Cytotoxicity of New Damsin Derivatives in Breast Cancer Cells

Research output: Contribution to journalArticle

Abstract

As a follow-up of a previous investigation in which semisynthetic damsin derivatives were shown to possess up to 10 times higher cytoxicity in JIMT-1 breast cancer cells compared to normal breast epithelial MCF-10A cells, a range of new derivatives were prepared and assayed toward the same cells. Damsin, a natural plant metabolite containing a α-methylene-γ-lactone (or 3-methylenedihydro- furan-2(3H)-one) moiety, was modified in position 3 by Claisen-Schmidt condensations with aromatic aldehydes, mainly mono- or disubstituted benzaldehydes, without affecting the α-methylene-γ-lactone function. This lactone ring is a Michael acceptor that is known to affect biological processes such as cell proliferation, death/apoptosis, and cell migration, by interfering with nucleophilic sites in cell signalling pathways. However, although Michael acceptors are reactive, the Michael addition is reversible and it can be assumed that also other parts of the molecules will moderate the binding to and the release from any given nucleophilic site in a protein, and thereby moderate a specific biological activity. In this investigation, the cytotoxicity of 20 α-methylene-γ-lactones towards normal breast epithelial MCF-10A cells as well as breast cancer JIMT-1 cells is compared, by determining the inhibitory concentration 50 (IC50) from dose response curves. The IC50 values in the two cell lines were found to depend on the overall structure of the assayed compounds, although less in this subset of compounds compared to a previous investigation. Structure-activity relationships that may explain the observed differences in potency and selectivity are discussed.

Details

Authors
Organisations
External organisations
  • Higher University of San Andrés
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • MCF-10A, JIMT-1, Semisynthesis, α-methylene-γ-lactones, Michael acceptors, SAR:s
Original languageEnglish
Number of pages19
JournalJournal of Pharmacy & Drug Development
Volume1
Issue number2
Publication statusPublished - 2019 Aug 27
Publication categoryResearch
Peer-reviewedYes