TY - JOUR
T1 - Cytotoxicity of New Damsin Derivatives in Breast Cancer Cells
AU - Lozano , Maribel
AU - Soria , Wendy
AU - Manner, Sophie
AU - Oredsson, Stina
AU - Villagomez, Juan R V
AU - Sterner, Olov
A2 - Almanza, Giovanna
PY - 2019/8/27
Y1 - 2019/8/27
N2 - 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.
AB - 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.
KW - MCF-10A
KW - JIMT-1
KW - Semisynthesis
KW - α-methylene-γ-lactones
KW - Michael acceptors
KW - SAR:s
M3 - Article
SN - 2348-9782
VL - 1
JO - Journal of Pharmacy & Drug Development
JF - Journal of Pharmacy & Drug Development
IS - 2
ER -