Diverted total synthesis and biological evaluation of gambierol analogues: elucidation of crucial structural elements for potent toxicity.
Gambierol is a polycyclic ether toxin, which has been isolated from the marine dinoflagellate Gambierdiscus toxicus. A series of gambierol analogues have been prepared from an advanced intermediate of our total synthesis of gambierol and investigated for their toxicity against mice, thus providing the first systematic structure-activity relationships (SAR) of this polycyclic ether class of marine toxin. The SAR studies described herein clearly indicate that 1) the C28=C29 double bond within the H ring and the unsaturated side chain are the crucial structural elements required for exerting potent biological activity and 2) the C1 and C6 hydroxy groups, the C30 methyl group, and the C37=C38 double bond have little influence on the degree of neurotoxicity against mice.
Fuwa
Haruhiko
H
Graduate School of Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kainuma
Noriko
N
Tachibana
Kazuo
K
Tsukano
Chihiro
C
Satake
Masayuki
M
Sasaki
Makoto
M
D000818:Animals; D002922:Ciguatoxins / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D035964:Oxocins
D002922:Ciguatoxins; D004988:Ethers, Cyclic; D011083:Polycyclic Compounds; C435770:gambierol; D035964:Oxocins