Trifluoromethylation of dihydrocoptisines and the effect on structural stability and XBP1-activating activity

Abstract

In order to obtain new dihydrocoptisine-type compounds with stable structure and activating XBP1 transcriptional activity, (±)-8-trifluoromethyldihydrocoptisine derivatives as target compounds were synthesized from quaternary ammonium chlorides of coptisine alkaloids as starting materials by a one-step reaction. The structures of the synthesized compounds were confirmed by ¹H-, ¹³C-, and ¹⁹F-NMR as well as HRESIMS methods. These compounds showed more significant structural stability and activating XBP1 transcription activity in vitro than dihydrocoptisine as positive control. No obvious cytotoxicity on normal cell in vitro was observed with (±)-8-trifluoromethyldihydrocoptisines. Trifluoromethylation can be used as one of the fluorine modification strategies for dihydrocoptisines to guide follow-up studies on structural modification of coptisine-type alkaloids and on anti-Ulcerative colitis drugs with coptisines.

Graphical abstract

Keywords:

• Dihydrocoptisines
• trifluoromethylation
• (±)-8-trifluoromethyldihydrocoptisines
• structural stability
• XBP1-activating activity

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by grant from CAMS Initiation Fund for Innovative Medicine (grant no. 2016-I2M-1-010), the Drug Innovation Major Project (grant no. 2019ZX09735002-002 and 2018ZX09711001-002).