Structural and synthetic investigations of tanikolide dimer, a SIRT2 selective inhibitor, and tanikolide seco-acid from the Madagascar marine cyanobacterium Lyngbya majuscula.
Structural and synthetic investigations of tanikolide dimer, a SIRT2 selective inhibitor, and tanikolide seco-acid from the Madagascar marine cyanobacterium Lyngbya majuscula.
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DOI：
10.1021/jo900578j
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发表时间：
2009-08-07
期刊：
影响因子：
--
通讯作者：
Gerwick WH
中科院分区：
文献类型：
--
作者：
Gutiérrez M;Andrianasolo EH;Shin WK;Goeger DE;Yokochi A;Schemies J;Jung M;France D;Cornell-Kennon S;Lee E;Gerwick WH
从马达加斯加海洋蓝藻Lyngbya majuscula中分离出Tanikbya seco acid 2和Tanikbya dimer 3，后者是一种新的选择性SIRT 2抑制剂。的结构2，分离为纯的R对映异构体，通过X-射线实验结合NMR和旋光度数据，而depside分子结构的3最初被认为是一个内消旋化合物，建立了NMR，MS和手性HPLC分析。随后全合成三种他尼克酰胺二聚体立体异构体4、5和ent-5，然后与天然产物进行手性GC-MS比较，显示其仅为R，R-异构体5。Taniklavin二聚体3（=5）抑制SIRT 2，在一种测定形式中IC 50 = 176 nM，在另一种测定形式中IC 50 = 2.4 µM。对称二聚体如化合物3的立体化学测定在结构解析中提出了有趣和微妙的问题，并且如在当前工作中所示，也许最好结合全合成来回答。
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 an 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 IC50 = 176 nM in one assay format, and 2.4 µM 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.
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