β-amino alcohols and their respective 2-phenyl-N-alkyl aziridines as potential DNA minor groove binders

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ri...

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Published in:European journal of medicinal chemistry 2018-09, Vol.157, p.657-664
Main Authors: Vaidergorn, Miguel M., Carneiro, Zumira A., Lopes, Carla D., de Albuquerque, Sérgio, Reis, Felipe C.C., Nikolaou, Sofia, Mello, Juliana F.R. e, Genesi, Giovani L., Trossini, Gustavo H.G., Ganesan, A., Emery, Flavio S.
Format: Article
Language:English
Subjects:
Aziridines
Minor groove binding
Triple negative breast cancer
β-amino alcohols
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Summary:It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, β-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation. [Display omitted] •A new insight of 2-phenyl-1-alkylaziridines and β-amino alcohols towards cancer cells.•Aziridine 5d was the most potent compound towards TNBC cell line.•β-amino alcohol 3f was the most active compound against MCF 7 cell line.•The compounds induced cell death most probably via an apoptotic pathway.•The compounds acted via a mechanism of action found on crescent-like shape molecules.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.07.055