Pyrano-isochromanones as IL-6 Inhibitors: Synthesis, in Vitro and in Vivo Antiarthritic Activity

Abstract

Bergenin (1), a unique fused C-glycoside isolated from Bergenia species, possesses interesting anti-inflammatory and antipain activities. To study SAR of this scaffold, first-generation derivatives were synthesized and evaluated for inhibition of lymphocyte proliferation and production of pro-inflammatory cytokines. The C-7 substituted derivatives showed inhibition of IL-6 as well as TNF-α production. Bergenin and its most potent IL-6 inhibitor derivatives 4e and 4f were then investigated in a panel of in vitro and in vivo inflammation/arthritis models. These compounds significantly decreased the expression of NF-kB and IKK-β in THP-1 cells. In in vivo study in BALB/c mice, a dose-dependent inhibition of SRBC-induced cytokines, reduction in humoral/cell-mediated immunity, and antibody titer was observed. The CIA study in DBA/1J mice indicated that compounds led to reduction in swelling of paws, cytokine levels, and anticollagen IgG1/IgG2a levels. The significant in vivo immunosuppressive efficacy of pyrano-isochromanones demonstrates the promise of this scaffold for development of next-generation antiarthritic drugs.

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

“…However, pharmacokinetic data of bergenin in mice are not reported, and the plasma concentrations obtained with the highest dose of bergenin administered (50 mg/kg) are thus not known. Therefore, concentrations of bergenin used in vitro experiments were according to references ( Jain et al, 2014 ; Yang et al, 2017 ), and 3, 10, 30 μM were selected. Results showed that bergenin (10, 30 μM) obviously inhibited the expressions of IL-6 and TNF-α in LPS-stimulated peritoneal macrophages and RAW267.4 cells.…”

“…Bergenin is the major bioactive ingredient in the herb drug. It could inhibit collagen-induced arthritis in mice by reducing serum levels of IL-2, TNF-α and IL-6, and down-regulate lipopolysaccharide (LPS)-induced activation of THP-1 cells by decreasing levels of NF-κB and IKKβ ( Jain et al, 2014 ). In addition, bergenin prevented the production of Th1 cytokines (IL-2, IFN-γ and TNF-α) while up-regulated Th2 cytokines (IL-4 and IL-5) in the peripheral blood of mice with adjuvant-induced arthritis ( Nazir et al, 2007 ); bergenin reduced the expressions of NO, TNF-α, IL-1β and IL-6 in mammary glands of mice with LPS-induced mastitis by inhibiting the activation of NF-κB and MAPKs signaling pathways ( Gao et al, 2015 ); bergenin had a therapeutic effect on LPS-induced acute lung injury by inhibiting NF-κB activation ( Yang et al, 2017 ).…”

Bergenin as a Novel Urate-Lowering Therapeutic Strategy for Hyperuricemia

“…Bergenin is the C-glucoside of 4- O -methyl gallic acid and can be found in several medicinal plants, including Bergenia crassifolia and Corylopsis spicata ( Liang et al, 2017 ). Bergenin has been reported to have multiple biological activities, including antiarthritic ( Jain et al, 2014 ; Singh et al, 2017 ), immunomodulatory ( Wang et al, 2017 ; Kumar et al, 2019 ), antidiabetic ( Veerapur et al, 2012 ), osteogenic ( Hou et al, 2019 ), neuroprotective ( Barai et al, 2019 ; Ji et al, 2019 ), and wound-healing effects ( Mukherjee et al, 2013 ). Wang et al (2017) showed that bergenin attenuated colitis by activating the peroxisome proliferator-activated receptor (PPAR) γ.…”

Synthesis of Novel Mannich Derivatives of Bakuchiol as Apoptotic Inducer through Caspase Activation and PARP‐1 Cleavage in A549 Cells

“…Manohar et al, enzymatically synthesized bakuchiol glycosides to increase the water solubility and reported their antioxidant and ACE inhibitory activities . The synthesis of Mannich derivatives of natural products has been of enormous interest for the production of leads with potent biological activities including anticancer,, antibacterial, anti‐inflammatory,, anti‐oxidant, antifungal and anticonvulsant . Mannich bases impart hydrophillicity by incorporation of nitrogen atom, hence increasing the bioavailability which in turn improves the efficacy against tumors ,.…”