A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective

作者：Gavin Jason; Quilty Fran; Majer Ferenc; Gilsenan Georgina; Byrne Anne Marie; Long Aideen; Radics Gabor; Gilmer John F^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(21): 5369-5372.

DOI：10.1016/j.bmcl.2016.06.059

• Bile acid
• ER stress
• TUDCA
• Cytoprotection
• Liver
• Fluorescent reporter

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective ER stress inhibitor and chemical chaperone. It has therapeutic potential in a wide array of diseases but a specific macromolecular target or molecular mechanism of action remains obscure. This Letter describes an effective new synthetic approach to taurine conjugation of bile acids which we used to prepare 3 alpha-dansyl TUDCA (4) as a probe for TUDCA actions.
As a model of ER stress we used the hepatocarcinoma cell line HUH7 and stimulation with either deoxycholic acid (DCA, 200 mu M) or tunicamycin (5 mu g/ml) and measured levels of Bip/GRP78, ATF4, CHOP and XBP1s/XBP1u. Compound 4 was more effective than UDCA at inhibiting ER stress markers and had similar effects to TUDCA. In a model of cholestasis using the cytotoxic DCA to induce apoptosis, pretreatment with 4 prevented cell death similarly to TUDCA whereas the unconjugated clinically used UDCA had no effect.
3 alpha-Dansyl TUDCA (4) appears to be a suitable reporter for TUDCA effects on ER stress and related cytoprotective activity.

• 出版日期2016-11-1