Morier-Teissier E, Bernier J L, Lohez M, Catteau J P, Hénichart J P
INSERM U16, Lille, France.
Anticancer Drug Des. 1990 Aug;5(3):291-305.
Two pseudopeptides incorporating a peptide metal-chelating moiety (Gly-His-Lys) and a polyhydroxy anthraquinone ring related to the nuclei of anti-tumor drugs such as mitoxantrone and ametantrone, have been synthesized. The goal was to conjugate the redox effects of a quinone ring with the iron-chelating properties of the peptide in order to generate free radical species capable of damaging DNA. Indeed quinone-containing drugs undergo, in vivo, one-electron reduction to the corresponding semiquinone radicals which, in the presence of molecular oxygen, produce a superoxide anion radical, hydrogen peroxide and ultimately, in the presence of metal, hydroxyl radical (Fenton reaction). Hydroxyl radicals (OH.) are short-lived and extremely reactive with their bioenvironment. The interaction of both drugs with DNA has been studied by fluorescence quenching and DNA melting experiments. Spectroscopic and e.s.r. studies demonstrated that several types of Cu-complex are formed depending on the copper-drug ratio. The production of free radicals, as evidenced by spin-trapping, is optimum with a Cu/drug ratio of 0.1; in this case the metal ion is chelated by the peptide moiety. This latter complex is able to induce DNA breakage at a high level. Thus, it appears that the proposed concept works but that care must be taken in the choice of the relative concentration of copper.
已合成了两种假肽，它们包含一个肽金属螯合部分（甘氨酸 - 组氨酸 - 赖氨酸）和一个与抗肿瘤药物如米托蒽醌和氨甲蒽醌的核相关的多羟基蒽醌环。目的是将醌环的氧化还原作用与肽的铁螯合特性结合起来，以产生能够破坏DNA的自由基。实际上，含醌药物在体内经历单电子还原生成相应的半醌自由基，在分子氧存在下，半醌自由基会产生超氧阴离子自由基、过氧化氢，最终在金属存在下产生羟基自由基（芬顿反应）。羟基自由基（OH.）寿命短且与生物环境反应性极强。通过荧光猝灭和DNA熔解实验研究了这两种药物与DNA的相互作用。光谱和电子自旋共振研究表明，根据铜 - 药物比例会形成几种类型的铜配合物。通过自旋捕获证明，当铜/药物比例为0.1时自由基的产生最为理想；在这种情况下，金属离子被肽部分螯合。后一种配合物能够高水平地诱导DNA断裂。因此，看来所提出的概念是可行的，但在选择铜的相对浓度时必须谨慎。
