Complexes of cytotoxic chelators from the dipyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues.
In an effort to better understand the antiproliferative effects of the tridentate hydrazone chelators di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and di-2-pyridyl ketone benzoyl hydrazone (HPKBH), we report the coordination chemistry of these ligands with the divalent metal ions, Mn, Co, Ni, Cu, and Zn. These complexes are compared with their Fe(II) analogues which were reported previously. The crystal structures of Co(PKIH)(2), Ni(PKIH)(2), Cu(PKIH)(2), Mn(PKBH)(2), Ni(PKBH)(2), Cu(PKBH)(2), and Zn(PKBH)(2) are reported where similar bis-tridenate coordination modes of the ligands are defined. In pure DMF, all complexes except the Zn(II) compounds exhibit metal-centered M(III/II) (Mn, Fe, Co, Ni) or M(II/I) (Cu) redox processes. All complexes show ligand-centered reductions at low potential. Electrochemistry in a mixed water/DMF solvent only elicited metal-centered responses from the Co and Fe complexes. Remarkably, all complexes show antiproliferative activity against the SK-N-MC neuroepithelioma cell line similar to (HPKIH) or significantly greater than that of the (HPKBH) ligand which suggests a mechanism that does not only involve the redox activity of these complexes. In fact, we suggest that the complexes act as lipophilic transport shuttles that allow entrance to the cell and enable the delivery of both the ligand and metal which act in concert to inhibit proliferation.
Bernhardt
Paul V
PV
Centre for Metals in Biology, Department of Chemistry, University of Queensland, Brisbane 4072, Australia. P.bernhardt@uq.edu.au
Mattsson
Johan
J
Richardson
Des R
DR
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D008024:Ligands; D019216:Metals, Heavy / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D002614:Chelating Agents; D006835:Hydrazones; D007659:Ketones; D008024:Ligands; D019216:Metals, Heavy; D009942:Organometallic Compounds; D011725:Pyridines; C511463:di-2-pyridyl ketone benzoyl hydrazone; C511462:di-2-pyridyl ketone isonicotinoyl hydrazone; D015082:2,2'-Dipyridyl