Polycationic sulfonamides for the sequestration of endotoxin.

Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.

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.

Structure-activity relationships in lipopolysaccharide neutralizers: design, synthesis, and biological evaluation of a 540-membered amphipathic bisamide library.

Lipopolysaccharides (LPS), also called "endotoxins", are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. We had earlier shown that small molecules bind and neutralize LPS if they contain (i) two protonatable cationic groups separated by a distance of approximately 14 A to facilitate interactions with the phosphate moieties on the lipid Angstrom component of LPS and (ii) a long-chain aliphatic hydrocarbon to promote hydrophobic interactions. In an effort to identify optimal scaffolds possessing the above structural requirements, we now present an evaluation of a rationally designed combinatorial library in which the elements of the scaffold are systematically varied to maximize sampling of chemical space. Leads obtained via molecular analyses of the screening results were resynthesized and evaluated in greater detail with regard to the affinity of the interaction with LPS, as well as neutralization of endotoxicity in in vitro assays. The examination of a moderately sized 6 x 6 x 15 (540-membered) focused library allowed the assessment of the structural contributions to binding by the long-chain aliphatic tails, distance between charged amino groups, and potential aromatic CH-pi or OH-pi interactions. These findings are of value in further iterations of design and development of specific and potent endotoxin sequestrants.