Ohshiro Taichi, Namatame Ichiji, Nagai Kenichiro, Sekiguchi Takafumi, Doi Takayuki, Takahashi Takashi, Akasaka Kazuaki, Rudel Lawrence L, Tomoda Hiroshi, Omura Satoshi
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Minato-ku, Tokyo 108-8641, Japan.
J Org Chem. 2006 Sep 29;71(20):7643-9. doi: 10.1021/jo0611667.
Fungal beauveriolide III (BeauIII, 1b), a cyclodepsipeptide inhibiting acyl-CoA:cholesterol acyltransferase (ACAT) and showing antiatherogenic activity in mouse models, consists of L-Phe, L-Ala, D-allo-Ile, and 3-hydroxy-4-methyloctanoic acid (HMA) moieties, but the stereochemistry of the HMA part has not until now been fully defined. To determine it, four HMA stereoisomers were synthesized and labeled with (S)-(+)-2-(anthracene-2,3-dicarboximido)-1-propyl trifluoromethane sulfonate (AP-OTf), a chiral fluorescent reagent. The derivatives were separated by HPLC and compared with the natural HMA derivative, which was thereby identified as (3S,4S)HMA in BeauIII. Furthermore, the four beauveriolide III isomers ((3S,4S)BeauIII (23a), (3R,4R)BeauIII (23b), (3R,4S)BeauIII (23c), and (3S,4R)BeauIII (23d)) were synthesized, and it was shown that all the spectral data for 23a were identical with those for natural 1b. Isomers 23a and 23d showed potent inhibitory activity of lipid droplet accumulation in macrophages, while the other two isomers caused weak inhibition. Thus, the 3S configuration of BeauIII is important for this activity. Furthermore, 23a and 23d showed rather specific inhibition against the ACAT1 isozyme.
真菌波沃利德III（BeauIII，1b）是一种环缩肽，可抑制酰基辅酶A：胆固醇酰基转移酶（ACAT），并在小鼠模型中显示出抗动脉粥样硬化活性，它由L-苯丙氨酸、L-丙氨酸、D-别异亮氨酸和3-羟基-4-甲基辛酸（HMA）部分组成，但HMA部分的立体化学至今尚未完全确定。为了确定其立体化学，合成了四种HMA立体异构体，并用手性荧光试剂（S）-（+）-2-（蒽-2,3-二甲酰亚胺）-1-丙基三氟甲磺酸酯（AP-OTf）进行标记。通过高效液相色谱法分离这些衍生物，并与天然HMA衍生物进行比较，从而确定BeauIII中的HMA为（3S，4S）HMA。此外，合成了四种波沃利德III异构体（（3S，4S）BeauIII（23a）、（3R，4R）BeauIII（23b）、（3R，4S）BeauIII（23c）和（3S，4R）BeauIII（23d）），结果表明23a的所有光谱数据与天然1b的光谱数据相同。异构体23a和23d对巨噬细胞中脂滴积累具有较强的抑制活性，而其他两种异构体的抑制作用较弱。因此，BeauIII的3S构型对该活性很重要。此外，23a和23d对ACAT1同工酶表现出相当特异性的抑制作用。
