4-Carbonyl-2,6-dibenzylidenecyclohexanone derivatives as small molecule inhibitors of STAT3 signaling pathway

Peng Ji; Congmin Yuan; Shuhua Ma; Junchao Fan; Wei Fu; Chunhua Qiao

doi:10.1016/j.bmc.2016.09.070

4-Carbonyl-2,6-dibenzylidenecyclohexanone derivatives as small molecule inhibitors of STAT3 signaling pathway

Bioorg Med Chem. 2016 Dec 1;24(23):6174-6182. doi: 10.1016/j.bmc.2016.09.070. Epub 2016 Sep 30.

Authors

Peng Ji¹, Congmin Yuan², Shuhua Ma³, Junchao Fan¹, Wei Fu², Chunhua Qiao¹

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmaceutical Science, Soochow University, 199 Ren Ai Road, Suzhou 215123, PR China.
² Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, PR China.
³ Department of Chemistry, Jess and Mildred Fisher College of Science and Mathematics, Towson University, 8000 York Road, Towson, MD 21252, United States.

PMID: 27816267
DOI: 10.1016/j.bmc.2016.09.070

Abstract

Inhibition of STAT3 signaling pathway is proposed to be a promising strategy for cancer treatment. In this study, a series of 4-carbonyl-2,6-dibenzylidenecyclohexanone derivatives were prepared and evaluated as anticancer agents. The most potent compound 13r was discovered to exhibit antiproliferative activity against a broad rang of cancer cell lines and relatively low cytotoxicity against normal human cells. Besides, 13r effectively suppressed STAT3 expression as well as phosphorylation, and surface plasmon resonance analysis confirmed the direct interaction of 13r with STAT3. Docking simulation showed that 13r could inhibit STAT3 by targeting SH2 domain. This study provided evidence for these compounds to be further developed as antitumor agents through inhibition of the STAT3 pathway.

Keywords: Antitumor; Apoptosis; Curcumin; Inhibitors; STAT3.

Publication types

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

MeSH terms

A549 Cells
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzylidene Compounds / chemical synthesis
Benzylidene Compounds / chemistry
Benzylidene Compounds / pharmacology*
Catalytic Domain
Cyclohexanones / chemical synthesis
Cyclohexanones / chemistry
Cyclohexanones / pharmacology*
Humans
Molecular Docking Simulation
Phosphorylation
Poly(ADP-ribose) Polymerases / metabolism
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Structure-Activity Relationship
src Homology Domains

Substances

Antineoplastic Agents
Benzylidene Compounds
Cyclohexanones
N-(2-(diethylamino)ethyl)-3,5-bis(4-fluorobenzylidene)-4-oxocyclohexanecarboxamide
STAT3 Transcription Factor
Poly(ADP-ribose) Polymerases