Design, synthesis, and bioactivity evaluation of macrocyclic benzo[b]pyrido[4,3-e][1,4]oxazine derivatives as novel Pim-1 kinase inhibitors

Jiwei Xu; Cheng Shen; Yuting Xie; Boxiang Qiu; Xintong Ren; Yu Zhou; Gudong Li; Guojun Zheng; Niu Huang

doi:10.1016/j.bmcl.2022.128874

Design, synthesis, and bioactivity evaluation of macrocyclic benzo[b]pyrido[4,3-e][1,4]oxazine derivatives as novel Pim-1 kinase inhibitors

Bioorg Med Chem Lett. 2022 Sep 15:72:128874. doi: 10.1016/j.bmcl.2022.128874. Epub 2022 Jun 30.

Authors

Jiwei Xu¹, Cheng Shen², Yuting Xie³, Boxiang Qiu⁴, Xintong Ren⁵, Yu Zhou⁶, Gudong Li⁷, Guojun Zheng⁸, Niu Huang⁹

Affiliations

¹ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: jwxu3@buct.edu.cn.
² National Institute of Biological Sciences, Beijing, 102206, China; Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: shencheng@nibs.ac.cn.
³ National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: xieyuting@nibs.ac.cn.
⁴ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: BXQiu@buct.edu.cn.
⁵ National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: renxintong@nibs.ac.cn.
⁶ National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: zhouyu@nibs.ac.cn.
⁷ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: 2020700011@mail.buct.edu.cn.
⁸ College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: zhenggj@mail.buct.edu.cn.
⁹ National Institute of Biological Sciences, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: huangniu@nibs.ac.cn.

PMID: 35779826
DOI: 10.1016/j.bmcl.2022.128874

Abstract

Pim-1 kinase is a serine/threonine kinase which is vital in many tumors. The Pim-1 inhibitor 10-DEBC and its derivatives discovered in our previous work were modified through macrocyclization strategy. A series of benzo[b]pyridine[4,3-e][1,4]oxazine macrocyclic compounds were designed, synthesized, and evaluated as novel Pim-1 kinase inhibitors. Among these compounds, compound H5 exhibited the highest activity with an IC₅₀ value of 35 nM. In addition, the crystal complex structure of Pim-1 kinase bound with compound H3 was determined, and the structure-activity relationship of these macrocyclic compounds was analyzed, which provides the structural basis of further optimization of novel macrocyclic Pim-1 kinase inhibitors..

Keywords: Inhibitory activity; Macrocyclization; Pim-1 kinase; Structure-activity relationships; Synthesis.

Publication types

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

MeSH terms

Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Molecular Structure
Oxazines
Protein Kinase Inhibitors / chemistry
Proto-Oncogene Proteins c-pim-1*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oxazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-pim-1