Namur Medicine and Drug Innovation Center (NAMEDIC-NARILIS), University of Namur (FUNDP), 61, Rue de Bruxelles, 5000 Namur, Belgium.
J Med Chem. 2012 Jul 26;55(14):6489-501. doi: 10.1021/jm300542e. Epub 2012 Jul 18.
To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel β-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 β-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 β-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.
为了克服癌细胞对凋亡刺激的内在抗性，我们设计并合成了大约 50 种新型与哈尔明相关的β-咔啉结构类似物。哈尔明具有抗癌特性，是 DYRK1A 抑制剂。在所合成的化合物中，在抑制五种癌细胞系生长方面最活跃的化合物是细胞生长抑制剂，其效力大约比哈尔明强 100 倍，但没有表现出 DYRK1A 抑制活性。这些新型β-咔啉在对凋亡刺激敏感和耐药的癌细胞中显示出相似的生长抑制活性。使用 ChemGPS-NP，我们发现，更活跃的β-咔啉比不活跃的化合物更亲脂性和更大。最后，基于 NCI 人类肿瘤细胞系抗癌药物筛选和 NCI COMPARE 算法，这些化合物中的一些，包括 5a 和 5k，似乎作为蛋白质合成抑制剂起作用。
