Regulating Bioactivity of Cu2+ Bis-1,10-phenanthroline Artificial Metallonucleases with Sterically Functionalized Pendant Carboxylates
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- 作者：Andreea Prisecaru ; Vickie McKee ; Orla Howe ; Garret Rochford ; Malachy McCann ; John Colleran ; Milan Pour ; Niall Barron ; Nicholas Gathergood ; Andrew Kellett
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：November 14, 2013
- 年：2013
- 卷：56
- 期：21
- 页码：8599-8615
- 全文大小：835K
- 年卷期：v.56,no.21(November 14, 2013)
- ISSN：1520-4804
文摘
The synthetic chemical nuclease, [Cu(1,10-phenanthroline)2]2+, has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is 鈥減romiscuous鈥?as it binds both dsDNA and protein biomolecules, without specificity, and induces general toxicity to a diversity of cell lineages. Here, we describe the synthesis and characterization of small-molecule metallonucleases containing the redox-active cation, [Cu(RCOO)(1,10-phen)2]+, where 1,10-phen = 1,10-phenanthroline and R = 鈭扝, 鈭扖H3, 鈭扖2H5, 鈭扖H(CH3)2, and 鈭扖(CH3)3. The presence of coordinated carboxylate groups in the complex cation functions to enhance dsDNA recognition, reduce serum albumin binding, and offer control of toxicity toward human cancer cells, Gram positive and negative bacteria, and fungal pathogens. The induction of genomic dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells using immunodetection of 纬-H2AX. Formate, acetate, and pivalate functionalized complexes induced DSBs in a higher percentage of cells compared with [Cu(1,10-phen)2]2+, which supports the importance of inner-sphere modification toward enhancing targeted biological application.