title: 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.affiliation: Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR) , Canal Road, Jammu-180001, India.
authors.forename: Shreyans K
authors.initials: SK
authors.lastname: Jain
authors.forename: Surjeet
authors.initials: S
authors.lastname: Singh
authors.forename: Anamika
authors.initials: A
authors.lastname: Khajuria
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Guru
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.forename: Samdarshi
authors.initials: S
authors.lastname: Meena
authors.forename: Janhavi R
authors.initials: JR
authors.lastname: Nadkarni
authors.forename: Amarinder
authors.initials: A
authors.lastname: Singh
authors.forename: Sonali S
authors.initials: SS
authors.lastname: Bharate
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001578:Benzopyrans / Q000737:chemistry; D002135:Calcium-Binding Proteins / Q000187:drug effects; D002839:Chromans / Q000737:chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism; D056724:Immunity, Humoral / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D002135:Calcium-Binding Proteins; D002839:Chromans; D065607:Cytochrome P-450 Enzyme Inhibitors; D016207:Cytokines; D051550:I-kappa B Kinase; D007074:Immunoglobulin G; D016328:NF-kappa B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C586920:Calcoco1 protein, mouse; C006741:bergenin