DNA Damage and Repair: Computations meet experiments

[Cu2(tetra-(2-pyridyl)-naphthalene)Cl4] Displays Non-Intercalative Major Groove Binding and Self-Activating Oxidative DNA Damage

Zara Molphy a* , Diego Montagnerb, Creina Slatora and Andrew Kelletta

aSchool of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University and bNational University of Ireland Galway.

*zara.molphy@dcu.ie

Oxygen radical generation is an inevitable consequence of an aerobic existence and is implicated in a wide variety of pathological conditions including cancer, cardiovascular disease, ageing and neurodegenerative disorder. However, oxygen radicals can also be used to our advantage since they are generated from synthetic artificial metallonucleases carrying designer ligands that selectively induce oxidative DNA scission. Our strategy for designing a new di-Cu2+ cytotoxic agent, [Cu2(tetra-(2-pyridyl)-naphthalene)Cl4] (Cu2TPNap), stems from observations on i.) the utility of the tetra-2-pyridine ligand scaffold for efficient nucleic acid catalytic cleavage within di-Zn2+

systems,[1] and ii.) the introduction of an aromatic DNA binding moiety[2] that could potentially enhance both nucleic acid targeting and binding affinity. Through the use of a number of molecular biology and biophysical techniques,[3,4] it was determined that Cu2TPNap binds DNA non-intercalatively at the major groove (Kapp 1 x 107 M(bp)-1) inducing guanine-cytosine specific deformation and condensation. The complex oxidatively damages DNA producing strand breakage using a superoxide-mediated process without involving co-activating species.

A.

B.

Figure 1. A. Molecular structure of the di-Cu2+ complex Cu2TPNap and perspective, space-filling view of Cu2TPNap, the copper ions are bridged by the naphthalene-diamine group. (Colour scheme: copper, teal; nitrogen, blue; carbon, turquoise; chlorine, black) and B. change in ellipticity of Cu2TPNap and classical major groove (MG), minor groove (net) and intercalating agents (EtBr) with respect to classical B-form stDNA at r = 0.1 and 0.2 loading ratios at 220 nm; 246 nm; and 276 nm and interactions of Cu2TPNap, MG and EtBr on alternating co-polymer poly[d(G-C)2].

References[1] G. Feng, D. Natale, R. Prabaharan, J. C. Mareque-Rivas, N. H. Williams, Angew. Chemie Int. Ed.

2006, 45, 7056–7059.[2] H.-K. Liu, P. J. Sadler, Acc. Chem. Res. 2011, 44, 349–359.[3] Z. Molphy, A. Prisecaru, C. Slator, N. Barron, M. McCann, J. Colleran, D. Chandran, N. Gathergood,

A. Kellett, Inorg. Chem. 2014, 53, 5392–5404.[4] Z. Molphy, C. Slator, C. Chatgilialoglu, A. Kellett, Front. Chem. 2015, 3, 1–9.

Lorentz Center Leiden 30th October – 3rd November 2017