title: Structural and synthetic investigations of tanikolide dimer, a SIRT2 selective inhibitor, and tanikolide seco-acid from the Madagascar marine cyanobacterium Lyngbya majuscula.
abstract: 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.
authors: 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.
authors: Marcelino
authors: M
authors: Gutiérrez
authors: Eric H
authors: EH
authors: Andrianasolo
authors: Won Kyo
authors: WK
authors: Shin
authors: Douglas E
authors: DE
authors: Goeger
authors: Alexandre
authors: A
authors: Yokochi
authors: Jörg
authors: J
authors: Schemies
authors: Manfred
authors: M
authors: Jung
authors: Dennis
authors: D
authors: France
authors: Susan
authors: S
authors: Cornell-Kennon
authors: Eun
authors: E
authors: Lee
authors: William H
authors: WH
authors: Gerwick
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; C400156:tanikolide; C474199:SIRT2 protein, human; D056565:Sirtuin 2