Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.
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.
Burns
Mark R
MR
MediQuest Therapeutics, Inc., 22322 20th Ave. SE, Bothell, WA 98021, USA.
Jenkins
Scott A
SA
Vermeulen
Nicolas M
NM
Balakrishna
Rajalakshmi
R
Nguyen
Thuan B
TB
Kimbrell
Matthew R
MR
David
Sunil A
SA
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
D008070:Lipopolysaccharides; D013449:Sulfonamides; D013096:Spermine