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Title: Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs.
Authors: Andrade, Silmara Nunes
Evangelista, Fernanda Cristina Gontijo
Seckler, Diego Eduardo Lima
Marques, Deisielly Ribeiro
Freitas, Tulio Resende
Nunes, Renata Rachide
Oliveira, Júlia Teixeira de
Ribeiro, Rosy Iara Maciel de Azambuja
Santos, Helio Batista dos
Thomé, Ralph Gruppi
Taranto, Alex Gutterres
Santos, Fabio Vieira dos
Viana, Gustavo Henrique Ribeiro
Freitas, Rossimiriam Pereira de
Humberto, Jorge Luiz
Sabino, Adriano de Paula
Keywords: Apoptosis
Issue Date: 2018
Citation: ANDRADE, S. N. et al. Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs. Medicinal Chemistry Research, v. 27, n. 11/12, p. 2397–2413, dez. 2018. Disponível em: <>. Acesso em: 7 mar. 2019.
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 3–9 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.
ISSN: 1554-8120
Appears in Collections:DEQUI - Artigos publicados em periódicos

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