k (Ki = 11.19–15.21 nM). These derivatives were further evaluated against Bcl-XL and Bcl-2 proteins. Some compounds were found to have dual Mcl-1/Bcl-XL such as 7i, or Bcl-XL/Bcl-2 inhibitory activity as 7d.

The most potent derivatives as Mcl-1 inhibitors were chosen as representative examples for determination of in-vitro anti-proliferative activity against PC-3, K-562 and MDA-MB-231 cell lines. They possessed excellent to good anti-proliferative activities. All of the synthesized compounds were docked into Mcl-1 active site. Drug-likeness properties and in silico pre-ADMET characters were also predicted.



中文翻译:

吲哚-嘧啶衍生物作为 Mcl-1 抑制剂的设计、合成、立体化学测定、分子对接研究、计算机模拟 pre-ADMET 预测和抗增殖活性

在这项研究中,设计并合成了 14 种新型吲哚-嘧啶杂化物。使用不同的光谱技术(1 H NMR、13 C NMR、IR 和质量)确认了它们的化学结构。它们的 ( E ) 立体化学构型是通过理论(MM2 特性)和实验使用 2D NMR 技术(NOESY 实验)确定的。将制备的化合物作为 Mcl-1 抑制剂进行初步生物学研究。大多数化合物表现出良好的靶向 Mcl-1 蛋白的能力,尤其是7d7e7i7k (K i = 11.19–15.21 nM)。针对 Bcl-XL 和 Bcl-2 蛋白进一步评估了这些衍生物。发现一些化合物具有双重 Mcl-1/Bcl-XL 如7i或 Bcl-XL/Bcl-2 抑制活性如7d

选择最有效的衍生物作为 Mcl-1 抑制剂作为确定对 PC-3、K-562 和 MDA-MB-231 细胞系的体外抗增殖活性的代表性实例。它们具有极好的抗增殖活性。所有合成的化合物都停靠在 Mcl-1 活性位点。还预测了药物相似性和计算机模拟前 ADMET 特征。

更新日期:2021-09-09
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