Double-helical cyclic peptides: Design, synthesis, and crystal structure of figure-eight mirror-image conformers of adamantane-constrained cystine-containing cyclic peptide cyclo (Adm-Cyst)s
Double-helical cyclic peptides: Design, synthesis, and crystal structure of figure-eight mirror-image conformers of adamantane-constrained cystine-containing cyclic peptide cyclo (Adm-Cyst)s
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DOI：
10.1021/jo0003807
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发表时间：
2000-07-14
影响因子：
3.6
通讯作者：
Karle, IL
中科院分区：
文献类型：
--
作者：
Ranganathan, D;Haridas, V;Karle, IL
大量的大环化合物含有交替重复的胱氨酸diOMe（-NH-CH-（CO_2Me）-CH_2-S-）（2）和在环骨架中的构象刚性的芳香族/脂环族部分或柔性的多亚甲基单元（X），环尺寸从13- 78元不等，通过光谱（H-1 NMR，FT-IR，CD）和X-射线晶体学研究了不寻常的构象偏好。1H-1 NMR结果表明，所有大环化合物均为类转角构象，分子内NH +4稳定其构象.在氯仿中的红外光谱也支持CO氢键，圆二色性研究为β转角结构提供了令人信服的证据。对39元环（Adm-L-Cyst）3的单晶X-射线研究揭示了大环的双螺旋折叠（8字形基序）。在由L-胱氨酸构建的大环中仅观察到右旋双螺旋。正如预期的那样，由D-胱氨酸单元组成的镜像大环呈现出螺旋方向完全相反的双螺旋。对映体的8位数是由两个分子内的NH…CO氢键，并表现出相同的H-1 NMR和FT-IR光谱。两种异构体的圆二色谱具有镜像关系。目前的结果清楚地表明了胱氨酸残基在诱导转角构象方面的重要性，这可能是含有多个S-S键的大环采用拓扑重要结构的重要决定因素。
A large number of macrocycles containing alternating repeats of cystine diOMe(-NH-CH-(CO2Me)-CH2-S-)(2) and either a conformationally rigid aromatic/alicyclic moiety or a flexible polymethylene unit (X) in the cyclic backbone with ring size varying from 13- to 78-membered have been examined by spectral (H-1 NMR, FT-IR, CD) and X-ray crystallography studies for unusual conformational preferences. While H-1 NMR measurements indicated a turnlike conformation for all macrocycles, stabilized by intramolecular NH ... CO hydrogen bonding, as also supported by FT-IR spectra in chloroform, convincing proof for beta-turn structures was provided by circular dichroism studies. Single-crystal X-ray studies on 39-membered cycle (Adm-L-Cyst)3 revealed a double-helical fold (figure-eight motif) for the macrocycle. Only a right-handed double helix was seen in the macrocycle constructed from L-cystine. The mirror-image macrocycle made up of D-cystine units exhibited a double helix with exactly the opposite screw sense, as expected. The enantiomeric figure-eights were stabilized by two intramolecular NH ... CO hydrogen bonds and exhibited identical H-1 NMR and FT-IR spectra. The CD spectra of both isomers had a mirror-image relationship. The present results have clearly brought out the importance of cystine residues in inducing turn conformation that may be an important deciding factor for the adoption of topologically important structures by macrocycles containing multiple S-S linkages.