Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of N-Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth.,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Synthesis and Biological Evaluation of B-Cell Lymphoma 6 Inhibitors of N-Phenyl-4-pyrimidinamine Derivatives Bearing Potent Activities against Tumor Growth.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-13 , DOI: 10.1021/acs.jmedchem.9b01618
Weikai Guo ₁ , Yajing Xing ₁ , Qiansen Zhang ₁ , Jiuqing Xie ₁ , Dongxia Huang ₁ , Haijun Gu ₁ , Peng He ₁ , Miaoran Zhou ₂ , Shifen Xu ₂ , Xiufeng Pang ₁ , Mingyao Liu ₁ , Zhengfang Yi ₁ , Yihua Chen ₁

Affiliation

The transcriptional repressor B-cell lymphoma 6 (BCL6) is frequently misregulated in diffuse large B-cell lymphoma (DLBCL) and has emerged as an attractive drug target for the treatments of lymphoma. In this article, a series of N-phenyl-4-pyrimidinamine derivatives were designed and synthesized as potent BCL6 inhibitors by optimizing hit compound N4-(3-chloro-4-methoxyphenyl)-N2-isobutyl-5-fluoro-2,4-pyrimidinediamine on the basis of the structure-activity relationship. Among them, compound 14j displayed the most potent activities, which significantly blocked the interaction of BCL6 with its corepressors, reactivated BCL6 target genes in a dose-dependent manner, and had better effects compared with the two positive controls. Further studies indicated that a low dose of 14j could effectively inhibit germinal center formation. More importantly, 14j not only showed potent inhibition of DLBCL cell proliferation in vitro but also strongly suppressed the growth of DLBCL in vivo.

中文翻译：

具有抗肿瘤生长潜能的N-苯基-4-嘧啶胺衍生物的B细胞淋巴瘤6抑制剂的合成和生物学评估。

转录抑制因子B细胞淋巴瘤6（BCL6）在弥漫性大B细胞淋巴瘤（DLBCL）中经常被错误调节，并已成为治疗淋巴瘤的引人注目的药物靶标。本文通过优化命中化合物N4-（3-氯-4-甲氧基苯基）-N2-异丁基-5-氟-2,4设计并合成了一系列N-苯基-4-嘧啶胺衍生物作为有效的BCL6抑制剂-嘧啶二胺的结构-活性关系的基础上。其中，化合物14j表现出最强的活性，与两个阳性对照相比，化合物14j显着地阻断了BCL6与它的corepressors的相互作用，重新激活了BCL6靶基因，并具有剂量依赖性。进一步的研究表明，低剂量的14j可以有效抑制生发中心的形成。更重要的是，

更新日期：2020-01-13

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南