Document Detail

Toll-like receptor-8 agonistic activities in C2, C4, and C8 modified thiazolo[4,5-c]quinolines.
MedLine Citation:
PMID:  23314908     Owner:  NLM     Status:  MEDLINE    
Toll-like receptor (TLR)-8 agonists typified by the 2-alkylthiazolo[4,5-c]quinolin-4-amine (CL075) chemotype are uniquely potent in activating adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds could be promising candidate vaccine adjuvants, especially for neonatal vaccines. Alkylthiazoloquinolines with methyl, ethyl, propyl and butyl groups at C2 displayed comparable TLR8-agonistic potencies; activity diminished precipitously in the C2-pentyl compound, and higher homologues were inactive. The C2-butyl compound was unique in possessing substantial TLR7-agonistic activity. Analogues with branched alkyl groups at C2 displayed poor tolerance of terminal steric bulk. Virtually all modifications at C8 led to abrogation of agonistic activity. Alkylation on the C4-amine was not tolerated, whereas N-acyl analogues with short acyl groups (other than acetyl) retained TLR8 agonistic activity, but were substantially less water-soluble. Immunization in rabbits with a model subunit antigen adjuvanted with the lead C2-butyl thiazoloquinoline showed enhancements of antigen-specific antibody titers.
Hari Prasad Kokatla; Euna Yoo; Deepak B Salunke; Diptesh Sil; Cameron F Ng; Rajalakshmi Balakrishna; Subbalakshmi S Malladi; Lauren M Fox; Sunil A David
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  11     ISSN:  1477-0539     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-23     Completed Date:  2013-11-06     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1179-98     Citation Subset:  IM    
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MeSH Terms
Dose-Response Relationship, Drug
Molecular Structure
Quinolines / chemical synthesis,  chemistry,  pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis,  chemistry,  pharmacology*
Toll-Like Receptor 8 / agonists*
Grant Support
HHSN272200900033C/AI/NIAID NIH HHS; HHSN272200900033C//PHS HHS
Reg. No./Substance:
0/Quinolines; 0/Thiazoles; 0/Toll-Like Receptor 8

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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