6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα

Yong Yin; Yan-Qing Zhang; Biao Jin; Shao Sha; Xun Wu; Chetan B Sangani; She-Feng Wang; Fang Qiao; Ai-Min Lu; Peng-Cheng Lv; Hai-Liang Zhu

doi:10.1016/j.bmc.2015.01.052

6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as selective inhibitors of PI3Kα

Bioorg Med Chem. 2015 Mar 15;23(6):1231-40. doi: 10.1016/j.bmc.2015.01.052. Epub 2015 Feb 7.

Authors

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
² College of Science, Nanjing Agriculture University, Nanjing 210095, People's Republic of China.
³ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.

PMID: 25693787
DOI: 10.1016/j.bmc.2015.01.052

Abstract

Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016μM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kβ. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.

Keywords: 6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives; Antitumor; PI3Kα.

Publication types

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

MeSH terms

Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases
Dose-Response Relationship, Drug
HCT116 Cells
HL-60 Cells
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Models, Molecular
Molecular Structure
Oxazepines / chemical synthesis
Oxazepines / chemistry
Oxazepines / pharmacology*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Heterocyclic Compounds, 4 or More Rings
Oxazepines
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human