4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model

Bart I Roman; Tine De Ryck; Atanas Patronov; Svetoslav H Slavov; Barbara W A Vanhoecke; Alan R Katritzky; Marc E Bracke; Christian V Stevens

doi:10.1016/j.ejmech.2015.06.029

4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model

Eur J Med Chem. 2015 Aug 28:101:627-39. doi: 10.1016/j.ejmech.2015.06.029. Epub 2015 Jul 10.

Authors

Bart I Roman¹, Tine De Ryck², Atanas Patronov³, Svetoslav H Slavov⁴, Barbara W A Vanhoecke⁵, Alan R Katritzky⁶, Marc E Bracke⁷, Christian V Stevens⁸

Affiliations

¹ Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: bart1.roman@ugent.be.
² Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: tine.deryck@ugent.be.
³ Center for Heterocyclic Compounds, Department of Chemistry, 127 Chemistry Research Building, University of Florida, Gainesville, FL 32611-7200, USA. Electronic address: atanas.patronov@tum.de.
⁴ Center for Heterocyclic Compounds, Department of Chemistry, 127 Chemistry Research Building, University of Florida, Gainesville, FL 32611-7200, USA. Electronic address: svetoslav.slavov@fda.hhs.gov.
⁵ Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: barbara.vanhoecke@ugent.be.
⁶ Center for Heterocyclic Compounds, Department of Chemistry, 127 Chemistry Research Building, University of Florida, Gainesville, FL 32611-7200, USA; Department of Chemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia. Electronic address: katritzky@chem.ufl.edu.
⁷ Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: marc1.bracke@ugent.be.
⁸ Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: chris.stevens@ugent.be.

PMID: 26204510
DOI: 10.1016/j.ejmech.2015.06.029

Abstract

Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.

Keywords: Cancer; Chalcone; Invasion; In vivo; Metastasis; QSAR.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / chemical synthesis
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / pharmacology*
Antineoplastic Agents, Phytogenic / therapeutic use
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology*
Biological Products / therapeutic use
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / pharmacology*
Chalcones / therapeutic use*
Chick Embryo
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Discovery*
Female
Humans
Mice
Mice, Nude
Molecular Structure
Myocardium / pathology
Neoplasm Invasiveness / pathology
Neoplasm Invasiveness / prevention & control*
Neoplasm Metastasis / drug therapy*
Neoplasm Metastasis / pathology
Quantitative Structure-Activity Relationship

Substances

4-fluoro-3',4',5'-trimethoxychalcone
Antineoplastic Agents, Phytogenic
Biological Products
Chalcones