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

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dc.creatorSilmara Nunes Andrade
dc.creatorFernanda Cristina Gontijo Evangelista
dc.creatorDiego Eduardo Lima Seckler
dc.creatorDeisielly Ribeiro Marques
dc.creatorTúlio Resende Freitas
dc.creatorRenata Rachide Nunes
dc.creatorJúlia Teixeira de Oliveira
dc.creatorRosy Iara Maciel de Azambuja Ribeiro
dc.creatorHélio Batista dos Santos
dc.creatorRalph Gruppi Thomé
dc.creatorAlex Gutterres Taranto
dc.creatorFabio Vieira dos Santos
dc.creatorGustavo Henrique Ribeiro Viana
dc.creatorRossimiriam Pereira de Freitas
dc.creatorJorge Luiz Humberto
dc.creatorAdriano de Paula Sabino
dc.creatorFlaviane Francisco Hilário
dc.creatorFernando de Pilla Varotti
dc.date.accessioned2024-07-15T19:16:49Z
dc.date.accessioned2025-09-08T23:59:43Z
dc.date.available2024-07-15T19:16:49Z
dc.date.issued2018
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
dc.identifier.doihttps://doi.org/10.1007/s00044-018-2244-3
dc.identifier.issn1554-8120
dc.identifier.urihttps://hdl.handle.net/1843/70590
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofMedical Chemistry Research
dc.rightsAcesso Restrito
dc.subjectQuímica farmacêutica
dc.subjectAgentes antineoplásicos
dc.subjectApoptose
dc.subjectCitotoxidade de mediação celular
dc.subjectMecanismo de ação (Bioquímica)
dc.subjectSíntese
dc.subject.otherSantacruzamate A analogs
dc.subject.otherCytotoxicity
dc.subject.otherMode of action
dc.subject.otherApoptosis
dc.subject.otherCancer
dc.titleSynthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs
dc.typeArtigo de periódico
local.citation.epage2413
local.citation.issue11-12
local.citation.spage2397
local.citation.volume27
local.description.resumoBreast 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.
local.identifier.orcidhttps://orcid.org/0000-0002-1975-0827
local.identifier.orcidhttps://orcid.org/0000-0003-4682-397X
local.identifier.orcidhttps://orcid.org/0000-0002-1430-4799
local.identifier.orcidhttps://orcid.org/0000-0002-2289-2201
local.identifier.orcidhttps://orcid.org/0000-0002-1239-5412
local.identifier.orcidhttps://orcid.org/0000-0002-7374-4743
local.identifier.orcidhttps://orcid.org/0000-0001-6813-8522
local.identifier.orcidhttps://orcid.org/0000-0002-1779-5036
local.identifier.orcidhttps://orcid.org/0000-0002-6086-1043
local.identifier.orcidhttps://orcid.org/0000-0002-1521-7486
local.identifier.orcidhttps://orcid.org/0000-0001-6974-3724
local.identifier.orcidhttps://orcid.org/0009-0001-9688-1812
local.identifier.orcidhttps://orcid.org/0000-0001-8562-8689
local.identifier.orcidhttps://orcid.org/0000-0002-2939-7780
local.publisher.countryBrasil
local.publisher.departmentFAR - DEPARTAMENTO DE ANÁLISES CLÍNICAS E TOXICOLÓGICAS
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://link.springer.com/article/10.1007/s00044-018-2244-3

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