Absolute stereochemistry of fungal beauveriolide III and ACAT inhibitory activity of four stereoisomers
Absolute stereochemistry of fungal beauveriolide III and ACAT inhibitory activity of four stereoisomers
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DOI：
10.1021/jo0611667
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发表时间：
2006-09-29
影响因子：
3.6
通讯作者：
Omura, Satoshi
中科院分区：
文献类型：
--
作者：
Ohshiro, Taichi;Namatame, Ichiji;Omura, Satoshi
真菌白僵菌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抗动脉粥样硬化活性，由L-Phe、L-Ala、D-allo-Ile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。合成了4种HMA立体异构体，用手性荧光试剂（S）-（+）-2-（蒽-2，3-二甲酰亚胺基）-1-丙基三氟甲烷磺酸酯（AP-OTf）标记。通过HPLC分离衍生物，并与天然HMA衍生物进行比较，从而在BeauIII中鉴定为（3S，4S）HMA。此外，还合成了四种BeauverironIII异构体（（3S，4S）BeauIII（23 a），（3R，4 R）BeauIII（23 b），（3R，4S）BeauIII（23 c）和（3S，4 R）BeauIII（23 d）），并且显示23 a的所有光谱数据与天然1b的光谱数据相同。异构体23 a和23 d对巨噬细胞内脂滴的积累有较强的抑制作用，而其他两种异构体的抑制作用较弱。因此，BeauIII的3S构型对于该活性是重要的。此外，23 a和23 d对ACAT 1同工酶有较强的抑制作用。
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.