Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines.
J Med Chem
; 48(7): 2589-99, 2005 Apr 07.
Article
en En
| MEDLINE
| ID: mdl-15801849
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Espermina
/
Lipopolisacáridos
/
Amidas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2005
Tipo del documento:
Article