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

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.
Jiwei Xu 1,  Cheng Shen 2,  Yuting Xie 3,  Boxiang Qiu 4,  Xintong Ren 5,  Yu Zhou 6,  Gudong Li 7,  Guojun Zheng 8,  Niu Huang 9
Affiliations

Affiliations

  • 1 College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].
  • 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: [email protected].
  • 3 National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: [email protected].
  • 4 College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].
  • 5 National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: [email protected].
  • 6 National Institute of Biological Sciences, Beijing, 102206, China. Electronic address: [email protected].
  • 7 College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].
  • 8 College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address: [email protected].
  • 9 National Institute of Biological Sciences, Beijing, 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: [email protected].
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.

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