Gutiérrez Marcelino, Andrianasolo Eric H, Shin Won Kyo, Goeger Douglas E, Yokochi Alexandre, Schemies Jörg, Jung Manfred, France Dennis, Cornell-Kennon Susan, Lee Eun, Gerwick William H
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.
J Org Chem. 2009 Aug 7;74(15):5267-75. doi: 10.1021/jo900578j.
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.
从马达加斯加海洋蓝藻巨大鞘丝藻中分离出了坦尼可立德二酸2和坦尼可立德二聚体3，后者是一种新型选择性SIRT2抑制剂。作为纯R对映体分离得到的2的结构，通过X射线实验结合核磁共振和旋光数据得以阐明，而3的缩酚酸分子结构最初被认为是一种内消旋化合物，这是通过核磁共振、质谱和手性高效液相色谱分析确定的。随后对三种坦尼可立德二聚体立体异构体4、5和对映体-5进行全合成，然后与天然产物进行手性气相色谱-质谱比较，结果表明它完全是R,R-异构体5。在一种测定形式中，坦尼可立德二聚体3（=5）对SIRT2的抑制IC(50)=176 nM，在另一种测定形式中为2.4 μM。像化合物3这样的对称二聚体的立体化学测定在结构解析中提出了有趣而微妙的问题，正如当前工作所示，或许最好结合全合成来解答。
