title: New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid.
abstract: 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.
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Ferenc
authors: F
authors: Májer
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Ruchika
authors: R
authors: Sharma
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Claire
authors: C
authors: Mullins
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Luke
authors: L
authors: Keogh
authors: Cell and Molecular Biology, Institute of Molecular Medicine, Trinity Centre for Health Science, St James's Hospital, Dublin 8, Ireland.
authors: Sinead
authors: S
authors: Phipps
authors: Cell and Molecular Biology, Institute of Molecular Medicine, Trinity Centre for Health Science, St James's Hospital, Dublin 8, Ireland.
authors: Shane
authors: S
authors: Duggan
authors: Cell and Molecular Biology, Institute of Molecular Medicine, Trinity Centre for Health Science, St James's Hospital, Dublin 8, Ireland.
authors: Dermot
authors: D
authors: Kelleher
authors: Molecular Medicine Lab, RCSI, Smurfit Building, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors: Stephen
authors: S
authors: Keely
authors: Cell and Molecular Biology, Institute of Molecular Medicine, Trinity Centre for Health Science, St James's Hospital, Dublin 8, Ireland.
authors: Aideen
authors: A
authors: Long
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Gábor
authors: G
authors: Radics
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors: Jun
authors: J
authors: Wang
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland. Electronic address: gilmerjf@tcd.ie.
authors: John F
authors: JF
authors: Gilmer
mesh_terms: D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D018938:Caco-2 Cells; D002470:Cell Survival; D002635:Chenodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism* / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D008095:Lithocholic Acid; D014580:Ursodeoxycholic Acid
keywords: Bile acid; Cytotoxicity; Deoxycholic acid; Lipophilicity; Ursodeoxycholic acid