Blasco Víctor, Cuñat Ana C, Sanz-Cervera Juan F, Marco J Alberto, Falomir Eva, Murga Juan, Carda Miguel
Dpto. de Química Orgánica, Univ. de Valencia, E-46100, Burjassot, Valencia, Spain.
Dpto. de Química Orgánica, Univ. de Valencia, E-46100, Burjassot, Valencia, Spain.
Eur J Med Chem. 2018 Apr 25;150:817-828. doi: 10.1016/j.ejmech.2018.03.039. Epub 2018 Mar 16.
Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N'-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties. The most promising derivatives were compounds 6 (o-Cl) and 14 (o,o-di-F) as they were able to downregulate all the tested targets at a concentration below their IC values. Thus, the arylurea unit enhances the potential of colchicine as an anticancer agent.
我们致力于获取用于癌症治疗的具有治疗作用的秋水仙碱衍生物，这促使我们合成并对27种含有秋水仙碱部分和芳基片段的N,N'-二取代脲进行生物学评估。已测定了这些化合物的细胞毒性、它们抑制与端粒酶激活以及VEGF/VEGFR-2自分泌过程相关的癌基因（如c-MYC、hTERT和VEGF）表达的能力，以及它们下调c-MYC和VEGFR-2蛋白及VEGF分泌的能力。在这些生物学评估中，我们发现秋水仙碱中的乙酰基被N-芳基脲单元取代后，抗癌特性有了很大改善。最有前景的衍生物是化合物6（邻氯）和14（邻，邻二氟），因为它们能够在低于其IC值的浓度下下调所有测试靶点。因此，芳基脲单元增强了秋水仙碱作为抗癌剂的潜力。
