Bi-aryl Analogues of Salicylic Acids: Design, Synthesis and SAR Study to Ameliorate Endoplasmic Reticulum Stress

Abstract

Introduction Endoplasmic reticulum (ER) stress condition is characterized as the accumulation of misfolded or unfolded proteins in lumen of ER. This condition has been implicated in various diseases and pathologies including β-cell apoptosis, Alzheimer’s disease and atherosclerosis. We have reported that hydroxynaphthoic acids (HNA), naphthalene analogues of salicylic acid (SA), reduced ER stress. In this study, we explored structural modification to bi-aryl analogues of SA. Methods Palladium-catalyzed cross-coupling was applied to synthesize bi-aryl analogues of SA. Anti-ER stress activity was monitored by using our cell-based assay system where ER stress is induced by tunicamycin. To monitor ER stress markers, ER stress was induced physiologically relevant palmitate system. Results Many analogues decreased ER stress signal induced by tunicamycin. Compounds creating dihedral angle between Ar group and SA moiety generally increased the activity but gave some cytotoxicity to indicate the crucial role of flat conformation of aromatic region. The best compound (16e) showed up to almost 6-fold and 90-fold better activity than 3-HNA and tauro-ursodeoxycholic acid, positive controls, respectively. ER stress markers such as p-PERK and p-JNK were accordingly decreased in Western blotting upon treatment of 16e under palmitate-induced condition. Conclusion Anti-ER stress activity and toxicity profile of bi-aryl analogues of SA could provide a novel platform for potential therapy for protein misfolding diseases.

Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases

“…Of these, 20 (Diflunisal), an anti-inflammatory drug with a biphenyl ring harboring a fluorine substituent, exhibited the best anti-ER stress activity. The EC 50 value (EC 50 = 58 μM) of Diflunisal ( 20 ) 63 was approximately 6- and 90-fold higher than 3-HNA ( 11 ) (EC 50 = 328 μM) and t-UDCA ( 2 ) (EC 50 = 5.2 mM), 64 respectively. Moreover, Diflunisal ( 20 ) ameliorated palmitate-induced ER stress and decreased UPR markers.…”

“… [ 21 ] 12 KM04794 Diabetes XBP1-s, BiP, Herpud1, ATF4 ↓ Enhances insulin production EC 50 = 9 ~16 μM Tm-induced UPRE-, AARE-, and ERSE-driven assay [ 44 ] 14 Azoramide Diabetes CHOP, GRP78, ↓ Improve insulin secretion and survival in β-cells EC 50 = 9 ~16 μM Tm-induced assay ob / ob mouse [ 45 ] 15 – Diabetes CHOP mRNA, cleaved PARP, cleaved caspase 3 ↓ blood glucose ↓ EC 50 = 2.8 μM CHOP reporter assay. STZ-induced diabetic mouse [ 46 ] 16 Berberine Anti-inflammatory, Hypoglycemic activity, Alzheimer’s disease, Anti-atherosclerosis FNF-alpha, IL-6, IL-1beta MCP-1, CHOP, ATF4, XBP-1s ↓ IC 50 = 6.6 μM [ 55 ] 19 Ar9273 Anti-inflammation sEH inhibitor Gastrointestinal diseases IL-6, TNF-α, CHOP TRB3, IL-1beta mRNA, MCP-1 mRNA, ATF3 ↓ IC 50 = 197 nM [ 62 ] 20 Diflunisal Anti-inflammation, NSAIDs p-PERK, p-JNK ↓ EC 50 = 58 μM Tm-induced GRP78 reporter assay [ 63 ] 22 Valsartan Angiotensin receptor blocker caspase 3, GRP78, PERK, IRE1-alpha, ATF-6, eIF2α, ATF-4, CHOP ↓ ...…”

“…Moreover, Diflunisal (20) ameliorated palmitate-induced ER stress and decreased UPR markers. 63 Cardiovascular Diseases 65,66 Chemical chaperones that inhibit ER stress and provide cardioprotective activity are shown in Figure 6. Doxorubicin (Dox) is an anticancer drug, but it induces cardiotoxicity, resulting in apoptosis of cardiomyocytes, which has been attributed to ER stress.…”