Chalcone-histone deacetylase inhibitors hybrids as antiproliferative agents: synthesis and evaluation in breast cancer cells and histone deacetylases

Author(s)

Mariana Bastos dos Santos

• Document type: Doctoral Thesis
• Press: São José do Rio Preto. 2019-08-15.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2019-07-25
• Advisor: Luis Octavio Regasini; Debora Aparecida Pires de Campos Zuccari

Abstract

Breast cancer is the type of cancer more incident in women worldwide. Current treatments have demonstrated resistance and recurrence rate, according to each subtype of disease, therefore the search for new compounds capable to act against these neoplasms becomes urgent. In the present work it was aimed the synthesis of chalcones, chalcone-HDAC inhibitors hybrids and analogues, as well as, biological evaluation of these compounds to breast cancer by cellular, molecular and enzymatic assays. In the second chapter is discussed the synthesis of 20 aminochalcones by Claisen-Schmidt condensation in yields ranging from 30 to 96 %. These compounds were evaluated against breast cancer cell lines MCF-7 and MDA-MB-231. The five most active compounds against each line had their IC50 values determined, highlighting 11 ((E)-2-fluoro-4'-aminochalcone) and 17 ((E)-3-pyridil-4'-aminochalcone) were the most active compounds against both cell lines with IC50 value of 13.2 ± 3.5 and 15.7 ± 5.9 μmol L-1 respectively, against MCF-7, and of 33,9 ± 7,1 and 34.7 ± 5.2 μmol L-1 against MDA-MB-231. These chalcones induced apoptosis death on both lines, and upregulated the p53 pro-apoptotic protein expression on MCF-7 cells. Chalcones 11 and 17 were capable to inhibit cell proliferation even in acidosis condition, demonstrating to be promising compounds to breast cancer treatment. In the chapter III it was designed and synthesized two new chalcone-HDAC inhibitor hybrids, using chalcones, belinostat and entinostat subunits, as well as sulfonamidic analogues, in yields ranging from 14 to 83 %. These compounds were tested against five HDAC isoforms (HDAC1, 2, 4, 6 and 11) at 10 μmol L-1. Compound 23a was the most potent hybrid, and analogue 27c was the most potent compound, showing IC50 values of 3.6 e 0.15 μmol L-1, respectively, against HDAC2. Sulfonamidic analogue 27c was as potent as the HDAC inhibitor suberanilohydroxamic acid (SAHA). Hybrid 23a demonstrated to be class Iselective, and 27c was active against class I and II. Compounds 23a and 27c had their antiproliferative activity against breast cancer cells (MCF-7 and MDA-MB-231) evaluated and exhibited IC50 values ranging from 9.10 ± 2.5 to 10.51 ± 1.0 μmol L-1. Therefore, the work has led to potent HDAC-inhibitors compounds and antiproliferative against breast cancer. (AU)

• FAPESP's process: 16/00580-5 - Chalcone-Histone Deacetylase Inhibitor Hybrids as Cytotoxic Agents and Wnt/beta-catenin pathway blockers: Synthesis and Breast Cells and Zebrafish Evaluations
• Grantee: Mariana Bastos dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate