Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[PtII(NH3)2Cl2], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.

Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu((2), and [Cu(HL I )(L I )]OAc (3), where HL I is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino) methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV-visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1-3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuL I ] + as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.Three well characterized discrete copper complexes with asymmetric phenol-substituted ligands are able to inhibit the proteolytic activity of the 20s proteasome. Evidence for a minimal pharmacophore suggests a potential basis for new cancer therapies with tunable and cost-effective metallodrugs.

In this study, we compare the proteasome inhibition capabilities of two anticancer candidates, [Ni(LIA)2] (1) and [Zn(LIA)2] (2), where LIA- is the deprotonated form of the ligand 2,4-diiodo-6-(((2-pyridinylmethyl)amino)methyl)phenol. Species 1 contains nickel(II), a considerably inert ion that favors covalency, whereas 2 contains zinc(II), a labile transition metal ion that favors predominantly ionic bonds. We report on the synthesis and characterization of 1 and 2 using various spectroscopic, spectrometric, and structural methods. Furthermore, the pharmacological effects of 1 and 2, along with the salts NiCl2 and ZnCl2, were evaluated in vitro and in cultured human cancer cells in terms of their proteasome-inhibitory and apoptotic cell death-inducing capabilities. It is shown that neither NiCl2 nor 1 have the ability to inhibit the proteasome activity at any sustained levels. However, ZnCl2 and 2 showed superior inhibitory activity to the chymotrypsin-like activity of both 26S proteasome (IC50 = 5.7 and 4.4 μmol/L, respectively) and purified 20S proteasome (IC50 = 16.6 and 11.7 μmol/L, respectively) under cell-free conditions. Additionally, inhibition of proteasomal activity in cultured prostate cancer cells by 2 was associated with higher levels of ubiquitinated proteins and apoptosis. Treatment with either the metal complex or the salt was relatively non-toxic toward human normal cells. These results strengthen the current working hypothesis that fast ligand dissociation is required to generate an [MLIA]+ pharmacophore, capable of interaction with the proteasome. This interaction, possibly via N-terminal threonine aminoacids present in the active sites, renders the proteasome inactive. Our results present a compelling rationale for 2, along with its gallium(III) and copper(II) congeners to be further investigated as potential anticancer drugs that act as proteasome inhibitiors.

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.

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