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

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dc.contributor.authorAndrade, Silmara Nunes
dc.contributor.authorEvangelista, Fernanda Cristina Gontijo
dc.contributor.authorSeckler, Diego Eduardo Lima
dc.contributor.authorMarques, Deisielly Ribeiro
dc.contributor.authorFreitas, Tulio Resende
dc.contributor.authorNunes, Renata Rachide
dc.contributor.authorOliveira, Júlia Teixeira de
dc.contributor.authorRibeiro, Rosy Iara Maciel de Azambuja
dc.contributor.authorSantos, Helio Batista dos
dc.contributor.authorThomé, Ralph Gruppi
dc.contributor.authorTaranto, Alex Gutterres
dc.contributor.authorSantos, Fabio Vieira dos
dc.contributor.authorViana, Gustavo Henrique Ribeiro
dc.contributor.authorFreitas, Rossimiriam Pereira de
dc.contributor.authorHumberto, Jorge Luiz
dc.contributor.authorSabino, Adriano de Paula
dc.date.accessioned2019-05-03T14:55:34Z
dc.date.available2019-05-03T14:55:34Z
dc.date.issued2018
dc.description.abstractBreast 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.pt_BR
dc.identifier.citationANDRADE, 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: <https://link.springer.com/article/10.1007/s00044-018-2244-3>. Acesso em: 7 mar. 2019.pt_BR
dc.identifier.doihttps://doi.org/10.1007/s00044-018-2244-3pt_BR
dc.identifier.issn1554-8120
dc.identifier.urihttp://www.repositorio.ufop.br/handle/123456789/11179
dc.identifier.uri2https://link.springer.com/article/10.1007%2Fs00044-018-2244-3pt_BR
dc.language.isoen_USpt_BR
dc.rightsrestritopt_BR
dc.subjectApoptosispt_BR
dc.subjectCancerpt_BR
dc.titleSynthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs.pt_BR
dc.typeArtigo publicado em periodicopt_BR
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