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.
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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)
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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
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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)
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