Natural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR) , Canal Road, Jammu-180001, India.
J Med Chem. 2014 Aug 28;57(16):7085-97. doi: 10.1021/jm500901e. Epub 2014 Aug 19.
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（1）是从 Bergenia 属植物中分离得到的一种独特的融合 C-糖苷，具有有趣的抗炎和抗痛活性。为了研究该支架的 SAR，合成了第一代衍生物，并对其抑制淋巴细胞增殖和产生促炎细胞因子的活性进行了评价。C-7 取代衍生物显示出对 IL-6 以及 TNF-α 产生的抑制作用。然后，在一系列体外和体内炎症/关节炎模型中研究了 Bergenin 及其最有效的 IL-6 抑制剂衍生物 4e 和 4f。这些化合物显著降低了 THP-1 细胞中 NF-kB 和 IKK-β 的表达。在 BALB/c 小鼠的体内研究中，观察到 SRBC 诱导的细胞因子、体液/细胞免疫的减少和抗体滴度呈剂量依赖性抑制。在 DBA/1J 小鼠的 CIA 研究中，化合物导致爪子肿胀、细胞因子水平和抗胶原蛋白 IgG1/IgG2a 水平降低。吡喃并异色满酮类化合物在体内具有显著的免疫抑制作用，这表明该支架有望开发下一代抗关节炎药物。
