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- Lozano, Maribel, et al.
(author)
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Cytotoxicity of New Damsin Derivatives in Breast Cancer Cells
- 2019
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In: Journal of Pharmacy & Drug Development. - 2348-9782. ; 1:2
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Journal article (peer-reviewed)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.
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- Lozano, Maribel, et al.
(author)
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Selective Cytotoxicity of Damsin Derivatives in Breast Cancer Cells
- 2019
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In: Journal of Advanced Pharmaceutical Science and Technology. - : Open Access Pub. - 2328-0182. ; 2:1, s. 23-37
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Journal article (peer-reviewed)abstract
- Cancer is the leading cause of death worldwide, and there is a constant need for new treatmentstrategies. Sesquiterpene lactones containing a 3-methylenedihydrofuran-2(3H)-one (or α-methylene-γ-lactone) moiety, for example damsin (1), are Michael acceptors that affect biological processes such as cell proliferation, death/apoptosis, and cell migration, by interfering with cell signalling pathways. Although the reactivity of the α-methylene-γ-lactone moiety is important for these effects, the Michael addition is reversible and it can be assumed that also other parts of the molecules will moderate any given biological activity. In this investigation, the cytotoxicity of 23 α-methylene-γ-lactones towards normal breast epithelial MCF-10A cells as well as breast cancer JIMT-1 cells is compared. Most of the investigated compounds are semisynthetic derivatives prepared by the condensation of the natural product damsin (1) with aldehydes. The two cell lines were treated with various concentrations of the compounds in dose response assays, and the 50 % inhibitory concentration (IC50) was determined from dose response curves. The IC50 values were found to depend strongly on the overall structure. The ratio between the IC50 values for MCF-10A and JIMT-1 cells, as a measure for the selectivity of a compound to kill cancer cells, was calculated, and found to vary between just over 1 to more than 10. The most potent derivatives formed from the condensation of 1 with aromatic aldehydes towards JIMT-1 cells are 3a and 3i, both with ratios between the IC50 values for MCF-10A and JIMT-1 cells close to 5. Also some aldol condensation products with acyclic aldehydes, i.e. 3r and 3u, were equally potent, and the latter showed the highest selectivity (ratio > 10). Structure-activity relationships that may explain the observed differences in potency and selectivity are discussed.
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