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

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• 作者：Jason Gavin^a ; Fran Quilty^a ; Ferenc Majer^a ; Georgina Gilsenan^a ; Anne Marie Byrne^b ; Aideen Long^b ; Gabor Radics^a ; John F. Gilmer^a ; ^{gilmerjf@tcd.ie" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Bile acid ; ER stress ; TUDCA ; Cytoprotection ; Liver ; Fluorescent reporter
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5369-5372
• 全文大小：515 K

文摘

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 3α-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 μM) or tunicamycin (5 μg/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.

3α-Dansyl TUDCA (4) appears to be a suitable reporter for TUDCA effects on ER stress and related cytoprotective activity.