title: 4-Fluoro-3',4',5'-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model.
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.
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: bart1.roman@ugent.be.
authors.forename: Bart I
authors.initials: BI
authors.lastname: Roman
authors.affiliation: 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.
authors.forename: Tine
authors.initials: T
authors.lastname: De Ryck
authors.affiliation: 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.
authors.forename: Atanas
authors.initials: A
authors.lastname: Patronov
authors.affiliation: 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.
authors.forename: Svetoslav H
authors.initials: SH
authors.lastname: Slavov
authors.affiliation: 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.
authors.forename: Barbara W A
authors.initials: BW
authors.lastname: Vanhoecke
authors.affiliation: 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.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Katritzky
authors.affiliation: 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.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Bracke
authors.affiliation: Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: chris.stevens@ugent.be.
authors.forename: Christian V
authors.initials: CV
authors.lastname: Stevens
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002642:Chick Embryo; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009206:Myocardium / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship
chemical_list: C000607745:4-fluoro-3',4',5'-trimethoxychalcone; D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D047188:Chalcones
keywords: Cancer; Chalcone; Invasion; In vivo; Metastasis; QSAR