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桥结构的新型环十肽抗生素S类似物，并对其抗菌活性进行了研究。结构与抗菌活性的关系为其活性的表现提供了新的视角。合成了含有吡咯酰胺基的GS衍生物，并研究了它们的二价金属离子结合特性。二吡啶甲酰基衍生物与铜(II)、锌(II)离子形成稳定的1：1络合物，而单吡啶甲酰基衍生物则观察到铜(II)离子介导的二聚体缔合，合成了含有两个双(吡啶甲酰基)氨基的GS的四甲酚基衍生物，并与锌离子形成稳定的1：2络合物。作为RNA模型底物，双核锌(II)络合物能促进HPNP(2-羟丙基-对-硝基苯基磷酸)磷酸二酯键的断裂。为了改进这一功能分子体系，将含有D-酪氨酸残基的GS类似物取代了D-苯丙氨酸残基，也将含有羟脯氨酸残基的GS类似物取代了Pro残基，因为利用这些含有羟基的氨基酸残基可以引入额外的官能团，如底物识别和/或活性控制。作为第二个成功的GS相关化合物的单晶分析的例子，也作为第一个获得令人满意的精确原子参数的例子，我们对GS的一个二-Boc-四-N-甲基衍生物进行了X射线单晶分析。除了观察到反平行的β-Sheet型主链-主链氢键外，还观察到了分子内侧链-主链氢键的相互作用。

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.