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

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

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...

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Bibliographic Details
Published in:Medicinal chemistry research Vol. 27; no. 11-12; pp. 2397 - 2413
Main Authors: Andrade, Silmara N., Evangelista, Fernanda C. G., Seckler, Diego, Marques, Deisielly R., Freitas, Túlio R., Nunes, Renata R., Oliveira, Júlia T., Ribeiro, Rosy I. M. A., Santos, Hélio B., Thomé, Ralph G., Taranto, Alex G., Santos, Fabio V., Viana, Gustavo H. R., Freitas, Rossimiriam P., Humberto, Jorge L., Sabino, Adriano de P., Hilário, Flaviane F., Varotti, Fernando P.
Format: Journal Article
Language:English
Published: New York Springer US 01-12-2018
Springer Nature B.V
Subjects:
Adenocarcinoma
Analogs
Anticancer properties
Antitumor activity
Apoptosis
Biochemistry
Biomedical and Life Sciences
Biomedicine
Breast cancer
Cancer
Cell Biology
Cell death
Chemical synthesis
Crystallography
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
Doxorubicin
Etoposide
Fibroblasts
Histone deacetylase
Modulators
Molecular modelling
mRNA
Original Research
Ovarian cancer
p53 Protein
Pharmacology/Toxicology
Selectivity
Side effects
Tumor cells
Tumors
Cytotoxicity
Santacruzamate A analogs
Mode of action
Apoptosis
Cancer
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Summary: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 IC 50 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:1054-2523
1554-8120
DOI:10.1007/s00044-018-2244-3