title: 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.
abstract: 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.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Ido
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hanaki
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kanoko
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Alps-Pharmaceutical Industry Co., Ltd. , Gifu 509-4241, Japan.
authors.forename: Satohiro
authors.initials: S
authors.lastname: Midorikawa
authors.affiliation: Alps-Pharmaceutical Industry Co., Ltd. , Gifu 509-4241, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Taniwaki
authors.affiliation: Alps-Pharmaceutical Industry Co., Ltd. , Gifu 509-4241, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Gunji
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University , Kyoto 606-8502, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D002470:Cell Survival; D004365:Drugs, Chinese Herbal; D006801:Humans; D007564:Japan; D015394:Molecular Structure; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments; D012294:Rifamycins; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D032070:Uncaria / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D004365:Drugs, Chinese Herbal; D010446:Peptide Fragments; D012294:Rifamycins; D014315:Triterpenes; C524644:Yi-Gan San; C412669:uncarinic acid-C; C006025:C 27