Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel.
Faculty of Medicine, School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, P.O. Box 12065, 91120 Jerusalem, Israel ; The Harvey M. Krueger Family Center for Nanoscience and Nanotechnology, The Hebrew University, 91904 Jerusalem, Israel ; The David R. Bloom Center of Pharmacy, The Hebrew University, 91120 Jerusalem, Israel.
Gastroenterol Res Pract. 2015;2015:939483. doi: 10.1155/2015/939483. Epub 2015 Apr 9.
A novel fused-cyclopentenone phosphonate compound, namely, diethyl 3-nonyl-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate (P-5), was prepared and tested in vitro (LPS-activated macrophages) for its cytotoxicity and anti-inflammatory activity and in vivo (DNBS induced rat model) for its potential to ameliorate induced colitis. Specifically, the competence of P-5 to reduce TNFα, IL-6, INFγ, MCP-1, IL-1α, MIP-1α, and RANTES in LPS-activated macrophages was measured. Experimental colitis was quantified in the rat model, macroscopically and by measuring the activity of tissue MPO and iNOS and levels of TNFα and IL-1β. It was found that P-5 decreased the levels of TNFα and the tested proinflammatory cytokines and chemokines in LPS-activated macrophages. In the colitis-induced rat model, P-5 was effective locally in reducing mucosal inflammation. This activity was equal to the activity of local treatment with 5-aminosalicylic acid. It is speculated that P-5 may be used for the local treatment of IBD (e.g., with the aid of colon-specific drug platforms). Its mode of action involves inhibition of the phosphorylation of MAPK ERK but not of p38 and had no effect on IκBα.
一种新型的融合环戊烯酮膦酸化合物，即二乙基 3-壬基-5-氧代-3,5,6,6a-四氢-1H-环戊[c]呋喃-4-基膦酸酯（P-5），已被制备并在体外（LPS 激活的巨噬细胞）进行细胞毒性和抗炎活性测试，在体内（DNBS 诱导的大鼠模型）评估其改善诱导性结肠炎的潜力。具体来说，测定了 P-5 降低 LPS 激活的巨噬细胞中 TNFα、IL-6、INFγ、MCP-1、IL-1α、MIP-1α 和 RANTES 的能力。在大鼠模型中，通过测量组织 MPO 和 iNOS 的活性以及 TNFα 和 IL-1β 的水平来量化实验性结肠炎。结果发现，P-5 降低了 LPS 激活的巨噬细胞中 TNFα 和测试的促炎细胞因子和趋化因子的水平。在结肠炎诱导的大鼠模型中，P-5 局部有效减轻了粘膜炎症。这种活性与局部用 5-氨基水杨酸治疗的活性相当。推测 P-5 可用于治疗 IBD（例如，借助结肠特异性药物平台）。其作用机制涉及抑制 MAPK ERK 的磷酸化，但不涉及 p38，并且对 IκBα 没有影响。
