Metal-mediated diradical tuning for DNA replication arrest via template strand scission [Chemistry]
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
→ 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.
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