Synthesis and Structure–Activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents

Thirty quaternary coptisine derivatives
from a synthesized library
were found to activate the in vitro transcription
of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines
were demonstrated by in vitro XBP1 transcriptional
activity assays and animal experiments to be much more active anti-ulcerative
colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines,
and the positive control. Unsubstituted dihydrocoptisine exhibited
more significant anti-UC efficacy than dihydrocoptisines substituted
at the C-8 or C-13 position. The EC50 value of dihydrocoptisine
for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine
exhibited a significant dose–effect relationship, as indicated
by biomarkers in in vitro and in vivo experiments. According to this study, the starting material’s
reductive states and the substitution patterns of the dihydrocoptisines
were determined to be the critical parameters for modulating their
anti-UC efficacy, and the dihydrocoptisine skeleton was designated
as the key pharmacophore. The synthesized dihydrocoptisine is a promising
lead for developing anti-UC drugs.