Saccharin Derivatives as Inhibitors of Interferon-Mediated Inflammation

Abstract

A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure–activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ6,2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

“…Others have reported that RAW 264.7 cells lack a functional TLR5 (Means et al, 2003). We probed the activating effect of TLR ligands along with HMGB1 in RAW 264.7 cells by performing a NO assay as previously described (Csakai et al, 2014). HMGB1 significantly activated the NF-κB-driven inducible NO synthase (iNOS) gene in comparison to other TLR ligands such as PAM2 (TLR2), LPS (TLR4) and the RAGE ligand AGE-BSA (Figure 1B).…”

“…We employed a previously reported nitric oxide (NO) assay (Csakai et al, 2014) on primary rat PBMCs. Treatment of the PBMCs with flagellin and HMGB1 resulted in significant production of NO that was decreased upon TH1020 treatment at 0.75 and 1.5 µM (Figure 4A).…”

Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors

“…Furthermore, it is predicted that overall hydrophobicity of active site residues can also play a role in SAC active site entry hence the observed difference in binding between CA IX and CA XII 12 . It has previously been shown that SAC can be u se d as a lead group for CA inhibitor design 19,31 . However until now, there was no structural information available as to how the tail regions of these compounds interact with the CA active site.…”

Sultams: Recent Syntheses and Applications

“…Yin et al identified a series of saccharin‐based antagonists for the interferon signaling pathway. The lead anti‐inflammatory compound, tert ‐butyl N ‐(furan‐2‐ylmethyl)‐ N ‐{4‐[(1,1,3‐trioxo‐2,3‐dihydro‐1λ 6 ,2‐benzothiazol‐2‐yl)methyl]benzoyl}carbamate ( 103 ), acts as a potent inhibitor in an established nitric oxide (NO) signaling assay . Benzosultam 104 acted as a lead compound for both general and partial epileptic seizures in minute levels …”

“…The lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ 6 ,2-benzothiazol-2-yl)methyl]benzoyl}carbamate (103), acts as a potent inhibitor in an established nitric oxide (NO) signaling assay. [85] Benzosultam 104 acted as a lead compound for both general and partial epileptic seizures in minute levels. [86] Fauber and co-workers engineered compound 105, which possessed potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc) inverse agonist potency in a cell assay with no distinguishable activity against any of the other RORs or NRs in the small cell panel.…”