Copper Phenanthrene Oxidative Chemical Nucleases

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• 作者：Zara Molphy ; Andreea Prisecaru ; Creina Slator ; Niall Barron ; Malachy McCann ; John Colleran ; Deepak Chandran ; Nicholas Gathergood ; Andrew Kellett
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：May 19, 2014
• 年：2014
• 卷：53
• 期：10
• 页码：5392-5404
• 全文大小：758K
• 年卷期：v.53,no.10(May 19, 2014)
• ISSN：1520-510X

文摘

Here we report the synthesis and isolation of a series of bis-chelate Cu²⁺ phenanthroline鈥損henazine cationic complexes of [Cu(DPQ)(Phen)]²⁺, [Cu(DPPZ)(Phen)]²⁺, and [Cu(DPPN)(Phen)]²⁺ (where Phen = 1,10-phenanthroline, DPQ = dipyridoquinoxaline, DPPZ = dipyridophenazine, and DPPN = benzo[i]dipyridophenazine). These compounds have enhanced DNA recognition relative to the well-studied chemical nuclease, [Cu(Phen)₂]²⁺ (bis-Phen), with calf thymus DNA binding constants of DPQ and DPPZ agents (10⁷ M(bp)^鈭?) being the highest currently known for Cu²⁺ phenanthrene compounds. Complex DNA binding follows DPQ 鈮?DPPZ > DPPN > bis-Phen, with fluorescence quenching and thermal melting experiments on poly[d(A-T)₂] and poly[d(G-C)₂] supporting intercalation at both the minor and major groove. Phenazine complexes, however, show enhanced targeting and oxidative cleavage on cytosine-phosphate-guanine-rich DNA and have comparable in vitro cytotoxicity toward the cisplatin-resistant ovarian cancer line, SKOV3, as the clinical oxidative DNA-damaging drug doxorubicin (Adriamycin). In this study we also describe how a novel 鈥渙n-chip鈥?method devised for the Bioanalyser 2100 was employed to quantify double-stranded DNA damage, with high precision, by the complex series on pUC19 DNA (49% A-T, 51% G-C). Both DPQ and bis-Phen complexes are highly efficient oxidizers of pUC19, with DPQ being the most active of the overall series. It is apparent, therefore, that oxidative chemical nuclease activity on homogeneous canonical DNA is not entirely dependent on dynamic nucleotide binding affinity or intercalation, and this observation is corroborated through catalytic interactions with the superoxide anion radical and Fenton breakdown of hydrogen peroxide.