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Chalcone-Histone Deacetylase Inhibitor Hybrids as Cytotoxic Agents and Wnt/beta-catenin pathway blockers: Synthesis and Breast Cells and Zebrafish Evaluations

Grant number: 16/00580-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2016
Effective date (End): June 30, 2019
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Luis Octávio Regasini
Grantee:Mariana Bastos dos Santos
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil


Antineoplastic agents are essential drugs for expectancy life maintenance. Several reasons justify the need for new antitumor agents, including high morbidity and mortality rate caused by cancer. Thus, efforts are urgent to develop innovative anticancer agents. The current project purposes synthesis of two molecular symbiotic hybrids, which were designed to act by three mode of actions; inhibition of histone-deacetylase (HDAC), blockage of Wnt/Beta-catenin pathway and inhibition of alpha estrogen receptor (ERalpha) expression. Structurally, these compounds exhibit two subunits; chalcone and HDAC-inhibitor moieties. Series I and II will be constitute by chalcone-hidroxamate hybrids and chalcone-benzamide hybrids, respectively. Synthetic route will be performed in four steps, including two divergent reactions, allowing simultaneous synthesis of series I and II. Compounds will be evaluated by cytotoxicity assays, using breast cancer cells (MCF-7 and MDA-MB-231) and non-tumorigenic breast cells (MCF-10A). Values of IC50 (half maximal inhibitory concentration to kill cells) will be established for three cell lines. These values will be compared to IC50 value of SAHA, an HDAC inhibitor and antitumor drug. Selectivity index (SI) will be calculated by IC50 values [SI = IC50 (non-tumorigenic cells) / IC50 (tumorigenic cells)]. Compounds displayed IC50 values equal or bellow to IC50 of SAHA, will be to submitted to inhibition of histones acetylation assays, as well as inhibition of HDAC and ERalpha expression assays, using Western Blot analysis. Blockage activity of Wnt/Beta-catenin pathway will be evaluated on zebrafish embryos model exposed to BIO (6-bromoindirubin-3'-oxime). BIO is an inhibitor of glycogen-synthase-kinase (GSK) and activator of Wnt/Beta-catenin pathway, leads to several phenotypic alterations, including absence of eyes. Thus, compounds that block superactivated Wnt/Beta-catenin pathway will produce embryos with eyes.

Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SANTOS, Mariana Bastos dos. Híbridos chalcona-inibidores de histona desacetilase como agentes antiproliferativos : síntese e avaliação em células de mama e em histona desacetilases. 2019. 159 f. Doctoral Thesis - Universidade Estadual Paulista "Júlio de Mesquita Filho" Instituto de Biociências, Letras e Ciências Exatas..

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