title: Thymines in single-stranded oligonucleotides and G-quadruplex DNA are competitive with guanines for binding to an organoruthenium anticancer complex.
abstract: Organometallic ruthenium(II) complexes [(η(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'-CTCTCTX7G8Y9CTTCTC-3' [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'-T compared to a 3'-T. Interestingly, the T bases in the human telomeric G-quadruplex sequence (5'-AGGGTTAGGGTTAGGGTTAGGG-3') 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.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, P. R. China.
authors.forename: Kui
authors.initials: K
authors.lastname: Wu
authors.forename: Suyan
authors.initials: S
authors.lastname: Liu
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.forename: Wenbing
authors.initials: W
authors.lastname: Hu
authors.forename: Xianchan
authors.initials: X
authors.lastname: Li
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
authors.forename: Renhui
authors.initials: R
authors.lastname: Zheng
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: Junfeng
authors.initials: J
authors.lastname: Xiang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shi
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000737:chemistry*; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012428:Ruthenium / Q000737:chemistry*; D013941:Thymine / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004277:DNA, Single-Stranded; D006147:Guanine; D012428:Ruthenium; D013941:Thymine