Chen Wen-Hua, Shao Xue-Bin, Moellering Robert, Wennersten Christine, Regen Steven L
Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Bioconjug Chem. 2006 Nov-Dec;17(6):1582-91. doi: 10.1021/bc060220n.
A short and efficient synthesis has been devised for a family of squalamine mimics, based on the use of cholic acid, deoxycholic acid, lithocholic acid, putrescine, and spermine as starting materials. Those mimics that contain two facially amphiphilic sterol-spermidine conjugates show strong antibacterial activity against a broad spectrum of Gram-positive bacteria; their corresponding activities against a broad spectrum of Gram-negative bacteria are relatively moderate. Larger mimics, containing four such sterol-spermidine conjugates, exhibit very weak activities. Reversal of the pendent spermidine moiety and a putrescine linkage on the A- and D-rings had little consequence on the antibacterial activity for the most active of the squalamine mimics, which contained two sterol-polyamine units; similar results were obtained with squalamine mimics made from only one sterol unit. Detailed structure-activity measurements, in combination with kinetic studies carried out using liposomes as model membranes, support a mechanism of action involving noncovalent dimers as ion transporting species, most probably via the formation of pores or channels.
基于使用胆酸、脱氧胆酸、石胆酸、腐胺和精胺作为起始原料，设计了一种针对鲨胺类似物家族的简短而高效的合成方法。那些含有两个面两亲性甾醇 - 亚精胺共轭物的类似物对多种革兰氏阳性菌显示出较强的抗菌活性；它们对多种革兰氏阴性菌的相应活性相对适中。含有四个此类甾醇 - 亚精胺共轭物的较大类似物表现出非常弱的活性。对于活性最强的含有两个甾醇 - 多胺单元的鲨胺类似物，在A环和D环上反转侧链亚精胺部分和腐胺连接对其抗菌活性影响不大；仅由一个甾醇单元制成的鲨胺类似物也得到了类似结果。详细的构效关系测定，结合使用脂质体作为模型膜进行的动力学研究，支持了一种作用机制，即涉及非共价二聚体作为离子转运物种，很可能是通过形成孔或通道来实现的。
