School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
Bioorg Med Chem Lett. 2020 Oct 15;30(20):127479. doi: 10.1016/j.bmcl.2020.127479. Epub 2020 Aug 9.
Two classes of piperazinone-containing thieno[3,2-d]pyrimidines were designed and synthesized as new PI3Kδ inhibitors in this study. Detailed SAR study with respect to the piperazinone substituents at the 6-position of thieno[3,2-d]pyrimidine core demonstrated that piperazinone-containing thieno[3,2-d]pyrimidines would be more potent and selective for PI3Kδ than their piperazine counterparts, which led to the discovery of several potent PI3Kδ inhibitors with comparable or better antiproliferative activity against a panel of non-Hodgkin lymphoma (NHL) cell lines as compared with idelalisib. Our study will promote the development of new PI3Kδ inhibitors based on piperazinone-containing thieno[3,2-d]pyrimidine scaffold.
本研究设计并合成了两类含哌嗪酮的噻吩并[3,2-d]嘧啶类化合物作为新型 PI3Kδ 抑制剂。对噻吩并[3,2-d]嘧啶核心 6 位哌嗪酮取代基的详细 SAR 研究表明，与哌嗪类化合物相比，含哌嗪酮的噻吩并[3,2-d]嘧啶类化合物对 PI3Kδ 的活性更高、选择性更强，由此发现了几种具有较强活性的 PI3Kδ 抑制剂，与idelalisib 相比，对一系列非霍奇金淋巴瘤（NHL）细胞系的增殖活性相当或更好。我们的研究将促进以含哌嗪酮的噻吩并[3,2-d]嘧啶为骨架的新型 PI3Kδ 抑制剂的开发。
