Structural and synthetic investigations of tanikolide dimer, a SIRT2 selective inhibitor, and tanikolide seco-acid from the Madagascar marine cyanobacterium Lyngbya majuscula.
Tanikolide seco-acid 2 and tanikolide dimer 3, the latter a novel and selective SIRT2 inhibitor, were isolated from the Madagascar marine cyanobacterium Lyngbya majuscula. The structure of 2, isolated as the pure R enantiomer, was elucidated by X-ray experiment in conjunction with NMR and optical rotation data, whereas the depside molecular structure of 3 was initially thought to be a meso compound as established by NMR, MS, and chiral HPLC analyses. Subsequent total synthesis of the three tanikolide dimer stereoisomers 4, 5, and ent-5, followed by chiral GC-MS comparisons with the natural product, showed it to be exclusively the R,R-isomer 5. Tanikolide dimer 3 (= 5) inhibited SIRT2 with an IC(50) = 176 nM in one assay format and 2.4 microM in another. Stereochemical determination of symmetrical dimers such as compound 3 pose intriguing and subtle questions in structure elucidation and, as shown in the current work, are perhaps best answered in conjunction with total synthesis.
Gutiérrez
Marcelino
M
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and The Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92037, USA.
Andrianasolo
Eric H
EH
Shin
Won Kyo
WK
Goeger
Douglas E
DE
Yokochi
Alexandre
A
Schemies
Jörg
J
Jung
Manfred
M
France
Dennis
D
Cornell-Kennon
Susan
S
Lee
Eun
E
Gerwick
William H
WH
D000458:Cyanobacteria / Q000737:chemistry*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D008270:Madagascar; D008968:Molecular Conformation; D015394:Molecular Structure; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007783:Lactones; C400156:tanikolide; C474199:SIRT2 protein, human; D056565:Sirtuin 2