title: Effects of tethered ligands and of metal oxidation state on the interactions of cobalt complexes with the 26S proteasome.
abstract: In this paper we report on the synthesis and characterization of three cobalt complexes described as [Co(II)(L(1))(2)] (1), [Co(II)(L(2))] (2), and [Co(III)(L(1))(2)]ClO(4)(3). These complexes contain the deprotonated forms of the [NN'O] tridentate ligand HL(1) and its newly synthesized [N(2)N'(2)O(2)] hexadentate counterpart H(2)L(2), namely, 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol and 6,6'-((ethane-1,2-diylbis((pyridin-2-ylmethyl) azanediyl))bis(methylene))bis(2,4-diiodophenol). Characterizations for 1-3 include electrospray ionization (ESI) spectrometry, infrared, and UV-visible spectroscopies, and elemental analyses. A detailed (1)H-NMR study was conducted for 3 and X-ray structural data was obtained for 2. The viability of this series as potential agents for proteasome inhibition and cell apoptotic induction involving PC-3 cancer cells is presented comparing the behavior of the untethered [NN'O](2) six-coordinate 1 and 3 and the tethered counterpart 2 with a 1:1 metal-to-ligand ratio. It is observed that the tethering in 2 decreases inhibition activity. When 1 and 3 are compared, the most inert, but redox-active, cobalt(III) species shows the highest chymotrypsin-like activity inhibition on purified proteasome and PC-3 cancer cells. A hypothesis based on the role of oxidation states for proteasome inhibition is offered.
authors: Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
authors: Dajena
authors: D
authors: Tomco
authors: Sara
authors: S
authors: Schmitt
authors: Bashar
authors: B
authors: Ksebati
authors: Mary Jane
authors: MJ
authors: Heeg
authors: Q Ping
authors: QP
authors: Dou
authors: Cláudio N
authors: CN
authors: Verani
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D061988:Proteasome Inhibitors
chemical_list: D056831:Coordination Complexes; D008024:Ligands; D061988:Proteasome Inhibitors; C505407:CASP3 protein, human; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease