Thymines in Single-Stranded Oligonucleotides and G-Quadruplex DNA Are Competitive with Guanines for Binding to an Organoruthenium Anticancer Complex

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• 作者：Kui Wu ; Suyan Liu ; Qun Luo ; Wenbing Hu ; Xianchan Li ; Fuyi Wang ; Renhui Zheng ; Jie Cui ; Peter J. Sadler ; Junfeng Xiang ; Qiang Shi ; Shaoxiang Xiong
• 刊名：Inorganic Chemistry
• 出版年：2013
• 出版时间：October 7, 2013
• 年：2013
• 卷：52
• 期：19
• 页码：11332-11342
• 全文大小：450K
• 年卷期：v.52,no.19(October 7, 2013)
• ISSN：1520-510X

文摘

Organometallic ruthenium(II) complexes [(畏⁶-arene)Ru(en)Cl]⁺ (arene = e.g., biphenyl (1), dihydrophenanthrene, tetrahydroanthracene) show promising anticancer activity both in vitro and in vivo and are cytotoxic to cisplatin-resistant cancer cells, implying that these monofunctional complexes have a different mechanism of action from that of bifunctional cisplatin. We demonstrate here that complex 1 binds selectively to the guanine base in the 15-mer single-stranded oligodeoxynucleotides (ODNs) 5鈥?CTCTCTX₇G₈Y₉CTTCTC-3鈥?[X = Y = T; X = C, Y = A; X = A, Y = T; X = T, Y = A] to form thermodynamically stable adducts, but thymine bases (T₇/T₁₁ or T₆/T₁₁) compete kinetically with guanine for binding to 1. The T-bound monoruthenated species eventually convert to diruthenated products via a second step of binding at G or/and to G-bound monoruthenated species through dissociation of the diruthenated adducts. Complex 1 was further shown to bind preferentially to the middle T in a sequence rather than to a T near the terminus and favor coordination to a 5鈥?T compared to a 3鈥?T. Interestingly, the T bases in the human telomeric G-quadruplex sequence (5鈥?AGGGTTAGGGTTAGGGTTAGGG-3鈥? were found to be more competitive both kinetically and thermodynamically with G bases for binding to 1. These results suggest that thymine bases play a unique role in the pathways of ruthenation of DNA by organoruthenium anticancer complexes and illustrate that kinetic studies can provide new insight into the mechanism of action of metallodrugs in addition to study of the structures and functions of the thermodynamically stable end products.