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.

• Authors: Shreyans K Jain, Surjeet Singh, Anamika Khajuria, Santosh K Guru, Prashant Joshi, Samdarshi Meena, Janhavi R Nadkarni, Amarinder Singh, Sonali S Bharate, Shashi Bhushan, Sandip B Bharate, Ram A Vishwakarma
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 16 Pg. 7085-97 (Aug 28 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25111439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Benzopyrans
• Calcium-Binding Proteins
• Calcoco1 protein, mouse
• Chromans
• Cytochrome P-450 Enzyme Inhibitors
• Cytokines
• Immunoglobulin G
• Interleukin-6
• NF-kappa B
• Transcription Factors
• Tumor Necrosis Factor-alpha
• I-kappa B Kinase
• bergenin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Arthritis, Experimental (drug therapy)
• Benzopyrans (chemistry)
• Calcium-Binding Proteins (drug effects)
• Chromans (chemistry)
• Cytochrome P-450 Enzyme Inhibitors (chemistry, pharmacology)
• Cytokines (metabolism)
• Drug Evaluation, Preclinical (methods)
• Female
• Humans
• I-kappa B Kinase (chemistry, metabolism)
• Immunity, Humoral (drug effects)
• Immunoglobulin G (metabolism)
• Interleukin-6 (antagonists & inhibitors)
• Lymphocytes (drug effects)
• Mice, Inbred BALB C
• Mice, Inbred DBA
• NF-kappa B (metabolism)
• Structure-Activity Relationship
• Transcription Factors
• Tumor Necrosis Factor-alpha (biosynthesis)