title: A bioconjugate approach toward squalamine mimics: Insight into the mechanism of biological action.
abstract: 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.
authors.affiliation: Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Chen
authors.forename: Xue-Bin
authors.initials: XB
authors.lastname: Shao
authors.forename: Robert
authors.initials: R
authors.lastname: Moellering
authors.forename: Christine
authors.initials: C
authors.lastname: Wennersten
authors.forename: Steven L
authors.initials: SL
authors.lastname: Regen
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002777:Cholestanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006095:Gram-Positive Cocci / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure
chemical_list: D000900:Anti-Bacterial Agents; D002777:Cholestanols; C079655:squalamine