SYNTHESIS, BIOLOGICAL-ACTIVITY, AND CONFORMATIONAL-ANALYSIS OF (2S,3R,4S)-MEBMT1-CYCLOSPORIN, A NOVEL 1-POSITION EPIMER OF CYCLOSPORINE-A
SYNTHESIS, BIOLOGICAL-ACTIVITY, AND CONFORMATIONAL-ANALYSIS OF (2S,3R,4S)-MEBMT1-CYCLOSPORIN, A NOVEL 1-POSITION EPIMER OF CYCLOSPORINE-A
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DOI：
10.1021/jm00128a048
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发表时间：
1989-08-01
影响因子：
7.3
通讯作者：
WEBER, AE
中科院分区：
文献类型：
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作者：
RICH, DH;SUN, CQ;WEBER, AE
环孢菌素A(CsA，1)是一种免疫抑制的环状十一肽，含有一种独特的氨基酸(4R)-4-[(E)-丁烯基]-4，N-二甲基-L-苏氨酸(MeBmt)，在CsA的生物活性中起重要作用。为了进一步探讨MeBmt中的结构元素对CsA构象和生物活性的影响，我们合成了MeBmt的4-异构体[(4S)-MeBmt，2]和相应的CsA类似物[(4S)-MeBmt1-CsA，3]。刀豆蛋白A刺激胸腺细胞的生物学实验表明，(4S)-MeBmt1-CsA(3)的免疫抑制活性仅为CsA的2-4%。一维和二维核磁共振分析确定了3的构象，其中33元环肽环与CsA在氯仿中的构象非常相似。然而，核磁共振分析也表明，(4S)-MeBmt1-CsA(3)的1位侧链取向与CsA有很大的不同。具体地说，(4S)-MeBmtα，β-扭转角(chi.1)已经旋转了大约120度。相对于CsA，丁烯基侧链相对于33元多肽背键的取向不同。(4S)-MeBmt侧链的取向与分子力学(真空中)计算的(4S)-MeBmt1-CsA(3)的可能构象一致。构象分析表明，3的生物活性丧失是由于MeBmt的C4手性改变导致1位侧链相对于多肽背键的构象改变所致。
Cyclosporin A (CsA, 1), an immunosuppressive cyclic undecapeptide, contains a unique amino acid, (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine (MeBmt), that appears to be critically involved in the biological activity of CsA. In order to further explore the effect that structural elements in MeBmt have on the conformation and biological activity of CsA, the 4-epimer of MeBmt [(4S)-MeBmt, 2] and the corresponding CsA analogue [(4S)-MeBmt1-CsA, 3] have been synthesized. Biological assay using concanavalin A stimulated thymocytes indicated that (4S)-MeBmt1-CsA (3) has only 2-4% immunosuppressive activity relative to CsA. The NMR analysis by 1D and 2D NMR methods establishes the conformation of 3, of which the 33-membered cyclic peptide ring system in chloroform is very similar to that of CsA. However, the NMR analysis also reveals that the 1-position side chain orientation in (4S)-MeBmt1-CsA (3) is very different from that of CsA. Specifically, the (4S)-MeBmt .alpha.,.beta.-torsion angle (.chi.1) has been rotated approximately 120.degree. relative to that of CsA, and the orientation of the butenyl side chain relative to the 33-membered peptide backbond is different. The orientation of the (4S)-MeBmt side chain is consistent with the possible conformations calculated for (4S)-MeBmt1-CsA (3) by using molecular mechanics (in vacuo) calculations. The conformational analysis suggests that the loss of biological activity for 3 results from an altered conformation of the 1-position side chain relative to the peptide backbond due to the changed chirality at C4 of MeBmt.