Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort

doi:10.1039/d1sc03356e

KIB OpenIR

	Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort
	Guo,Yi ; Huang,Fang ; Sun,Weiguang ; Zhou,Yuan; Chen,Chunmei ; Qi,Changxing ; Yang,Jing; Li,Xiao-Nian ; Luo,Zengwei ; Zhu,Hucheng ; Wang,Xiaochuan ; Zhang,Yonghui
	2021
发表期刊	CHEMICAL SCIENCE
ISSN	2041-6520
卷号	12 期号:34 页码:11438-11446
摘要	Hyperforones A-J (1-10), ten degraded and reconstructed polycyclic polyprenylated acylphloroglucinols (PPAPs) with six different types of unusual architectures, were isolated from Hypericum perforatum (St. John's wort). Compound 1 is characterized by an unprecedented 1,5-epoxyfuro[3 ',4 ':1,5]cyclopenta[1,2-c]oxecine ring system; compounds 2 and 3 represent the first PPAPs with a contracted B-ring leading to the unique 5/5 core skeletons; compound 4, a proposed biosynthetic precursor of 2, is defined by an oxonane-2,7-dione architecture; compound 5 features an unusual spiro[furo[3 ',4 ':1,5]cyclopenta[1,2-b]oxepine-3,2 '-oxetane] ring system; compounds 6-8 possess a rare macrocyclic lactone ring in addition to the newly formed C-ring; and compounds 9 and 10 contain a newly formed six-membered C-ring, which constructed the unexpected 6/6 scaffold with the B-ring. Hypothetic biosynthetic pathways to generate these scaffolds starting from the classic [3.3.1]-type PPAPs helped to elucidate their origins and validate their structural assignments. Compounds 4 and 6 simultaneously displayed notable activation of PP2A (EC50: 258.8 and 199.0 nM, respectively) and inhibition of BACE1 in cells (IC50: 136.2 and 98.6 nM, respectively), and showed better activities than the positive controls SCR1693 (a PP2A activator, EC50: 413.9 nM) and LY2811376 (a BACE1 inhibitor, IC50: 260.2 nM). Furthermore, compound 6 showed better therapeutic effects with respect to the reduction of pathological and cognitive impairments in 3 x Tg AD mice than LY2811376. Compound 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights compound 6 as a promising lead compound and a versatile scaffold in AD drug development.
关键词	AMYLOID-BETA NEUROFIBRILLARY DEGENERATION HYPERFORIN NEUROTOXICITY PATHOGENESIS INHIBITION BACE1 DRUG TAU
DOI	10.1039/d1sc03356e
WOS记录号	WOS:000679987700001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/73043
专题	中国科学院昆明植物研究所
作者单位	1.Huazhong Univ Sci & Technol, Hubei Key Lab Nat Med Chem & Resource Evaluat, Sch Pharm, Tongji Med Coll, Wuhan 430030, Peoples R China 2.Huazhong Univ Sci & Technol, Dept Pathophysiol, Sch Basic Med, Tongji Med Coll, Wuhan 430030, Peoples R China 3.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources West Ch, Kunming Inst Bot, Kunming 650204, Yunnan, Peoples R China
推荐引用方式 GB/T 7714	Guo,Yi,Huang,Fang,Sun,Weiguang,et al. Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort[J]. CHEMICAL SCIENCE,2021,12(34):11438-11446.
APA	Guo,Yi.,Huang,Fang.,Sun,Weiguang.,Zhou,Yuan.,Chen,Chunmei.,...&Zhang,Yonghui.(2021).Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort.CHEMICAL SCIENCE,12(34),11438-11446.
MLA	Guo,Yi,et al."Unprecedented polycyclic polyprenylated acylphloroglucinols with anti-Alzheimer's activity from St. John's wort".CHEMICAL SCIENCE 12.34(2021):11438-11446.