Design, synthesis and Anti-multiple sclerosis activity evaluation of ursolic acid prodrugs
10.13748/j.cnki.issn1007-7693.20222265
- VernacularTitle:熊果酸前药的设计合成及抗多发性硬化症活性评价
- Author:
FU Yuhan
1
;
WANG Maolin
1
;
CHEN Kaixian
1
;
FENG Chenguo
1
;
LI Yiming
1
Author Information
1. Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Publication Type:Journal Article
- Keywords:
ursolic acid;
prodrug;
succinate;
multiple sclerosis;
structural modification
- From:
Chinese Journal of Modern Applied Pharmacy
2023;40(15):2076-2085
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE Designing and synthesizing ursolic acid prodrugs to improve the water solubility and anti-multiple sclerosis(MS) activity of ursolic acid. METHODS succinic acid, dipeptide amino acid and the amino acids segments of side chains of isavuconazole wers selected according to the prodrug strategy, combined with 3-position hydroxyl of ursolic acid via condensation and esterification reaction. Using ultraviolet-visible spectrophotometry to determine the water solubility of prodrugs, and establish the experimental allergic encephalomyelitis mice model for its anti-MS efficacy evaluation. RESULTS Three prodrugs were synthesized and their structures were confirmed by 1H-NMR, 13C-NMR and LCMS(ESI). The water solubility of prodrugs 1 and 2 was over 110 times higher than ursolic acid, and that of prodrug 3 was over 200 times higher than ursolic acid. The in vivo anti-MS activity results showed that the three prodrugs showed significant anti-MS activity, among which prodrug 1 showed significantly better anti-MS activity than ursolic acid group. The mechanism might be through inhibition of peripheral inflammatory cell infiltration into the center and anti-demyelination, so as to exert the anti-MS activity. The metabolism of prodrug 1 in vivo showed that the exposure of prodrug 1 in vivo was 6 times that of ursolic acid, indicating that prodrug 1 might exert anti-MS activity mainly as sodium prototype. CONCLUSION Prodrug 1 has great anti-MS potential, which is worthy of further study. This study provides some basis and useful guidance for the development of ursolic acid prodrugs with anti-MS activity.
