Total synthesis and biological evaluation of neodysiherbaine A and analogues.
Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.
Shoji
Muneo
M
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, Sendai 981-8555, Japan.
Akiyama
Nobuyuki
N
Tsubone
Koichi
K
Lash
L Leanne
LL
Sanders
James M
JM
Swanson
Geoffrey T
GT
Sakai
Ryuichi
R
Shimamoto
Keiko
K
Oikawa
Masato
M
Sasaki
Makoto
M
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001681:Biological Assay; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007276:Injections, Intraventricular; D051379:Mice; D015394:Molecular Structure; D018092:Kainic Acid Receptors / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000409:Alanine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018092:Kainic Acid Receptors; C121741:dysiherbaine; C438974:neodysiherbaine A