Semisynthesis and Structure–Activity Studies of Uncarinic Acid C Isolated from Uncaria rhynchophylla as a Specific Inhibitor of the Nucleation Phase in Amyloid β42 Aggregation

• Published in: Journal of natural products (Washington, D.C.) Vol. 79; no. 10; pp. 2521 - 2529
• Main Authors: Yoshioka, Takuya, Murakami, Kazuma, Ido, Kyohei, Hanaki, Mizuho, Yamaguchi, Kanoko, Midorikawa, Satohiro, Taniwaki, Shinji, Gunji, Hiroki, Irie, Kazuhiro
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 28.10.2016
• Subjects: Alzheimer Disease - drug therapy; Amyloid beta-Peptides - antagonists & inhibitors; Cell Survival; Drugs, Chinese Herbal; Humans; Japan; Molecular Structure; Neurons - metabolism; Peptide Fragments; Rifamycins; Structure-Activity Relationship; Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Uncaria - chemistry
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.6b00392

Oligomers of the 42-mer amyloid-β protein (Aβ42), rather than fibrils, cause synaptic dysfunction in the pathology of Alzheimer’s disease (AD). The nucleation phase in a nucleation-dependent aggregation model of Aβ42 is related to the formation of oligomers. Uncaria rhynchophylla is one component of “Yokukansan”, a Kampo medicine, which is widely used for treating AD symptoms. Previously, an extract of U. rhynchophylla was found to reduce the aggregation of Aβ42, but its active principles have yet to be identified. In the present work, uncarinic acid C (3) was identified as an inhibitor of Aβ42 aggregation that is present in U. rhynchophylla. Moreover, compound 3 acted as a specific inhibitor of the nucleation phase of Aβ42 aggregation. Compound 3 was synthesized from saponin A (10), an abundant byproduct of rutin purified from Uncaria elliptica. Comprehensive structure–activity studies on 3 suggest that both a C-27 ferulate and a C-28 carboxylic acid group are required for its inhibitory activity. These findings may aid the development of oligomer-specific inhibitors for AD therapy.