Condensation Approach to Aliphatic Oligourea Foldamers: Helices with N-(Pyrrolidin-2-ylmethyl)ureido Junctions
Condensation Approach to Aliphatic Oligourea Foldamers: Helices with N-(Pyrrolidin-2-ylmethyl)ureido Junctions
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DOI：
10.1002/anie.201105416
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发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
Guichard, Gilles
中科院分区：
文献类型：
--
作者：
Fremaux, Juliette;Fischer, Lucile;Guichard, Gilles
设计和合成类似于天然生物聚合物的大而复杂的折叠结构是折叠体领域当前的挑战之一。[1]尽管困难重重，但过去几年在这方面取得了重大进展。由脂肪族B肽、[2] a/b-肽杂合物[3]或芳香族低聚酰胺[4]构建的显著长的螺旋片段、三级结构和四级排列（螺旋束）已在原子分辨率下表征。长螺旋折叠体也显示出作为α-螺旋模拟物抑制蛋白质-蛋白质相互作用的前景。例如，设计用于模拟HIV蛋白gp 41的七肽重复2结构域的33个残基长的螺旋a/B肽是病毒融合的有效抑制剂，并显示出相对于相应的a肽的蛋白水解稳定性的显著改善。[5]同样有希望的是使用蛋白质，其中二级结构的元件已被合成的折叠体取代，以解决单个折叠片段的作用，并复制或调节蛋白质拓扑结构和功能。[6]然而，获得高分子量折叠体的先决条件是开发稳健的合成方法。在脂肪族和芳香族低聚酰胺的情况下，涉及活化链段的会聚缩合[6，7，8a]和逐步固相合成（最终通过微波辐射辅助）[8]的优化程序已被证明特别有用。然而，这些方法几乎没有应用于长的非低聚酰胺链段的构建。通式[NHCH（R）CH 2NHCO] n的脂肪族寡脲代表一类有趣的拟肽折叠体，其具有与生物大分子相互作用的潜力。[9]在溶液和晶体状态下的高分辨率结构研究表明，这些g4肽的氮杂类似物形成由三中心氢键稳定的明确定义的2.5螺旋结构。[10]虽然脂肪族寡脲可以通过固相技术制备，但由于需要长的偶联时间和N-保护基的选择所带来的限制，迄今为止将寡脲螺旋的合成限制在约10个单元长的短链段。[11为了减少合成步骤的数量，从而更快地向更长的寡聚体进化，我们现在将迭代片段缩合方法引入寡聚体折叠体。我们最初的计划是用琥珀酰亚胺碳酸酯活化带有氨基末端的短寡脲，以产生相应的活化片段A。然而，发现由活化的琥珀酰亚胺基氨基甲酸酯被最近的脲NH攻击导致的环状缩二脲（B）的竞争性形成显著降低了A的产率（方案1a）。[13]虽然考虑了安装临时保护基团以阻止相邻尿素的NH的反应性，[14]但我们认为这会损害快速进入长螺旋片段的方法的通用性。因此，我们设想在末端引入N-烷基化单元，其不容易形成缩二脲，从而促进片段活化。为了扩大我们的蛋白质积木的收藏-
The design and synthesis of large and complex folded structures resembling those of natural biopolymers is one of the current challenges in the field of foldamers.[1] Despite the difficulty, significant progress in this direction has been made over the last few years. Remarkably long helical segments, tertiary-type structures, and quaternary arrangements (helix bundles) constructed from aliphatic b peptides,[2] a/b-peptide hybrids,[3] or aromatic oligoamides,[4] have been characterized at atomic resolution. Long helical foldamers also show promise as a-helical mimics to inhibit protein–protein interactions. For example, 33-residue-long helical a/b peptides designed to mimic the heptad repeat 2 domain of the HIV protein gp41 are potent inhibitors of virus fusion and display significant improvement in proteolytic stability over corresponding a peptides.[5] Also promising is the use of proteins in which elements of the secondary structure have been replaced by synthetic foldamers to address the role of individual folded segments and to replicate or modulate protein topology and function.[6] Nevertheless, a prerequisite to accessing highmolecular-weight foldamers is the development of a robust synthetic methodology. In the case of aliphatic and aromatic oligoamides, optimized procedures involving convergent condensation of activated segments,[6, 7, 8a] and stepwise solidphase synthesis (eventually assisted by microwave irradiation),[8] have proven particularly useful. However, such methods have hardly been applied to the construction of long non-oligoamide segments. Aliphatic oligoureas of the general formula [NHCH (R) CH2NHCO] n represent an interesting class of peptidomimetic foldamers with potential for interacting with bio-macromolecules.[9] High resolution structural studies in solution and in the crystal state have shown that these aza analogues of g4 peptides form well-defined 2.5-helical structures stabilized by three-centered hydrogen bonds.[10] Although aliphatic oligoureas can be prepared by solidphase techniques, the need for long coupling times and the limitations imposed by the choice of the N-protecting group have so far limited the synthesis of oligourea helices to short segments of about 10 units long.[11, 12] To decrease the number of synthetic steps and thus evolve more rapidly towards longer oligomers, we now introduce an iterative segment condensation approach to oligourea foldamers. Our initial plan was to activate short oligoureas bearing an amino terminus with succinimidyl carbonate to yield the corresponding activated segment A. However, the competitive formation of cyclic biuret (B) resulting from the attack of the activated succinimidyl carbamate by the nearest urea NH was found to significantly reduce the yield of A (Scheme 1 a).This side reaction was also found to be problematic in the segment coupling step.[13] Although the installation of a temporary protecting group to block the reactivity of the NH of the neighboring urea was considered,[14] we felt that it would compromise the versatility of the method for rapid access to long helical segments. Therefore, we envisioned the introduction of an N-alkylated unit at the terminus that would not be prone to biuret formation and would thus facilitate segment activation. To expand our collection of building blocks with proteino-