Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines

作者：Shukla Nikunj M; Mutz Cole A; Malladi Subbalakshmi S; Warshakoon Hemamali J; Balakrishna Rajalakshmi; David Sunil A^*

来源：Journal of Medicinal Chemistry, 2012, 55(3): 1106-1116.

DOI：10.1021/jm2010207

Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N-1-aryl positions. Dinners linked at the C4, C8, and N-1-aryl positions were agonistic at TLR7; only the N-1-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8.

• 出版日期2012-2-9