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Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs

  • Silmara N. Andrade
  • Fernanda C. G. Evangelista
  • Diego Seckler
  • Deisielly R. Marques
  • Túlio R. Freitas
  • Renata R. Nunes
  • Júlia T. Oliveira
  • Rosy I. M. A. Ribeiro
  • Hélio B. Santos
  • Ralph G. Thomé
  • Alex G. Taranto
  • Fabio V. Santos
  • Gustavo H. R. Viana
  • Rossimiriam P. Freitas
  • Jorge L. Humberto
  • Adriano de P. Sabino
  • Flaviane F. Hilário
  • Fernando P. Varotti
Original Research

Abstract

Breast and ovarian cancer are the most common cancers in women. Available cancer treatments, in general, have limited efficacy and frequent, undesirable side effects. Recently, scientists have focused on searching for new epigenetic modulators such as inhibitors of DNA methyltransferases and histone deacetylases (HDACs), with novel properties and selectivity. We report the synthesis of seven new analogs of Santacruzamate A. Molecular modeling showed that compounds 39 presented the best binding energies (kcal/mol) against HDAC4 compared to that of crystallographic ligand. The compounds were evaluated against MCF-7 and MDA-MB-231 (breast cancer), TOV-21G (ovarian adenocarcinoma), and WI-26VA4 (non-tumor lung fibroblasts) cells. Compound 5, the most potent and selective of the series, exhibited remarkably enhanced anticancer potency, with IC50 values for the tumor cells of 24.3–44.93 μM, compared with that of etoposide (12–18.57 μM) and doxorubicin (2.1–4.37 μM). Further investigation showed that compound 5 could promote DNA damage, increase the activity of caspases-3 and -9, and upregulate mRNA levels of p21, TP53, and BAK, suggesting apoptotic cell death of the tumor cells via the intrinsic pathway. This study demonstrated that synthetic analogs of santacruzamate A with zinc-linked groups are effective for improving both HDAC inhibition and antitumor activity.

Keywords

Santacruzamate A analogs Cytotoxicity Mode of action Apoptosis Cancer 

Notes

Acknowledgements

The authors would like to acknowledge the financial support received from the following institutions: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) FAPEMIG and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Author contributions

SNA, FCGE, DRM, TRF, JTO, RIMAR, HBS, RGT and FVS performed the biological experiments. DS, GHRV, RPF and JLH performed the synthesis and structural elucidation. RRN and AGT performed the in silico approach. APS, FFH and FPV coordinated the research. All authors wrote the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2244_MOESM1_ESM.doc (3.6 mb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Silmara N. Andrade
    • 1
  • Fernanda C. G. Evangelista
    • 2
  • Diego Seckler
    • 3
  • Deisielly R. Marques
    • 1
  • Túlio R. Freitas
    • 1
  • Renata R. Nunes
    • 1
  • Júlia T. Oliveira
    • 1
  • Rosy I. M. A. Ribeiro
    • 4
  • Hélio B. Santos
    • 5
  • Ralph G. Thomé
    • 5
  • Alex G. Taranto
    • 1
  • Fabio V. Santos
    • 1
  • Gustavo H. R. Viana
    • 1
  • Rossimiriam P. Freitas
    • 6
  • Jorge L. Humberto
    • 3
  • Adriano de P. Sabino
    • 2
  • Flaviane F. Hilário
    • 3
  • Fernando P. Varotti
    • 1
  1. 1.Núcleo de Pesquisa em Química Biológica (NQBio)Universidade Federal de São João Del Rei - Campus Centro OesteDivinópolisBrazil
  2. 2.Departamento de Análises Clínicas e Toxicológicas, Faculdade de FarmáciaUniversidade Federal de Minas Gerais - Campus PampulhaBelo HorizonteBrazil
  3. 3.Departamento de Química (DEQUI), Instituto de Ciências Exatas e Biológicas (ICEB)Universidade Federal de Ouro Preto - Campus Universitário Morro do CruzeiroOuro PretoBrazil
  4. 4.Experimental Pathology LaboratoryUniversidade Federal de São João Del Rei - Campus Centro OesteDivinópolisBrazil
  5. 5.Laboratório de Processamento de TecidoUniversidade Federal de São João Del Rei - Campus Centro OesteDivinópolisBrazil
  6. 6.Departamento de Química, Instituto de Ciências ExatasUniversidade Federal de Minas GeraisBelo HorizonteBrazil

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