On October 15, 2019, Lei, Hongrui; Jia, Fang; Cao, Meng; Wang, Jie; Guo, Ming; Zhu, Minglin; Zuo, Daiying; Zhai, Xin published an article.Synthetic Route of 10472-24-9 The title of the article was An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects. And the article contained the following:
The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 39. All compounds were assayed cytotoxicity and enzymic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, resp. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymic activities with IC50 values below 0.06μM. Besides, 39 induced cell apoptosis in a dose-dependent manner in H2228 cells. Finally, the binding models of 39 with ALKwt, ROS1, ALKL1196M and ALKG1202R were ideally established which further clearly elucidated their mode of action within the active site. The experimental process involved the reaction of Methyl 2-cyclopentanonecarboxylate(cas: 10472-24-9).Synthetic Route of 10472-24-9
The Article related to pyrimidine diamine derivative preparation alk ros1 inhibitor resistant cancer, 4-diamine, alk & ros1 inhibitors, apoptosis-inducing, mutation-combating, pyrimidine-2, solvent front and other aspects.Synthetic Route of 10472-24-9
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