The Hebrew University of Jerusalem, Faculty of Medicine, The School of Pharmacy, Institute for Drug Research, PO Box 12065, Jerusalem 91120, Israel.
Bioorg Med Chem Lett. 2010 Nov 15;20(22):6518-23. doi: 10.1016/j.bmcl.2010.09.048. Epub 2010 Sep 16.
Some carbamoylphosphonates (CPOs) inhibit matrix metalloproteinases (MMPs). Although MMPs are involved in inflammatory processes, the anti-inflammatory activity of CPOs has not been reported. In this context we compared the biological activity of the three aminoCPOs, PYR-CPO, PIP-CPO and cis-ACCP. We were particularly interested in their capability to modulate the secretion of tumor necrosis factor alpha (TNFα). LPS-activated mouse peritoneal macrophages and LPS-activated mouse splenocytes were used to explore this question. It was found that the aminoCPOs were able to reduce TNFα secretion to a level equivalent to the reduction caused by the steroid drug budesonide (BUD). The reduction in TNFα levels was neither accompanied by cytotoxicity, nor did it inhibit cell proliferation. To explicate whether the aminoCPOs affect TNFα processing by TNFα-converting enzyme (TACE), TACE inhibitory properties of the three molecules was tested in vitro. Only PIP-CPO exerted TACE inhibitory activity at therapeutic (non-cytotoxic) concentrations, indicating on its potential to serve as an anti-inflammatory agent by reducing TNFα secretion.
一些氨甲酰磷酸酯（CPOs）能抑制基质金属蛋白酶（MMPs）。尽管 MMPs 参与炎症过程，但 CPOs 的抗炎活性尚未得到报道。在这种情况下，我们比较了三种氨基 CPOs（PYR-CPO、PIP-CPO 和顺式 ACCP）的生物学活性。我们特别关注它们调节肿瘤坏死因子-α（TNFα）分泌的能力。使用 LPS 激活的小鼠腹腔巨噬细胞和 LPS 激活的小鼠脾细胞来探讨这个问题。结果发现，氨基 CPOs 能够将 TNFα 分泌减少到与类固醇药物布地奈德（BUD）引起的减少相当的水平。TNFα 水平的降低既不伴有细胞毒性，也不抑制细胞增殖。为了阐明氨基 CPOs 是否通过 TNFα 转化酶（TACE）影响 TNFα 的加工，我们在体外测试了这三种分子对 TACE 的抑制特性。只有 PIP-CPO 在治疗（非细胞毒性）浓度下表现出 TACE 抑制活性，表明其通过减少 TNFα 分泌有作为抗炎剂的潜力。
