title: Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines.
abstract: Lipopolysaccharides (LPS), otherwise termed "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. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C(16) for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED(50) of 1.37 muM. Nitric oxide production in murine J774A.1 cells, as well as TNF-alpha in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to d-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.
authors.affiliation: Department of Medicinal Chemistry, Life Sciences Research Laboratories, 1501 Wakarusa Drive, University of Kansas, Lawrence, Kansas 66049, USA. sdavid@ku.edu
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Miller
authors.forename: E V K
authors.initials: EV
authors.lastname: Suresh Kumar
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Wood
authors.forename: Jens R
authors.initials: JR
authors.lastname: Cromer
authors.forename: Apurba
authors.initials: A
authors.lastname: Datta
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli; D005260:Female; D006461:Hemolysis; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018805:Sepsis / Q000401:mortality / Q000517:prevention & control; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D008050:Lipid A; D008070:Lipopolysaccharides; C500164:N(1)-heptadecanoyl-1,16-diamino-4,8,13-triazahexadecane; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D013096:Spermine; D009569:Nitric Oxide