title: Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.
abstract: Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize this complex carbohydrate. A series of aryl and aliphatic spermine-sulfonamide analogs were synthesized and tested in a series of binding and cell-based assays in order to probe the effect of lipophilicity on sequestration ability. A strong correlation was indeed found, supporting the hypothesis that endotoxin-neutralizing ability involves a lipophilic or membrane attachment event. The research discussed herein may be useful for the design of additional carbohydrate recognizing molecules and endotoxin-neutralizing drugs.
authors.affiliation: MediQuest Therapeutics, Inc., 22322 20th Ave. SE, Bothell, WA 98021, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Burns
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jenkins
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Vermeulen
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Thuan B
authors.initials: TB
authors.lastname: Nguyen
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kimbrell
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D002236:Carbohydrate Conformation; D007700:Kinetics; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000302:isolation & purification*; D008958:Models, Molecular; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D008070:Lipopolysaccharides; D013449:Sulfonamides; D013096:Spermine