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

• Published in: Journal of medicinal chemistry Vol. 55; no. 3; pp. 1106 - 1116
• Main Authors: Shukla, Nikunj M, Mutz, Cole A, Malladi, Subbalakshmi S, Warshakoon, Hemamali J, Balakrishna, Rajalakshmi, David, Sunil A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.02.2012; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Dimerization; Genes, Reporter; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Immunity, Innate; Interferon-alpha - biosynthesis; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - biosynthesis; Interleukin-8 - antagonists & inhibitors; Interleukin-8 - biosynthesis; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Structure-Activity Relationship; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 7 - antagonists & inhibitors; Toll-Like Receptor 8 - antagonists & inhibitors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; DOUBLE-STRANDED-RNA; INTERFERON; ACTIVATION; ACID; CERVICAL-CANCER; TLR7; POLY(I-C); DERIVATIVES; PATHOGEN RECOGNITION; PROTECTS
• ISSN: 0022-2623; 1520-4804
• 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. Dimers 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.