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http://hdl.handle.net/1843/70590| Tipo: | Artigo de Periódico |
| Título: | Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs |
| Autor(es): | Silmara Nunes Andrade Fernanda Cristina Gontijo Evangelista Diego Eduardo Lima Seckler Deisielly Ribeiro Marques Túlio Resende Freitas Renata Rachide Nunes Júlia Teixeira de Oliveira Rosy Iara Maciel de Azambuja Ribeiro Hélio Batista dos Santos Ralph Gruppi Thomé Alex Gutterres Taranto Fabio Vieira dos Santos Gustavo Henrique Ribeiro Viana Rossimiriam Pereira de Freitas Jorge Luiz Humberto Adriano de Paula Sabino Flaviane Francisco Hilário Fernando de Pilla Varotti |
| Resumen: | 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. |
| Asunto: | Química farmacêutica Agentes antineoplásicos Apoptose Citotoxidade de mediação celular Mecanismo de ação (Bioquímica) Síntese |
| Idioma: | eng |
| País: | Brasil |
| Editor: | Universidade Federal de Minas Gerais |
| Sigla da Institución: | UFMG |
| Departamento: | FAR - DEPARTAMENTO DE ANÁLISES CLÍNICAS E TOXICOLÓGICAS ICX - DEPARTAMENTO DE QUÍMICA |
| Tipo de acceso: | Acesso Restrito |
| Identificador DOI: | https://doi.org/10.1007/s00044-018-2244-3 |
| URI: | http://hdl.handle.net/1843/70590 |
| Fecha del documento: | 2018 |
| metadata.dc.url.externa: | https://link.springer.com/article/10.1007/s00044-018-2244-3 |
| metadata.dc.relation.ispartof: | Medical Chemistry Research |
| Aparece en las colecciones: | Artigo de Periódico |
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