Studies on self-assembling peptides containing novel amino acids with hetero-rings in side-chains

本课题拟开发含有新型α，α-二取代杂环甘氨酸的自组装肽，并研究了各种含有新型α，α-二取代杂环甘氨酸，α，α-二（2-吡啶基）甘氨酸（2Dpy）， α-苯基-α-（2-吡啶基）甘氨酸（2Ppg）， α-甲基-α-（2-吡啶基）甘氨酸（2Pmg）， α-甲基-α-（2-吡酰基）甘氨酸（2Pzm）和α-甲基-α-（2-噻唑基）甘氨酸（2Tmg）的肽的合成，构象和cu络合物的形成。通过Ugi反应合成了含有2Dpy和2Ppg的三肽（Z-AA_1-2Dpy/2Ppg- aa_3 - ome）。核磁共振分析表明，这些肽采用一种新的构象，其中每个吡啶环的氮原子与酰胺键的氢原子形成分子内氢键。采用固相Ugi反应合成了含2Dpy的三肽。与溶液法相比，该方法明显提高了这些肽的收率。采用固相Ugi反应首次合成了含2Pmg…More的三肽。这些三肽采用一种独特的构象，在2pm - nh和吡啶氮之间有一个分子内氢键。含2dpy的三肽与Cu（II）离子形成2:1的配合物，并通过x射线分析澄清了晶体结构。进一步研究了配合物的ESR谱。合成了含有两个2Dpy残基的六肽。该肽采用扩展构象，在2Dpy-NH和一个吡啶氮之间有四个分子内氢键。将研究这种肽与金属离子的络合物形成。通过合成含2Ppg的三、四肽、分离非对映体、x射线晶体分析和CD谱测定，研究了2Ppg在多肽中的手性。采用Ugi反应合成了含有其他杂环的三肽Z-AA_1-(N-Bzl)Xaa- aa_3 - ome （Xaa=2Pzm,2Tmg）。在这两种多肽中，分别观察到吡嗪氮和AA_3-NH之间以及噻唑氮和AA_3-NH之间的分子内氢键。比较了吡啶氮、噻唑氮和吡嗪氮分子内氢键的稳定性。少

In this research project, we have intended to develop new self-assembling peptides containing novel α,α-disubstituted glycines with hetero-rings, and investigated synthesis, conformation and Cu-complex formation of various peptides containing novel α, α-disubstituted glycines with hetero-rings, α, α-di(2-pyridyl)glycine (2Dpy), α-phenyl-α-(2-pyridyl)glycine (2Ppg), α-methyl-α-(2-pyridyl)glycine (2Pmg), α-methyl-α-(2-pyrazyl)glycine (2Pzm) and α-methyl-α-(2-thiazolyl)glycine (2Tmg).1.Tripeptides (Z-AA_1-2Dpy/2Ppg-AA_3-OMe) containing 2Dpy and 2Ppg were synthesized by the Ugi reaction. NMR analysis revealed these peptides adopt a novel conformation in which each nitrogen atom of pyridine rings forms an intramolecular hydrogen bond with a hydrogen atom of an amide bond.2.The tripeptides containing 2Dpy were synthesized by the solid-phase Ugi reaction. By this method, yields of these peptides were markedly improved, compared with yields by the solution method.3.Tripeptides containing 2Pmg … More were first synthesized by the solid-phase Ugi reaction. These tripeptides adopt a unique conformation with an intramolecular hydrogen bond between 2Pmg-NH and the pyridine nitrogen.4.The 2Dpy-containing tripeptides afforded the 2:1 complex with Cu(II) ion, and the crystal structure was clarified by X-ray analysis. Further, ESR spectrum of the complex was also studied.5.A hexapeptide containing two 2Dpy residues was synthesized. The peptide adopts an extended conformation with four intramolecular hydrogen bonds between 2Dpy-NH and a pyridine nitrogen. Complex formation of the peptide with metal ions will be investigated.6.Chirality of 2Ppg in peptides was investigated by synthesis of tri-and tetrapeptides containing 2Ppg followed by separation of the diastereomers and X-ray crystal analysis, and measurement of CD spectra.7.Tripeptides, Z-AA_1-(N-Bzl)Xaa-AA_3-OMe (Xaa=2Pzm,2Tmg), containing other hetero-rings were synthesized by the Ugi reaction. In both peptides, the intramolecular hydrogen bonding between a pyrazine nitrogen and AA_3-NH and between a thiazole nitrogen and AA_3-NH, respectively, were observed. Stabilities of the intramolecular hydrogen bonding by a pyridine nitrogen, a thiazole nitrogen and a pyrazine nitrogen are compared. Less