title: Illicium sesquiterpenes: divergent synthetic strategy and neurotrophic activity studies.
abstract: Majucin-type sesquiterpenes from Illicium sp., such as jiadifenolide (2), jiadifenin (3), and (1R,10S)-2-oxo-3,4-dehydroxyneomajucin (4, ODNM), possess a complex caged chemical architecture and remarkable neurotrophic activities. As such, they represent attractive small-molecule leads against various neurodegenerative diseases. We present an efficient, enantioselective, and unified synthesis of 2, 3, and 4 and designed analogues that diverge from tetracyclic key intermediate 7. The synthesis of 7 is highlighted by the use of an enantioselective Robinson annulation reaction (construction of the AB rings), a Pd-mediated carbomethoxylation reaction (construction of the C ring), and a one-pot oxidative reaction cascade (construction of the D ring). Evaluation of the neurotrophic activity of these compounds led to the identification of several highly potent small molecules that significantly enhanced the activity of nerve growth factor (NGF) in PC-12 cells. Moreover, efforts to define the common pharmacophoric motif suggest that substitution at the C-10 center significantly affects bioactivity, while the hemiketal moiety of 2 and 3 and the C-1 substitution might not be critical to the neurotrophic activity.
authors.affiliation: Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA.
authors.forename: Lynnie
authors.initials: L
authors.lastname: Trzoss
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Lacoske
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
mesh_terms: D000818:Animals; D029523:Illicium / Q000737:chemistry*; D015394:Molecular Structure; D009414:Nerve Growth Factors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009414:Nerve Growth Factors; D012717:Sesquiterpenes; C457979:jiadifenin; C546282:jiadifenolide