Bugge Steffen, Buene Audun Formo, Jurisch-Yaksi Nathalie, Moen Ingri Ullestad, Skjønsfjell Ellen Martine, Sundby Eirik, Hoff Bård Helge
Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway.
Kavli Institute for Systems Neuroscience and Center for Neural Computation, Norwegian University of Science and Technology, Olav Kyrres gate 9, MTFS, NO-7491 Trondheim, Norway.
Eur J Med Chem. 2016 Jan 1;107:255-74. doi: 10.1016/j.ejmech.2015.11.012. Epub 2015 Nov 11.
Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents.
噻吩并[2,3 - d]嘧啶是用于癌症治疗的有吸引力的衍生物，尤其是通过调节表皮生长因子受体酪氨酸激酶（EGFR - TK）。在一项扩展的构效关系（SAR）研究中，已对该类别的44种新化合物作为抑制剂进行了评估，同时关注药物代谢动力学性质（ADME）。通过应用生物电子等排体、杂化结构、增溶尾以及组合方法，在活性和理化性质方面实现了若干成功的改变。发现基于苄胺的化合物在活性和ADME谱方面优于苯胺杂化结构。对前一类化合物的探索表明，间位和对位酰胺是有利的6 - 芳基取代基，有助于活性增加并作为增溶尾的连接基团。接下来，在同一骨架上的活性诱导基团的组合产生了新的候选药物。发现含有具有（2 - （二甲基氨基）乙基）氨基甲酰基取代基的6 - 芳基的化合物与厄洛替尼等效。与这种商业药物相比，观察到溶解度和代谢稳定性有所提高。然而，通过Caco - 2实验发现带有增溶尾的噻吩并[2,3 - d]嘧啶存在渗透性问题，这使得进一步的药物开发变得困难。对选定的化合物在斑马鱼胚胎中进行了毒性和致畸性的进一步分析。发现两种噻吩并嘧啶的致死性均低于厄洛替尼，并且在致畸性方面表现良好。最后，在一组人类癌细胞系中对最有前景的噻吩并嘧啶药物进行了评估，结果表明噻吩并嘧啶作为抗癌剂具有明显的潜力。
