Synthesis of Gramicidin S Analogs as β-Structured Functional Molecular Units

合成了具有分子内和分子间寡亚甲基桥的环状十肽抗生素短杆菌肽S（GS）类似物，并研究了它们的抗菌活性。结构与抗菌活性的关系为研究其抗菌活性提供了新的思路。合成了含吡啶甲酰胺基团的GS衍生物，并研究了它们与二价金属离子的结合特性。吡啶甲酰基衍生物与Cu（II）和Zn（II）离子形成稳定的1：1络合物，而吡啶甲酰基衍生物与Cu（II）离子形成稳定的2：1络合物.合成了含有两个吡啶甲酰基氨基的GS四吡啶甲酰基衍生物，并与Zn（II）离子形成稳定的1：2络合物.双核Zn（II）配合物被证明可以促进HPNP（2-羟丙基对硝基苯基磷酸）作为RNA模型底物的磷酸二酯键的裂解。为了改善这种功能性分子系统，含有D-酪氨酸残基代替D-苯丙氨酸残基的GS类似物以及含有羟脯氨酸残基代替脯氨酸残基的GS类似物，因为通过使用这些含有羟基的氨基酸残基可以引入额外的官能团，例如底物识别和/或活性控制。GS的甲基衍生物作为GS相关化合物的成功晶体学分析的第二个例子，也作为第一个例子，它提供了令人满意的准确的原子参数。除了反平行β折叠型主链-主链氢键外，还观察到分子内侧链-主链氢键相互作用。

Novel analogs of the cyclic decapeptide antibiotic, gramicidin S (GS), possessing intra- and intermolecular oligomethylene bridge were prepared and their antibacterial activity was studied. The structure-antibacterial activity relationships afforded new insight concerning the manifestation of their activity.Picolinoylamide group-containing derivatives of GS were prepared and their divalent metal ion-binding characteristics were investigated. The dipicolinoyl derivative formed stable 1:1 complex with Cu(II) and Zn(II) ions, while in the case of monopicolinoyl derivative Cu(II) ion-mediated dimeric association was observed.The tetrapicolyl derivative of GS containing two bis(picolyl)amino groups were prepared and were shown to form a stable 1:2 complex with Zn(II) ion. The dinuclear Zn(II) complex was shown to promote the cleavage of the phosphodiester bond of HPNP (2-hydroxypropyl p-nitrophenyl phosphate) as an RNA model substrate. For the purpose of improving this functional molecular system the analogs of GS containing D-tyrosine residues in place of D-phenylalanine residues and also those containing hydroxyproline residues in place of proline residues since additional functional groups such as substrate-recognition and/or activity controle could be introduced by the use of these hydroxy group-containing amino acid residues.X-ray single crystal analysis of a di-Boc-tetra-N-methyl derivative of GS has been performed as the second example of successful crystallographic analysis of GS-related compounds and also as the first example which afforded satisfactorily accurate atomic parameters. Intramolecular side chain-main chain hydrogen-bonding interactions were observed in addition to the antiparallel β-sheet type main chain-main chain hydrogen bonds.