%0 Journal Article
%T Selective Cytotoxicity of Damsin Derivatives in Breast Cancer Cells - Selective Cytotoxicity of Damsin Derivatives in Breast Cancer Cells - Open Access Pub
%A Giovanna R. Almanza
%A Maribel Lozano
%A Olov Sterner
%A Rodrigo Villagomez
%A Sophie Manner
%A Stina Oredsson
%A Wendy Soria
%J OAP | Home | Journal of Advanced Pharmaceutical Science And Technology | Open Access Pub
%D 2018
%X Cancer is the leading cause of death worldwide, and there is a constant need for new treatment strategies. Sesquiterpene lactones containing a 3-methylenedihydrofuran-2(3H)-one (or ¦Á-methylene-¦Ã-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 ¦Á-methylene-¦Ã-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 £¿-methylene-£¿-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. DOI10.14302/issn.2328-0182.japst-19-2759 The incidence of cancer is increasing, and different strategies for controlling the disease are developed. The pool of secondary plant metabolites has always been an important provider of low-molecular anti-cancer drugs, and is expected to be so also in the future. As our understanding about the molecular mechanisms of cancer development and progression, as well as the development of treatment resistance, has increased, our ability to design new anti-cancer drugs has improved.1,2 One of the cellular molecular pathways that is important for chemoresistance and metastasis in many cancer cells is the NF-¦ÊB pathway, where constitutive activation, or
%U https://www.openaccesspub.org/japst/article/1071