BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud, CNRS, University Paris-Saclay, F-92290, Châtenay Malabry, France.
Institut de Chimie Organique et Analytique (ICOA), UMR7311 Université d'Orléans-CNRS, Rue de Chartres, BP 6759, 45067, Orléans, Cedex 2, France.
Eur J Med Chem. 2020 Aug 1;199:112355. doi: 10.1016/j.ejmech.2020.112355. Epub 2020 May 5.
In this work, unique flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound 13c resulting from a structure-activity relationship (SAR) study and in silico docking showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9, CDK10, and GSK3β protein kinases.
在这项工作中，我们制备了一系列独特的含有硫代糖、氨基酸和杂环部分的氟维司群类似物，这些类似物通过硫醚键和胺键主要连接在氟维司群的 C 环上。含有硫醚-苯并咪唑取代基的类似物在体外对多达七种癌细胞系表现出高细胞毒性活性。它们的细胞毒性作用与氟维司群相当。通过构效关系（SAR）研究和计算机对接得到的最活性化合物 13c 显示出最佳的抗增殖活性，并且比对照化合物更有效。此外，化合物 13c 对 CDK9、CDK10 和 GSK3β 蛋白激酶表现出显著的纳摩尔抑制作用。
