Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines.
We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH(2)-(CH(2))(3)-NH-(CH(2))(4)-NH(2)] and norspermidine [NH(2)-(CH(2))(3)-NH-(CH(2))(3)-NH(2)] backbones, with the N-alkyl group being held constant at C(16) in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.
Shrestha
Anurupa
A
Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA.
Sil
Diptesh
D
Malladi
Subbalakshmi S
SS
Warshakoon
Hemamali J
HJ
David
Sunil A
SA