A bioconjugate approach toward squalamine mimics: Insight into the mechanism of biological action

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.