| Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines. | |
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MedLine Citation:
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PMID: 19064323 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Wenyan Wu; Diptesh Sil; Michal L Szostak; Subbalakshmi S Malladi; Hemamali J Warshakoon; Matthew R Kimbrell; Jens R Cromer; Sunil A David |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-11-24 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: 17 ISSN: 1464-3391 ISO Abbreviation: Bioorg. Med. Chem. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2009-01-26 Completed Date: 2009-03-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: England |
Other Details:
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Languages: eng Pagination: 709-15 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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chemical synthesis*,
pharmacology Binding Sites Gram-Negative Bacteria Hydrazones / chemistry* Lipid A / metabolism Lipopolysaccharides / antagonists & inhibitors, metabolism* Polyamines / chemistry*, pharmacology Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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1R01 AI50107/AI/NIAID NIH HHS; 1U01AI077947/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Hydrazones; 0/Lipid A; 0/Lipopolysaccharides; 0/Polyamines |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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