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Cytotoxicity of New Damsin Derivatives in Breast Cancer Cells

Author:
  • Maribel Lozano
  • Wendy Soria
  • Sophie Manner
  • Stina Oredsson
  • Juan R V Villagomez
  • Olov Sterner
Other contributions:
  • Giovanna Almanza
Publishing year: 2019-08-27
Language: English
Pages:
Publication/Series: Journal of Pharmacy & Drug Development
Volume: 1
Issue: 2
Document type: Journal article

Abstract english

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.

Keywords

  • Cell and Molecular Biology
  • MCF-10A
  • JIMT-1
  • Semisynthesis
  • α-methylene-γ-lactones
  • Michael acceptors
  • SAR:s

Other

Published
  • ISSN: 2348-9782
Stina Oredsson
E-mail: stina [dot] oredsson [at] biol [dot] lu [dot] se

Professor

Functional zoology

+46 46 222 94 97

B-C208

4

Principal investigator

LUCC - Lund University Cancer Centre

Research group

Animal Physiology

Projects

Cell proliferation

Doctoral students and postdocs

PhD Students, main supervisor

Wendy Soria Sotillo

PhD Students, assistant supervisor

Atena Malakpour Permlid