Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide -: Alkyne 1,3-dipolar cycloaddition
Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide -: Alkyne 1,3-dipolar cycloaddition
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DOI：
10.1021/jo800142s
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发表时间：
2008-08-01
影响因子：
3.6
通讯作者：
Chorev, Michael
中科院分区：
文献类型：
--
作者：
Cantel, Sonia;Isaad, Alexandra Le Chevalier;Chorev, Michael
分子内侧链到侧链环化是实现特定构象稳定的既定方法和提高对蛋白水解降解的抗性的公认策略。为此，环化，这是生物电子等排的内酰胺型侧链侧链修饰，不需要正交保护方案，是非常感兴趣的。在本文中，我们报告了Cu（I）催化的1，3-偶极环加成的侧链与叠氮基和炔基官能团的修饰，并探索替代的合成路线，以有效地产生1，4-二取代的[1，2，3]三唑基含环肽。分别在i和i+4位包含c-叠氮基正亮氨酸和炔丙基甘氨酸（Pra）的线性前体的固相组装通过使树脂结合的肽在树脂上进行选择性的Lys重氮转化为Nle（ε-N（3））或在树脂结合的肽1b的逐步构建期间掺入Fmoc-Nle（ε-N3）-OH来完成。溶液相Cu（I）催化的1，3-偶极环加成将线性前体Ac-Lys-Gly-Nle（ε-N（3））-Ser-Ile-Gln-Pra-Leu-Arg-NH（2）（2）转化为含1，4-二取代[1，2，3]三唑基的环肽[Ac-Lys-Gly-Xaa（1））-Ser-Ile-Gln-Yaa（2））-Leu-Arg-NH（2）] [（1）（CH（2））（4）-1，4 [1，2，3]三唑基-CH（2）&（2））]（3）。将模型环肽3（III）的构象偏好与相应的内酰胺类似物Ac[Lys（13）（&（1）），Asp（17）（&（2））]hPTHrP（11-19）NH（2）（II）进行比较，所述模型环肽3（III）衍生自甲状旁腺素相关肽（PTHrP）的高度螺旋和有效的i至i+4侧链至侧链含内酰胺的拮抗剂的序列。CD和NMR研究3和II在水/六氟丙酮（HFA）（50：50，v/v）揭示了一个高患病率的转向螺旋结构，特别是涉及的环状区域的分子。尽管主链排列略有不同，但位于成环序列i+1至i+3处的Ser、Gln和Ile的侧链共享相同的空间取向。这两个环肽不同的位置的转向螺旋段，其中在II涉及noncyclized残基，而在3它与残基参与的环状结构重叠。因此，i至i+4侧链对侧链环肽的合成可及性和构象相似性含有内酰胺型的1，4-二取代[1，2，3]三唑基部分，可能导致类似的生物活性。
Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to sidechain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of Cu(I)-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including c-azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(epsilon-N(3)) or the incorporation of Fmoc-Nle(epsilon-N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase Cu(I)-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(epsilon-N(3))-Ser-Ile-Gln-Pra-Leu-Arg-NH(2) (2) into the 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptide [Ac-Lys-Gly-Xaa(&(1))-Ser-Ile-Gin-Yaa(&(2))-Leu-Arg-NH(2)] [(&(1) (CH(2))(4)-1,4[ 1,2,3]triazolyl-CH(2)&(2))] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys(13)(&(1)),Asp(17)(&(2))]hPTHrP(11-19)NH(2) (II). CD and NMR studies of 3 and II in water/hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.