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

制备了具有分子内和分子间低亚甲基桥的新型环十肽抗生素gramicidin S （GS）的类似物，并对其抑菌活性进行了研究。结构-抗菌关系为其活性的表现提供了新的认识。制备了含picolinylamide基团的GS衍生物，并研究了它们的二价金属离子结合特性。二吡啶醇基衍生物与Cu（II）和Zn（II）离子形成稳定的1:1配合物，而单吡啶醇基衍生物则观察到Cu（II）离子介导的二聚体缔合。制备了含有两个双（picolyl）氨基的GS的四聚基衍生物，并与Zn（II）离子形成稳定的1:2配合物。双核Zn（II）配合物作为RNA模型底物，可促进HPNP（2-羟丙基对硝基苯基磷酸）的磷酸二酯键的断裂。为了改进这一功能分子体系，GS的类似物含有d -酪氨酸残基代替d -苯丙氨酸残基，也含有羟脯氨酸残基代替脯氨酸残基，因为使用这些含羟基的氨基酸残基可以引入额外的功能基团，如底物识别和/或活性控制。本文对GS的二羧基四甲基衍生物进行了x射线单晶分析，这是GS相关化合物晶体学分析成功的第二个例子，也是第一个获得令人满意的精确原子参数的例子。除了反平行的β-片型主链-主链氢键外，还观察到分子内侧链-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.