Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres
Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres
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DOI：
10.1002/bip.20676
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发表时间：
2007-01-01
期刊：
影响因子：
2.9
通讯作者：
Fujii, Nobutaka
中科院分区：
文献类型：
--
作者：
Tomita, Kenji;Narumi, Tetsuo;Fujii, Nobutaka
合成了受Fmoc保护的Phe - Gly - type (Z) -烯二肽异构体（ADI）和(E) -氟烯二肽异构体（FADI），并将其应用于Fmoc基固相肽合成（SPPS）。这些顺肽键模拟物被引入具有生物活性的五肽[H - Amb - Phe - Gly - Leu - Arg - Trp - NH2；Amb = 4‐（氨基甲基）苯甲酸]，具有强大的GPR54激动活性。与亲本肽和含有(E)‐ADI‐的衍生物相比，得到的五肽衍生物显示出较低的GPR54激动活性。这表明亲本肽的Phe - Gly肽键的反式酰胺构象对生物活性具有重要意义。与我们的预期相反，含有(Z) - FADI的衍生物基本上没有表现出活性，这表明了FADI -生物等构性的关键验证的必要性。©2007 Wiley期刊公司生物工程学报（自然科学版），32(2):387 - 398,2007。本文最初作为可接受的预印本在网上发表。“在线发布”日期对应于预印本。您可以通过发送电子邮件至biopolymers@wiley.com向Biopolymers编辑部索取预印本
Fmoc‐protected Phe‐Gly‐type (Z)‐alkene dipeptide isostere (ADI) and (E)‐fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc‐based solid‐phase peptide synthesis (SPPS). These cis‐peptide bond mimetics were introduced into a bioactive pentapeptide [H‐Amb‐Phe‐Gly‐Leu‐Arg‐Trp‐NH2; Amb = 4‐(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)‐ADI‐containing derivative. This suggests that the trans‐amide conformer of Phe‐Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)‐FADI‐containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI‐bioisosterism. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 272–278, 2007.This article was originally published online as an accepted preprint. The ‘Published Online’ date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com