Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors

Ning-Yu Wang; Wei-Qiong Zuo; Rong Hu; Wan-Li Wang; Yong-Xia Zhu; Ying Xu; Luo-Ting Yu; Zhi-Hao Liu

doi:10.1016/j.bmcl.2020.127479

Design, synthesis and structure-activity relationship study of piperazinone-containing thieno[3,2-d]pyrimidine derivatives as new PI3Kδ inhibitors

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127479. doi: 10.1016/j.bmcl.2020.127479. Epub 2020 Aug 9.

Authors

Ning-Yu Wang¹, Wei-Qiong Zuo², Rong Hu³, Wan-Li Wang³, Yong-Xia Zhu², Ying Xu², Luo-Ting Yu², Zhi-Hao Liu⁴

Affiliations

¹ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China. Electronic address: wangny-swjtu@swjtu.edu.cn.
² Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
³ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
⁴ Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China. Electronic address: liuzhihao@scu.edu.cn.

PMID: 32784091
DOI: 10.1016/j.bmcl.2020.127479

Abstract

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.

Keywords: Antiproliferative activity; PI3Kδ; Piperazinone; SAR; Thieno[3,2-d]pyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Chlorocebus aethiops
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Piperazines / chemistry
Piperazines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Piperazines
Pyrimidines
thieno(2,3-d)pyrimidine
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human