Randazzo R A S, Bucki R, Janmey P A, Diamond S L
Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, 1024 Vagelos Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Bioorg Med Chem. 2009 May 1;17(9):3257-65. doi: 10.1016/j.bmc.2009.03.049. Epub 2009 Apr 1.
A family of cationic lipids was synthesized via direct amide coupling of spermine to the C-24 position of cholic acid analogs. Four monosubstituted spermines and a bis-substituted spermine were evaluated as plasmid transfection reagents, as bacteriostatic agents, and as bactericidal agents. The incorporation of a double bond in the sterol moiety enhanced transfection efficiency significantly and produced two compounds with little cytotoxicity and transfection potency comparable to Lipofectamine2000. Inclusion of the double bond had no effect on the general trend of increasing bactericidal activity with increasing sterol hydrophobicity. Co-formulation of the most hydrophilic of the compounds with its bis-substituted analogue led to enhancement in transfection activity. The bis-substituted compound, when tested alone, emerged as the most bacteriostatic compound in the family with minimum inhibitory concentrations (MIC) of 4 microM against Bacillus subtilis and 16 microM against Escherichia coli and therapeutic indexes (minimum hemolytic concentration/minimum inhibitory concentration) of 61 and 15, respectively. Cationic lipids can be optimized for both gene delivery and antibacterial applications by similar modifications.
通过将精胺直接酰胺偶联到胆酸类似物的C-24位合成了一族阳离子脂质。评估了四种单取代精胺和一种双取代精胺作为质粒转染试剂、抑菌剂和杀菌剂的性能。在甾醇部分引入双键显著提高了转染效率，并产生了两种细胞毒性小且转染能力与Lipofectamine2000相当的化合物。引入双键对随着甾醇疏水性增加杀菌活性增强的总体趋势没有影响。将该族中亲水性最强的化合物与其双取代类似物共同配制可提高转染活性。单独测试时，双取代化合物是该族中抑菌性最强的化合物，对枯草芽孢杆菌的最低抑菌浓度（MIC）为4 microM，对大肠杆菌的最低抑菌浓度为16 microM，治疗指数（最低溶血浓度/最低抑菌浓度）分别为61和15。通过类似的修饰可以优化阳离子脂质用于基因递送和抗菌应用。
