Preparation of S14161 and its analogues and the discovery of 6-bromo-8-ethoxy-3-nitro-2H-chromene as a more potent antitumor agent in vitro

Shu-Qiang Yin; Min Shi; Ting-Ting Kong; Cheng-Mei Zhang; Kunkun Han; Biyin Cao; Zubin Zhang; Xiaolin Du; Long-Qian Tang; Xinliang Mao; Zhao-Peng Liu

doi:10.1016/j.bmcl.2013.03.097

Preparation of S14161 and its analogues and the discovery of 6-bromo-8-ethoxy-3-nitro-2H-chromene as a more potent antitumor agent in vitro

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3314-9. doi: 10.1016/j.bmcl.2013.03.097. Epub 2013 Apr 4.

Authors

Shu-Qiang Yin¹, Min Shi, Ting-Ting Kong, Cheng-Mei Zhang, Kunkun Han, Biyin Cao, Zubin Zhang, Xiaolin Du, Long-Qian Tang, Xinliang Mao, Zhao-Peng Liu

Affiliation

¹ Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China.

PMID: 23601711
DOI: 10.1016/j.bmcl.2013.03.097

Abstract

The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Benzopyrans / chemical synthesis*
Benzopyrans / chemistry*
Benzopyrans / pharmacology
Binding Sites
Catalysis
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Human Umbilical Vein Endothelial Cells
Humans
Molecular Docking Simulation
Neovascularization, Physiologic / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation / drug effects
Piperazines / chemistry
Proline / chemistry
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt / metabolism

Substances

6-bromo-8-ethoxy-3-nitro-2H-chromene
8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene
Antineoplastic Agents
Benzopyrans
Phosphoinositide-3 Kinase Inhibitors
Piperazines
Proline
Proto-Oncogene Proteins c-akt
triethylenediamine