Self-Organization Ability of Chiral Nα‑Substituted, Nβ‑Boc Protected α‑Hydrazinoacetamides in the Crystal and Solution States

The
limitations of peptides have severely hampered their use in
pharmacology, thus prompting the design of new peptidomimetic foldamers.
This requires precise knowledge of the secondary structure of new
compounds and the ability to predict their folding. Conformational
studies of the basic units of these foldamers can be of invaluable
assistance in designing new bioactive compounds. To this end, we investigated
the conformation of three chiral Nα-substituted, Nβ-Boc protected
α-hydrazinoacetamide model compounds containing various side
chains both on the Nα- and Cα-atoms in both the crystal and solution
states. On the basis of IR absorption spectroscopy, NMR, molecular
dynamics calculations and X-ray diffraction experiments, we demonstrated
that these three models adopt conformational preferences, relying
on eight-, six- or five-membered H-bonded pseudocycles (C8, C6 or C5), depending on the steric bulk of
both Nα- or Cα-side chains. This study sheds light onto the versatile
folding ability of the specific class of α-Nα-hydrazinopeptides and emphasizes the key role
of the Cα-side chain on the conformational
preference of the folding.

肽类化合物的局限性严重阻碍了其在药理学中的应用，从而催生了新型肽类似物折叠体的设计。此设计需求对新型化合物的二级结构有精确的认知，以及预测其折叠的能力。对这些折叠体基本单元的构象研究，在新型生物活性化合物的设计上具有无与伦比的帮助。为此，我们研究了三种手性Nα-取代、Nβ-Boc保护的α-肼基乙酰胺模型化合物在晶体和溶液状态下的构象。基于红外吸收光谱、核磁共振、分子动力学计算和X射线衍射实验，我们证明了这三种模型具有构象偏好，其依赖于Nα-或Cα侧链的立体体积，形成八、六或五元环的氢键假环（C8、C6或C5）。本研究揭示了特定类α-Nα-肼基肽的广泛折叠能力，并强调了Cα侧链在折叠构象偏好中的关键作用。