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

Miguel M. Vaidergorn, Zumira A. Carneiro, Carla D. Lopes, Sérgio de Albuquerque, Felipe C.C. Reis, Sofia Nikolaou, Juliana F.R. Mello, Giovani L. Genesi, Gustavo H.G. Trossini, A. Ganesan, Flavio S. Emery

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8 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)657-664
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume157
Early online date27 Jul 2018
DOIs
Publication statusPublished - 5 Sep 2018

Keywords

  • Aziridines
  • Triple negative breast cancer
  • Minor groove binding
  • β-amino alcohols

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