Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines.
The toxicity of gram-negative bacterial endotoxin (lipopolysaccharide, LPS) resides in its structurally highly conserved glycolipid component called lipid A. Our major goal has been to develop small-molecules that would sequester LPS by binding to the lipid A moiety, so that it could be useful for the prophylaxis or adjunctive therapy of gram-negative sepsis. We had previously identified in rapid-throughput screens several guanylhydrazones as potent LPS binders. We were desirous of examining if the presence of the guanylhydrazone (rather than an amine) functionality would afford greater LPS sequestration potency. In evaluating a congeneric set of guanylhydrazone analogues, we find that C(16) alkyl substitution is optimal in the N-alkylguanylhydrazone series; a homospermine analogue with the terminal amine N-alkylated with a C(16) chain with the other terminus of the molecule bearing an unsubstituted guanylhydrazone moiety is marginally more active, suggesting very slight, if any, steric effects. Neither C(16) analogue is significantly more active than the N-C(16)-alkyl or N-C(16)-acyl compounds that we had characterized earlier, indicating that basicity of the phosphate-recognizing cationic group, is not a determinant of LPS sequestration activity.
Wu
Wenyan
W
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA.
Sil
Diptesh
D
Szostak
Michal L
ML
Malladi
Subbalakshmi S
SS
Warshakoon
Hemamali J
HJ
Kimbrell
Matthew R
MR
Cromer
Jens R
JR
David
Sunil A
SA
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D006090:Gram-Negative Bacteria; D006835:Hydrazones / Q000737:chemistry*; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006835:Hydrazones; D008050:Lipid A; D008070:Lipopolysaccharides; D011073:Polyamines