Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
Nat Chem. 2011 Nov 27;4(1):31-6. doi: 10.1038/nchem.1206.
The helicates--chiral assemblies of two or more metal atoms linked by short or relatively rigid multidentate organic ligands--may be regarded as non-peptide mimetics of α-helices because they are of comparable size and have shown some relevant biological activity. Unfortunately, these beautiful helical compounds have remained difficult to use in the medicinal arena because they contain mixtures of isomers, cannot be optimized for specific purposes, are insoluble, or are too difficult to synthesize. Instead, we have now prepared thermodynamically stable single enantiomers of monometallic units connected by organic linkers. Our highly adaptable self-assembly approach enables the rapid preparation of ranges of water-stable, helicate-like compounds with high stereochemical purity. One such iron(II) 'flexicate' system exhibits specific interactions with DNA, promising antimicrobial activity against a Gram-positive bacterium (methicillin-resistant Staphylococcus aureus, MRSA252), but also, unusually, a Gram-negative bacterium (Escherichia coli, MC4100), as well as low toxicity towards a non-mammalian model organism (Caenorhabditis elegans).
螺旋配合物——由两个或多个金属原子通过短的或相对刚性的多齿有机配体连接而成的手性组装体——可以被视为α-螺旋的非肽类似物，因为它们的大小相当，并显示出一些相关的生物活性。不幸的是，由于这些漂亮的螺旋化合物含有异构体混合物、不能针对特定目的进行优化、不溶或合成过于困难，因此它们在药物领域仍然难以使用。相反，我们现在已经制备了热力学稳定的单金属单元的单一对映异构体，这些单金属单元通过有机连接物连接。我们高度适应性的自组装方法能够快速制备一系列水稳定的、具有高立体化学纯度的类似螺旋配合物的化合物。这样一个铁(II)“柔性配合物”系统表现出与 DNA 的特异性相互作用，有望对革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌，MRSA252）具有抗菌活性，但也不同寻常地对革兰氏阴性菌（大肠杆菌，MC4100）具有活性，并且对非哺乳动物模式生物（秀丽隐杆线虫）的毒性较低。
