Synthesis and activity evaluation of new second-generation santacruzamate a analogs against breast cancer cells

Samira Fagundes de Andrade; Fernanda Cristina Gontijo Evangelista; Silmara Nunes Andrade; Caique Lopes Duarte; Hélio Batista dos Santos; Ralph Gruppi Thomé; Jorge Luiz Humberto; Rossimiriam Pereira de Freitas; Adriano de Paula Sabino; Flaviane Francisco Hilário; Fernando de Pilla Varotti; Túlio Resende Freitas

doi:10.1590/s2175-97902025e24545

Authors

Samira Fagundes de Andrade Departamento de Química (DEQUI), Instituto de Ciências Exatas e Biológicas (ICEB), Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, Brazil , Federal University of Ouro Preto
Fernanda Cristina Gontijo Evangelista Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, Belo Horizonte, MG, Brazil , Federal University of Minas Gerais
Silmara Nunes Andrade Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei
Caique Lopes Duarte Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei
Hélio Batista dos Santos Laboratório de Processamento de Tecido, Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei
Ralph Gruppi Thomé Laboratório de Processamento de Tecido, Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei
Jorge Luiz Humberto Departamento de Química (DEQUI), Instituto de Ciências Exatas e Biológicas (ICEB), Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, Brazil , Federal University of Ouro Preto
Rossimiriam Pereira de Freitas Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Campus Pampulha, Belo Horizonte, MG, Brazil , Federal University of Minas Gerais
Adriano de Paula Sabino Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Campus Pampulha, Belo Horizonte, MG, Brazil , Federal University of Minas Gerais
Flaviane Francisco Hilário Departamento de Química (DEQUI), Instituto de Ciências Exatas e Biológicas (ICEB), Universidade Federal de Ouro Preto, Campus Universitário Morro do Cruzeiro, Ouro Preto, MG, Brazil , Federal University of Ouro Preto
Fernando de Pilla Varotti Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei
Túlio Resende Freitas Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei, Campus Centro Oeste, Divinópolis, MG, Brazil , Federal University of São João del-Rei https://orcid.org/0000-0002-2289-2201

DOI:

https://doi.org/10.1590/s2175-97902025e24545

Keywords:

Synthesis, Santacruzamate A analogs, HDACi, Apoptosis, Cytotoxic activity

Abstract

A series of second-generation compounds analogous to Santacruzamate A were designed, synthesized, and evaluated for their selective cytotoxic activity against the breast cancer cell line MDA-MB-231 (ATCC HTB-26). Compound 7 demonstrated the highest cytotoxicity and selectivity among the tested compounds, with an IC50 value of 8.30 μM, comparable to those of the positive controls cisplatin (8.46 μM) and etoposide (12 μM). In silico studies identified histone deacetylase 8 (HDAC8) as a potential target of compound 7, supporting its role as an HDAC inhibitor. Experimental data further confirmed the pro-apoptotic activity of compound 7, as it significantly increased caspase-3 and caspase-9 activities, along with TP53 and BAK expression compared to the untreated group. These findings indicate that compound 7 induces apoptotic cell death in tumor cells through the intrinsic mitochondrial pathway. This study highlights compound 7 as a promising candidate for further exploration as a selective anticancer agent targeting breast cancer cells.

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Synthesis and activity evaluation of new second-generation santacruzamate a analogs against breast cancer cells

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