新型苯基吡啶/苯基嘧啶-羧胺类8-咪唑咪唑[1,2-a]吡嗪衍生物的合成及生物学评价

Shan Xu, Chengyu Sun, Chen Chen, Pengwu Zheng, Yong Zhou, Hongying Zhou, Wufu Zhu
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引用次数: 4

摘要

本文设计并合成了3个新型的含苯基吡啶/苯基嘧啶羧胺的8-啉咪唑[1,2-a]吡嗪衍生物(化合物12a-g、13a-g和14a-g)。所有化合物对3种癌细胞(A549、PC-3和MCF-7)的IC50值进行了评估。大多数目标化合物对三种癌细胞系表现出中等的细胞毒性。进一步测定了化合物14b、14c对PI3Kα激酶的抑制活性,结果表明化合物14c对PI3Kα激酶的抑制活性为1.25 μM。构效关系和药理学结果表明,用咪唑吡嗪取代硫代吡喃嘧啶有利于活性的提高,芳基的位置对这些化合物的活性有显著影响。在吡啶环的C-4位置上取代芳基的化合物13a-g比在C-5位置上取代芳基的化合物12a-g活性更高。此外,含14a-g苯基嘧啶-羧胺类化合物的细胞毒性优于含12a-g、13a-g苯基嘧啶-羧胺类化合物。此外,苯环上的取代基对细胞毒性也有显著影响,药理学结果表明,给电子基团对细胞毒性有促进作用。
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Synthesis and Biological Evaluation of Novel 8-Morpholinoimidazo[1,2-a]pyrazine Derivatives Bearing Phenylpyridine/Phenylpyrimidine-Carboxamides
Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-a]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds 12a–g, 13a–g and 14a–g). All the compounds were evaluated for their IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds 14b, 14c were further tested for their activity against PI3Kα kinase, and the results indicated that compound 14c showed inhibitory activity against PI3Kα kinase with an IC50 value of 1.25 μM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds 13a–g in which an aryl group substituted at the C-4 position of the pyridine ring were more active than 12a–g substituted at the C-5 position. Moreover, the cytotoxicity of compounds 14a–g bearing phenylpyrimidine-carboxamides was better than that of the compounds 12a–g, 13a–g bearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.
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