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New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid.
We have prepared a new panel of 23 BA derivatives of DCA, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) in order to study the effect of dual substitution with 3-azido and 24- amidation, features individually associated with cytotoxicity in our previous work. The effect of the compounds on cell viability of HT-1080 and Caco-2 was studied using the 3-[4,5-dimethylthizol-2- yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds with high potency towards reduction of cell viability were further studied using flow cytometry in order to understand the mechanism of cell death. Several compounds were identified with low micromolar IC50 values for reducing cell viability in the Caco-2 and HT1080 cell lines, making them among the most potent BA apoptotic agents reported to date . There was no evidence of relationship between overall hydrophobicity and cytotoxicity supporting the idea that cell death induction by BAs may be structure ?specific. Compounds derived from DCA caused cell death through apoptosis. There was some evidence of selectivity between the two cell lines studied which may be due to differing expression of CD95/FAS. The more toxic compounds increased ROS production in Caco-2 cells, and co- incubation with the antioxidant N-acetyl cysteine blunted pro-apoptotic effects. The properties these compounds suggest that there may be specific mechanism(s) mediating BA induced cell death. Compound 8 could be useful for investigating this phenomenon.
Keyword(s): bile acid,; cytotoxicity
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: Trinity College Dublin
Citation(s): M?jer F, Sharma R, Mullins C, Keogh L, Phipps S, Duggan S, Kelleher D, Keely S, Long A, Radics G, Wang J, Gilmer JF, New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid., Bioorganic & medicinal chemistry, 22, 1, 2014, 256-68
First Indexed: 2014-05-13 05:53:12 Last Updated: 2019-11-29 06:46:18