Chegaev Konstantin, Lazzarato Loretta, Rolando Barbara, Marini Elisabetta, Tosco Paolo, Cena Clara, Fruttero Roberta, Bertolini Francesca, Reist Marianne, Carrupt Pierre-Alain, Lucini Valeria, Fraschini Franco, Gasco Alberto
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Torino, Italy.
J Pineal Res. 2007 Apr;42(4):371-85. doi: 10.1111/j.1600-079X.2007.00429.x.
Numerous studies document that melatonin possesses a broad-spectrum antioxidant activity. It traps a number of reactive oxygen species (ROS) such as hydroxyl and peroxyl radicals, singlet oxygen and hypochlorous acid. It also inhibits peroxynitrite-induced reactions. It is known that atherosclerosis progression involves ROS-induced oxidation of low-density lipoproteins in sub-endothelial space and the depletion of nitric oxide (NO) in blood vessels, as well as a decreased sensitivity of the vessels to the actions of NO. Considering this, a series of new NO-donor antioxidants were designed and synthesized by joining melatonin with NO-donor nitrooxy and furoxan moieties as polyvalent agents potentially useful for the treatment of cardiovascular diseases involving atherosclerotic vascular changes. The in vitro antioxidant properties of the resulting products were assessed in the thiobarbituric acid reactive substances assay (TBARS), the ABTS(+.) as well as in the alkaline phosphatase (ALP) assay. The antioxidant capacities of NO-donor melatonins to inhibit lipoperoxidation (TBARS-IC(50)) was predominantly dependent on their lipophilicity, and therefore on their partitioning process into membranes. On the other hand, their comparable capacity to inhibit protein oxidation (ALP-IC(50)) was independent of their lipophilicity and was consistent with their similar ability to participate in electron transfer reactions. All the NO-donor melatonins were also evaluated for their ability to relax rat aorta strips precontracted with 1 microM phenylephrine. Finally, binding affinities and intrinsic activity studies, carried out at MT(1) and MT(2) receptor subtypes, showed a rather complex picture in need of further investigation.
大量研究表明褪黑素具有广谱抗氧化活性。它能捕获多种活性氧（ROS），如羟基和过氧自由基、单线态氧和次氯酸。它还能抑制过氧亚硝酸盐诱导的反应。已知动脉粥样硬化的进展涉及内皮下空间中ROS诱导的低密度脂蛋白氧化以及血管中一氧化氮（NO）的消耗，以及血管对NO作用的敏感性降低。考虑到这一点，通过将褪黑素与作为多价试剂的NO供体硝基氧基和呋咱部分连接起来，设计并合成了一系列新型的NO供体抗氧化剂，这些试剂可能对治疗涉及动脉粥样硬化血管变化的心血管疾病有用。通过硫代巴比妥酸反应物质测定法（TBARS）、ABTS(+.)以及碱性磷酸酶（ALP）测定法评估了所得产物的体外抗氧化性能。NO供体褪黑素抑制脂质过氧化（TBARS-IC(50)）的抗氧化能力主要取决于它们的亲脂性，因此取决于它们向膜中的分配过程。另一方面，它们抑制蛋白质氧化（ALP-IC(50)）的相当能力与其亲脂性无关，并且与它们参与电子转移反应的相似能力一致。还评估了所有NO供体褪黑素舒张用1 microM去氧肾上腺素预收缩的大鼠主动脉条的能力。最后，在MT(1)和MT(2)受体亚型上进行的结合亲和力和内在活性研究显示出一幅相当复杂的图景，需要进一步研究。
