Synthesis, anticancer screening, and in silico ADME prediction of novel 2‐pyridones as Pim inhibitors,Journal of Heterocyclic Chemistry

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Synthesis, anticancer screening, and in silico ADME prediction of novel 2‐pyridones as Pim inhibitors
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2020-07-20 , DOI: 10.1002/jhet.4064
Magda M. F. Ismail ₁ , Amel M. Farrag ₁ , Dalal Abou‐El‐Ela ₂

Affiliation

A novel series of 26 substituted N‐(2‐ethylphenyl)‐2‐oxo‐pyridine‐3‐carbonitriles have been designed and synthesized via one‐pot synthesis of various aromatic aldehydes, different aromatic acetophenones, and 2‐cyano‐N‐(2‐ethylphenyl)acetamide 1. Moreover, cytotoxicity of the target compounds was evaluated by NCI, which selected 14 compounds for one‐dose screening. Among them, compound 21 was selected for five‐dose screening, which confirmed its potency against most of cancer cell lines. This compound elicited selectivity profile against human cell line WI‐38. Cell cycle analysis was carried out, revealed that compound 21 is an apoptosis inducer causing cell cycle arrest at G2/M. Further exploration on the mode of action by evaluating its effect against Pim‐1, Pim‐2, and Pim‐3 demonstrated its inhibitory effect on Pim‐1 and Pim‐3 rather than Pim‐2. Molecular docking showed that compound 21 binds with high affinity to the active site of Pim‐1 enzyme through three hydrogen bonds and two arene‐H bonds.

中文翻译：

新型2-吡啶酮作为Pim抑制剂的合成，抗癌筛选和计算机模拟ADME预测

通过一锅合成各种芳族醛，不同的芳族苯乙酮和2-氰基-N-（一锅法），设计和合成了一系列新颖的26种取代的N-（2-乙基苯基）-2-氧代吡啶-3-腈。2-乙基苯基）乙酰胺1。此外，通过NCI评估了目标化合物的细胞毒性，NCI选择了14种化合物进行一次剂量筛选。其中，选择化合物21进行五剂量筛选，证实了其对大多数癌细胞系的效力。该化合物引起针对人类细胞株WI-38的选择性。进行了细胞周期分析，发现化合物21是细胞凋亡诱导因子，导致细胞周期停滞在G2 / M。通过评估作用方式对Pim-1，Pim-2和Pim-3的作用，进一步研究了作用方式，显示了其对Pim-1和Pim-3（而非Pim-2）的抑制作用。分子对接表明，化合物21通过三个氢键和两个芳烃-H键以高亲和力与Pim-1酶的活性位点结合。

更新日期：2020-09-08

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