Novel 1H-pyrazole-3-carboxamide derivatives: synthesis, anticancer evaluation and identification of their DNA-binding interaction.
Novel 1H-pyrazole-3-carboxamide derivatives: synthesis, anticancer evaluation and identification of their DNA-binding interaction.
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DOI：
10.1248/cpb.c13-00676
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发表时间：
2014-03
影响因子：
1.7
通讯作者：
Yi Lu;T. Ran;Guowu Lin;Q. Jin;Jianlin Jin;Hongmei Li;Hao Guo;T. Lu;Yue Wang
中科院分区：
文献类型：
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作者：
Yi Lu;T. Ran;Guowu Lin;Q. Jin;Jianlin Jin;Hongmei Li;Hao Guo;T. Lu;Yue Wang
合成了4个新的1H-吡唑-3-甲酰胺衍生物，并研究了它们对肿瘤细胞的抑制增殖作用、激酶抑制作用，特别是与DNA的相互作用，以阐明其抗肿瘤机制。建立了一个DNA小沟结合模型，并预测了化合物的结合能。在生理条件下，通过电子吸收光谱测定了化合物的结合能力，并通过粘度测量进一步验证了预测的一致性。其中5-（3-环丙基脲基）-N-[4-[（4-甲基哌嗪-1-基）甲基]苯基]-1-H-吡唑-3-甲酰胺（pym-5）的DNA结合亲和力最高（K（pym-5）= 1.06 × 10（5）M（-1））。荧光光谱显示，pym-5使溴化乙锭-小牛胸腺DNA（EB-CT-DNA）复合物的荧光强度降低了50%以上，表明pym-5对DNA构象有很强的影响。此外，在pBR 322 DNA切割试验中，pym-5对超螺旋质粒pBR 322 DNA显示切割活性。我们的研究表明，DNA可能作为一个潜在的目标，这些吡唑衍生物。
Four novel 1H-pyrazole-3-carboxamide derivatives were synthesized, and their antiproliferative effect on cancer cells, kinase inhibition, and in particular, the DNA-binding interaction were investigated to interpret the antitumor mechanisms. A DNA minor groove binding model was developed, and the binding energy was predicted for the compounds. In consistence with the prediction, the binding ability was determined by the electronic absorption spectroscopy under physiological conditions for the compounds, and further verified by viscosity measurement. One compound 5-(3-cyclopropylureido)-N-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1-H-pyrazole-3-carboxamide (pym-5) exerted the highest DNA-binding affinity (K(pym-5)=1.06×10(5) M(-1)). And it demonstrated more than 50% decrease of the emission intensity of the ethidium bromide-calf thymus DNA (EB-CT-DNA) complex in fluorescence spectra, suggesting that pym-5 could strongly affect the DNA conformation. Furthermore, pym-5 showed the cleavage activity upon the supercoiled plasmid pBR322 DNA in the pBR322 DNA cleavage assay. Our study suggests that DNA may serve as a potential target to these pyrazole derivatives.