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

Abstract

) 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)·SO 4 (IC 50 = 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. metal-mediated radicals | DNA degradation | polymerase inhibition | enediyne | Bergman cyclization

Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells

“…We sought to determine the mechanism by which hyperthermia potentiates metalloenediyne toxicity. In a recent study, Zaleski and co-workers (19) tested the ability of PyED or PyED-metalloenediyne complexes containing Cu(II), Fe (II), and Zn (II) to damage supercoiled DNA. They found that efficient nicking of the DNA occurred in the presence of all three divalent metalloenediynes ions, but reported only minimal degradation when DNA was exposed to free PyED; thus, they concluded that the extent of the chelation-induced radical generation event is strongly metal-dependent.…”

“…Previous studies showed that when DNA is exposed to Cu(II), Fe(II), and Zn(II) complexes of PyED in the presence of DNA, considerable DNA degradation occurs within 1 h under hyperthermic conditions, with Cu(II) activation producing >50% degradation of DNA within 5 min. The importance of thermally-activated radical production is evidenced by the lack of compromised DNA observed using the cyclized non-radical-generating control complex PyBD, pyridine-2-ylmethyl-(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine or free (unmetallated) PyED (19) Additionally, in situ activation of PyED via chelation of Cu(II) and Zn(II) has been shown to result in radical-induced disaggregation of Aβ fibrils at 37 °C relative to the cyclized control PyBD complex. The extent of radical damage is elevated upon treatment under hyperthermic conditions, consistent with the increased radical generation after exposure to elevated temperatures (20).…”

Enhancement of Cytotoxicity of Enediyne Compounds by Hyperthermia: Effects of Various Metal Complexes on Tumor Cells

“…All syntheses of compounds and subsequent complexations were performed under nitrogen atmosphere employing standard Schlenk and dry box techniques using chemicals of the highest purity available and purchased from commercial sources. The ligand (Z)-N,N′-bis[1pyridin-2-yl-meth-(E)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine (PyED) and metal complexes were prepared using a previously published synthesis (8). Briefly, a cooled methanol solution of PyED (1 eq) was added to a stirring solution of MSO 4 •×H 2 O or MCl 2 •×H 2 O (M=Cu(II), Fe(II), Zn(II); 1 eq) in methanol and stirred for 4 h at 0°C.…”

“…In an effort to further evaluate the geometric structure/Bergman cyclization relationship under physiological conditions, we recently reported the preparation of novel PyED-metalloenediyne complexes containing Cu(II), Fe(II), and Zn(II). Bergman cyclization from thermal activation of each of these constructs resulted in diradical generation within 3 h at 37°C (8). A significant metal dependence on the rate of the reaction is observed with these complexes [Cu(II) > Fe(II) > Zn(II)], and reaction rate was directly correlated to efficiency of DNA degradation.…”

Coordination‐Accelerated Radical Formation from Acyclic Enediynes for Tumor Cell Suppression

“…After the chelation with Cu II , Zn II or Mg II , the onset temperatures significantly decreased to 55 °C (Figure B), 125 °C (Figure S4 A), and 100 °C (Figure S4 B), respectively. The greatly accelerated cycloaromatization and the reduction of onset temperature are consistent with the reduction of CD distance after metal coordination with enediyne compounds . Meanwhile, the charge separation assistance in the metal‐ion‐catalyzed Bergman cyclization should not be excluded as well .…”