DNA three-way junctions are critical in various biological processes and hold significant potential for disease treatment and therapeutic applications. In this study, it is demonstrated that triple-stranded dinuclear [Ni2L3]4+ cylinders (L = C25H20N4) exhibit a preferential binding affinity for Y-shaped DNA three-way junctions (3WJs), even in the presence of an excess of competing DNA structures, including G-quadruplexes. Notably, the investigated Ni(II) cylinders are capable of halting DNA synthesis catalyzed by DNA polymerase by stabilizing the 3WJ on the template strand. Using an extended 1D nanoarchitecture model, it is further established the high affinity and selectivity of the cylinders for DNA 3WJs and explored their potential application in stabilizing short-armed 3WJs for constructing DNA nanomaterials. The combined use of Ni(II) cylinders and DNA damage response inhibitors also revealed that the cylinders promote DNA damage, leading to the formation of double-strand breaks. This effect is likely associated with i) the binding of cylinders to 3WJs and ii) the cytotoxic activity of the cylinders in cancer cells.

• Klíčová slova
• DNA damage, DNA nanomaterials, DNA three‐way junctions, Ni(II) cylinders, cytotoxicity,
• MeSH
• DNA * chemie   metabolismus   MeSH
• G-kvadruplexy MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   patologie   metabolismus   MeSH
• nikl * chemie   MeSH
• poškození DNA * MeSH
• replikace DNA účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA * MeSH
• nikl * MeSH

Highly diastereoselective self-assembly reactions give both enantiomers (Λ and Δ) of anti-parallel triple-stranded bimetallic Co(ii) and Co(iii) cationic helices, without the need for resolution; the first such reaction for Co. The complexes are water soluble and stable, even in the case of Co(ii). Studies in a range of cancer and healthy cell lines indicate high activity and selectivity, and substantial differences between enantiomers. The oxidation state has little effect, and correspondingly, Co(iii) compounds are reduced to Co(ii) e.g. by glutathione. In HCT116 colon cancer cells the Λ enantiomer induces dose-dependent G2-M arrest in the cell cycle and disrupts microtubule architectures. This Co(ii) Λ enantiomer is ca. five times more potent than the isostructural Fe(ii) compound. Since the measured cellular uptakes are similar this implies a higher affinity of the Co system for the intracellular target(s); while the two systems are isostructural they have substantially different charge distributions as shown by calculated hydrophobicity maps. In contrast to the Λ enantiomer, Δ-Co(ii) induces G1 arrest in HCT116 cells, efficiently inhibits the topoisomerase I-catalyzed relaxation of supercoiled plasmid DNA, and, unlike the isostructural Fe(ii) system, causes DNA damage. It thus seems very likely that redox chemistry plays a role in the latter.

• Publikační typ
• časopisecké články MeSH