Metal-mediated diradical tuning for DNA replication arrest via template strand scission

Porter MR, Lindahl SE, Lietzke A., Metzger EM, Wang Q, Henck E, Chen CH, Hengyao Niu, Zaleski JM
Publication Date
September 2017
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A series of M(PyED)·X (X = 2Cl-, SO42-) pyridine-metalloenediyne complexes [M = Cu(II), Fe(II), or Zn(II)] and their independently synthesized, cyclized analogs have been prepared to investigate their potential as radical-generating DNA-damaging agents. All complexes possess a 1:1 metal-to-ligand stoichiometry as determined by electronic absorption spectroscopy and X-ray diffraction. Solution structural analysis reveals a pπ Cl [Formula: see text] Cu(II) LMCT (22,026 cm-1) for Cu(PyED)·2Cl, indicating three nitrogens and a chloride in the psuedo-equatorial plane with the remaining pyridine nitrogen and solvent in axial positions. EPR spectra of the Cu(II) complexes exhibit an axially elongated octahedron. This spectroscopic evidence, together with density functional theory computed geometries, suggest six-coordinate structures for Cu(II) and Fe(II) complexes and a five-coordinate environment for Zn(II) analogs. Bergman cyclization via thermal activation of these constructs yields benzannulated product indicative of diradical generation in all complexes within 3 h at 37 °C. A significant metal dependence on the rate of the reaction is observed [Cu(II) > Fe(II) > Zn(II)], which is mirrored in in vitro DNA-damaging outcomes. Whereas in situ chelation of PyED leads to considerable degradation in the presence of all metals within 1 h under hyperthermia conditions, Cu(II) activation produces >50% compromised DNA within 5 min. Additionally, Cu(II) chelated PyED outcompetes DNA polymerase I to successfully inhibit template strand extension. Exposure of HeLa cells to Cu(PyBD)·SO4 (IC50 = 10 μM) results in a G2/M arrest compared with untreated samples, indicating significant DNA damage. These results demonstrate metal-controlled radical generation for degradation of biopolymers under physiologically relevant temperatures on short timescales.


Porter MR, Lindahl SE, Lietzke A, Metzger EM, Wang Q, Henck E, Chen CH, Niu H, Zaleski JM.
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7405-E7414. doi: 10.1073/pnas.1621349114. Epub 2017 Jul 31.
PMID: 28760964