Structure–Activity Relationship Studies To Identify Affinity Probes in Bis-aryl Sulfonamides That Prolong Immune Stimuli

Agents
that safely induce, enhance, or sustain multiple innate
immune signaling pathways could be developed as potent vaccine adjuvants
or coadjuvants. Using high-throughput screens with cell-based nuclear
factor κB (NF-κB) and interferon stimulating response
element (ISRE) reporter assays, we identified a bis-aryl sulfonamide
bearing compound 1 that demonstrated sustained NF-κB
and ISRE activation after a primary stimulus with lipopolysaccharide
or interferon-α, respectively. Here, we present systematic structure–activity
relationship (SAR) studies on the two phenyl rings and amide nitrogen
of the sulfonamide group of compound 1 focused toward
identification of affinity probes. The murine vaccination studies
showed that compounds 1 and 33 when used
as coadjuvants with monophosphoryl lipid A (MPLA) showed significant
enhancement in antigen ovalbumin-specific immunoglobulin responses
compared to MPLA alone. SAR studies pointed to the sites on the scaffold
that can tolerate the introduction of aryl azide, biotin, and fluorescent
rhodamine substituents to obtain several affinity and photoaffinity
probes which will be utilized in concert for future target identification
and mechanism of action studies.