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

Author(s)

Altei, Wanessa F. ^{[1, 2]} ; Pachane, Bianca C. ^[2] ; Martins, Lucimara J. ^[3] ; Gomes, Ralph C. ^[3] ; Santos, Ricardo N. ^{[1, 4]} ; Fernandes, Daniara C. ^{[3, 5]} ; Selistre-de-Araujo, Heloisa S. ^[2] ; Coelho, Fernando ^[3] ; Andricopulo, Adriano D. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Phys Sao Carlos, Ctr Res & Innovat Biodivers & Drug Discovery, Lab Med & Computat Chem, Sao Carlos, SP - Brazil

^[2] Univ Fed Sao Carlos, Dept Physiol Sci, Biochem & Mol Biol Lab, Sao Carlos, SP - Brazil

^[3] Univ Estadual Campinas, Inst Chem, Lab Sintese Prod Nat & Farmacos, Campinas, SP - Brazil

^[4] Latam Datalab Serasa Experian, Sao Paulo, SP - Brazil

^[5] IFSP Inst Fed Educ Ciencia & Tecnol Sao Paulo, Campus Matao, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY; v. 21, n. 14, p. 1901-1910, 2021.
• Web of Science Citations: 0

Abstract

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. Objective: Here, we evaluated the potential of eight synthetic spirocyclohexadienones as cell migration inhibitors. 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. 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. 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. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/11437-7 - Integrin molecular mechanisms of action during tumor progression and metastasis development: an intercellular approach
• Grantee: Heloisa Sobreiro Selistre de Araújo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/06741-4 - Structure- and ligand based-drug design of new chemotherapeutic agents for the treatment of cancer
• Grantee: Ricardo Nascimento dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)