Photomodulation of conformational states. Synthesis of cyclic peptides with backbone-azobenzene moieties
Photomodulation of conformational states. Synthesis of cyclic peptides with backbone-azobenzene moieties
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DOI：
10.1002/(sici)1099-1387(199911)5:11
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发表时间：
1999-11-01
影响因子：
2.1
通讯作者：
Moroder, L
中科院分区：
文献类型：
--
作者：
Behrendt, R;Schenk, M;Moroder, L
伴随着物理化学和生物学性质的变化的光响应性构象转变的搜索导致我们设计的小环肽含有偶氮苯部分的骨干。为此，合成了（4-氨基甲基）苯基偶氮苯甲酸（H-AMPB-OH）和（4-氨基）苯基偶氮苯甲酸（H-APB-OH），并用于环化双半胱氨酸八肽，得到单环衍生物，其中通过转化为具有二硫桥的双环结构可以引入额外的构象限制。虽然用H-AMPB-OH的合成在具有Fmoc/tBu化学的氯三苯甲基树脂上顺利进行，但H-APB-OH的芳氨基的弱亲核性需要特殊的化学以令人满意地掺入到肽链中。在从半胱氨酸残基还原裂解S-叔丁硫基时遇到了额外的困难，因为伴随的偶氮苯部分的还原以竞争速率发生。这个困难最终通过使用S-三苯甲基保护而被绕过。APE-肽的侧链环化被证明是困难的，这表明受限的构象自由已经以单环形式存在，这一事实通过NMR结构分析得到了充分证实。相反地，AMPB部分中的亚甲基间隔基引入了足够的灵活性，以使双环形式的侧链环化容易且定量。单环肽和双环肽都是光响应性分子，其可逆地进行顺式/反式异构化。版权所有（C）1999 European Peptide Society and John Wiley & Sons，Ltd.
The search for photoresponsive conformational transitions accompanied by changes in physicochemical and biological properties led us to the design of small cyclic peptides containing azobenzene moieties in the backbone. For this purpose, (4-aminomethyl)phenylazobenzoic acid (H-AMPB-OH) and (4-amino)phenylazobenzoic acid (H-APB-OH) were synthesized and used to cyclize a bis-cysteinyl-octapeptide giving monocyclic derivatives in which additional conformational restriction could be introduced by conversion to bicyclic structures with a disulphide bridge. While synthesis with H-AMPB-OH proceeded smoothly on a chlorotrityl-resin with Fmoc/tBu chemistry, the poor nucleophilicity of the arylamino group of H-APB-OH required special chemistry for satisfactory incorporation into the peptide chain. Additional difficulties were encountered in the reductive cleavage of the S-tert-butylthio group from the cysteine residues since concomitant reduction of the azobenzene moiety took place at competing rates. This difficulty was eventually bypassed by using the S-trityl protection. Side-chain cyclization of the APE-peptide proved to be difficult, suggesting that restricted conformational freedom was already present in the monocyclic form, a fact that was fully confirmed by NMR structural analysis. Conversely, the methylene spacer in the AMPB moiety introduced sufficient flexibility for facile and quantitative side-chain cyclization to the bicyclic form. Both of the monocyclic peptides and both of the bicyclic peptides are photoresponsive molecules which undergo cis/trans isomerization reversibly. Copyright (C) 1999 European Peptide Society and John Wiley & Sons, Ltd.