Design, synthesis and biological evaluation of novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold derivatives as PI3Kα inhibitors

Fu-Dan Dong; Dan-Dan Liu; Cheng-Long Deng; Xiao-Chun Qin; Kai Chen; Jian Wang; Hong-Rui Song; Huai-Wei Ding

doi:10.1016/j.bmc.2018.06.022

Design, synthesis and biological evaluation of novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold derivatives as PI3Kα inhibitors

Bioorg Med Chem. 2018 Aug 7;26(14):3982-3991. doi: 10.1016/j.bmc.2018.06.022. Epub 2018 Jun 18.

Authors

Fu-Dan Dong¹, Dan-Dan Liu², Cheng-Long Deng², Xiao-Chun Qin³, Kai Chen², Jian Wang², Hong-Rui Song², Huai-Wei Ding⁴

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁴ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: dinghuaiwei627@163.com.

PMID: 29937355
DOI: 10.1016/j.bmc.2018.06.022

Abstract

The abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.

Keywords: 2H-Benzo[b][1,4]oxazin-3(4H)-one; 2H-Benzo[b][1,4]oxazine; Anticancer; PI3Kα,.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
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 Docking Simulation
Molecular Structure
Oxazines / chemical synthesis
Oxazines / chemistry
Oxazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Oxazines
Protein Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human