Pontiki Eleni, Hadjipavlou-Litina Dimitra, Patsilinakos Alexandros, Tran Trang M, Marson Charles M
Christopher Ingold Laboratories, Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK.
Department of Pharmaceutical Chemistry, Faculty of Health Sciences, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Future Med Chem. 2015;7(14):1937-51. doi: 10.4155/fmc.15.104. Epub 2015 Oct 1.
Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species.
A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%).
The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties.
活性氧与涉及癌症、动脉粥样硬化和自身免疫性疾病的炎症相关。炎症和氧化应激的复杂性质表明，双靶点药物可能对对抗涉及活性氧的疾病有效。
已合成了一系列新型的N-取代2,4-二氨基蝶啶，并在多种测定中作为抗氧化剂进行了评估。许多化合物表现出强大的脂质抗氧化性能，有些是大豆脂氧合酶的抑制剂，两个靶点的IC50值低至100 nM。几种蝶啶衍生物在大鼠结肠炎模型中以0.01 mmol/kg的剂量显示出疗效，且组织损伤很小。2-(4-甲基哌嗪-1-基)-N-(噻吩-2-基甲基)蝶啶-4-胺(18f)在0.01 mmol/kg时表现出强大的抗炎活性(降低41%)。
2,4-二氨基蝶啶核心代表了一种用于抑制脂氧合酶以及维持抗炎特性的新支架。
