Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity
Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity
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DOI：
10.1021/jm300542e
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发表时间：
2012-07-26
影响因子：
7.3
通讯作者：
Wouters, Johan
中科院分区：
文献类型：
--
作者：
Frederick, Raphael;Bruyere, Celine;Wouters, Johan
为了克服癌细胞对凋亡刺激的内在抵抗力，我们设计并合成了大约50个结构上与骆驼蓬碱相关的新的β-卡宾。三尖杉酯碱以其抗癌特性而闻名，是一种DYRK1A抑制剂。在所合成的化合物中，对五种癌细胞株的生长抑制活性最强的是细胞抑制活性，其效力大约是去氢骆驼蓬碱的100倍，但没有显示出DYRK1A抑制活性。这些新的β-卡宾在对凋亡刺激敏感和抵抗的癌细胞中显示出类似的生长抑制活性。使用ChemGPS-NP，我们发现活性较高的β-Caroline都比活性较低的化合物更亲油且更大。最后，根据NCI人类肿瘤细胞系的抗癌药物筛选和NCI比较算法，似乎这些化合物中的一些化合物，包括5a和5k，似乎具有蛋白质合成抑制剂的作用。
To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel beta-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel beta-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active beta-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.