Synthetic Spirocyclohexadienones as New Anti-Migratory Compounds in Triple- Negative Breast Cancer Cell Migration

Author(s):

Wanessa F. Altei, Bianca C. Pachane, Lucimara J. Martins, Ralph C. Gomes, Ricardo N. Santos, Daniara C. Fernandes, Heloisa S. Selistre-de-Araújo, Fernando Coelho * and Adriano D. Andricopulo*   Pages 1901 - 1910 ( 10 )

Abstract:

<p>Background: Triple-negative BC is the most aggressive type of breast cancer and its lack of responsiveness to conventional therapies requires screening of new chemical entities. Anti-migratory compounds are promising to treat metastatic cancer since they inhibit one of the main steps of the metastatic cascade. Spirocyclic compounds are non-conventional structures used as building blocks for the synthesis of biologically active molecules and considered interesting structures in the search for new targets in cancer research. </P><P> Objective: Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. </P><P> Methods: The anti-migratory ability of compounds was tested by wound healing and Boyden chamber approaches. Experiments in tubulin were performed by fluorescence and tubulin polymerization techniques. Finally, compounds were submitted to cell proliferation inhibition and flow cytometry assays to explore the mechanism by which they inhibit cell migration. </P><P> Results: Four compounds inhibited cell migration significantly. Analogs containing the 3,4,5-trimethoxyphenil ring at R¹ position were the most potent and, thus, selected for additional experiments. Tubulin polymerization and fluorescence assays highlighted a possible binding of spirocyclohexadienones in the colchicine binding site; however, these compounds did not affect the cell cycle to the same extent as colchicine. Cell proliferation was affected and, notably, the most potent analogs induced apoptosis of tumor cells, suggesting a different mechanism by which they inhibit cell migration. </P><P> Conclusion: We presented, for the first time, a series of eight synthetic spirocyclohexadienones with the ability to inhibit TNBC cell migration. These compounds represent a new category to be explored as anticancer agents.</p>

Keywords:

Breast cancer, metastasis, cell migration inhibition, spirocyclohexadienones, tubulin, apoptosis.

Affiliation:

Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Institute of Physics of Sao Carlos, University of Sao Paulo, (USP), Sao Carlos, SP, Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of Sao Carlos, Sao Carlos, SP, Laboratorio de Sintese de Produtos Naturais e Farmacos - Institute of Chemistry, University of Campinas, Campinas, SP, Laboratorio de Sintese de Produtos Naturais e Farmacos - Institute of Chemistry, University of Campinas, Campinas, SP, Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Institute of Physics of Sao Carlos, University of Sao Paulo, (USP), Sao Carlos, SP, Laboratorio de Sintese de Produtos Naturais e Farmacos - Institute of Chemistry, University of Campinas, Campinas, SP, Biochemistry and Molecular Biology Laboratory, Department of Physiological Sciences, Federal University of Sao Carlos, Sao Carlos, SP, Laboratorio de Sintese de Produtos Naturais e Farmacos - Institute of Chemistry, University of Campinas, Campinas, SP, Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Institute of Physics of Sao Carlos, University of Sao Paulo, (USP), Sao Carlos, SP

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