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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 28, 2014
• 年：2014
• 卷：57
• 期：16
• 页码：7085-7097
• 全文大小：618K
• ISSN：1520-4804

文摘

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-伪 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-尾 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.