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 [CoII(L1)2] (1), [CoII(L2)] (2), and [CoIII(L1)2]ClO4 (3). These complexes contain the deprotonated forms of the [NN′O] tridentate ligand HL1 and its newly synthesized [N2N′2O2] hexadentate counterpart H2L2, 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 1H-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.

Platinum-containing compound platinum pyrithione is stronger and safer than cisplatin in cancer therapy

“…Chemical complexes containing metal ions, such as gallium (III), copper (II), zinc (II), nickel (II), and cobalt (II), were designed to target the 26S proteasome in the past decade [ 30 – 33 ]. The discovery that these metal-based complexes exert their antiproliferative action by suppressing proteasomal proteolytic peptidase activities provided a potentially new direction in developing new cancer therapy.…”

Cobalt derivatives as promising therapeutic agents

“…who studied Co(L NN′O ) x complexes (L NN′O = 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol) [40,41*]. These complexes are thought to inhibit proteasomes through ligand exchange with amino acid residues in the active site.…”

“…Co(III)(L NN′O ) 2 was found to be far more inert to substitution than Co(II)(L NN′O ) 2 . However, the Co(III) complex exhibited higher inhibition of chymotrypsin-like activity in purified proteasomes as well as improved apoptotic induction in PC-3 cancer cells [40]. …”

“…A) Co(III)(L NN′O) 2 undergoes reduction to the more labile Co(II) counterpart to yield an active proteasome inhibitor [40,41*]. In the presence of the reducing agent ascorbic acid, one of the L NN′O ligands of Co(III)(L NN′O) 2 is lost and replaced by a solvent (DMF) molecule, as identified by mass spectrometry.…”

Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes

“…1,2 The in vivo compatibility of cobalt has motivated the investigation of coordination complexes of this metal as less toxic alternatives to conventional precious metal-based therapeutic agents, such as cisplatin. [3][4][5] The medicinal applications of cobalt complexes have been explored in the context of imaging agents, [6][7][8][9] drug-delivery scaffolds, 6,[10][11][12][13][14][15][16][17] anticancer agents, 14,[18][19][20][21][22] enzyme inhibitors, [23][24][25][26][27][28][29][30][31][32] and antiviral drugs. [33][34][35][36] The unique chemical properties of cobalt, in comparison to other first row transition metal ions, render it particularly useful for medicinal applications.…”