Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity

Chengze Tian; Chengbin Yang; Tianze Wu; Mingzhu Lu; Yi Chen; Yongtai Yang; Xiaofeng Liu; Yun Ling; Mingli Deng; Yu Jia; Yaming Zhou

doi:10.1016/j.bmcl.2021.128271

Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity

Bioorg Med Chem Lett. 2021 Sep 15:48:128271. doi: 10.1016/j.bmcl.2021.128271. Epub 2021 Jul 17.

Authors

Chengze Tian¹, Chengbin Yang¹, Tianze Wu¹, Mingzhu Lu¹, Yi Chen¹, Yongtai Yang¹, Xiaofeng Liu¹, Yun Ling¹, Mingli Deng¹, Yu Jia², Yaming Zhou³

Affiliations

¹ Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, China.
² Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, China. Electronic address: yujia@fudan.edu.cn.
³ Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University, Shanghai, China. Electronic address: ymzhou@fudan.edu.cn.

PMID: 34284105
DOI: 10.1016/j.bmcl.2021.128271

Abstract

Cinnoline is a potential pharmacophore which has rarely been reported for uses as PI3K inhibitors. In this study, a series of cinnoline derivatives were developed as PI3K inhibitors and evaluated for enzymatic and cellular activities. Most compounds displayed nanomolar inhibitory activities against PI3Ks, among which 25 displayed high LLE and micromolar inhibitory potency against three human tumor cell lines (IC₅₀ = 0.264 μM, 2.04 μM, 1.14 μM).

Keywords: Cinnoline; PI3K inhibitor; PI3K/Akt pathway.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Heterocyclic Compounds, 2-Ring / chemical synthesis
Heterocyclic Compounds, 2-Ring / chemistry
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Heterocyclic Compounds, 2-Ring
Phosphoinositide-3 Kinase Inhibitors
cinnoline