Novel metals and metal complexes as platforms for cancer therapy

Abstract

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-[Pt(II) (NH(3))(2)Cl(2)], 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.

Fig. (1)

Chemical structures of platinum(II) complexes, Cisplatin, Carboplatin, and Oxaliplatin. The platinum(IV) complex Satraplatin has been used to overcome concerns of low bioavailability. Platinum(IV)-complexes have been designed with appended moieties (estrogen and the GHT inhibitor ethacraplatin) to optimize the anticancer effects of cisplatin. Platinum(IV) diazide complexes have been designed that are activated upon irradiation.

Fig. (2)

The ubiquitin-proteasome pathway plays a crucial role in maintaining cellular homeostatic function by selectively degrading various proteins including those involved in critical cellular functions. Proteins destined for degradation are first tagged with a chain of ubiquitin molecules by a multi-enzymatic system consisting of Ub-activating (E1), Ub-conjugating (E2), and Ub-ligating (E3) enzymes. The ubiquitin tagged protein is then translocated to the 26S proteasome where it undergoes degradation and the ubiquitin molecules are subsequently recycled. The 20S proteasome constitutes the proteolytic core and consists of a series of outer α-subunits and inner β-subunits mediated by atleast three distinct enzymatic activities. These include the chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide hydrolyzing-like/PGPH.

Fig. (3)

Chemical structures of synthetic gold complexes as proteasome inhibitors: Au(DMDT)Br₂, AUL12, and AUL15. Both Au(DMDT)Br₂ and AUL12 have a trivalent oxidation state, whereas AUL15 is monovalent.

Fig. (4)

Chemical structures of synthesized Zinc and Copper-containing complexes as proteasome inhibitors from the dithiocarbamate family, (PyDTC) and (EtDTC).

Fig. (5)

Chemical structures of copper-chelating ligands DSF, DDTC PDTC, and CQ.

Fig. (6)

Asymmetric [NN’O]-containing metal complexes as proteasome inhibitors. R represents different groups at the 4^th and 6^th positions. M represents the metal ion, in this case, gallium(III), copper(II), nickel(II), and zinc(II) were used. Complexes were synthesized at a two ligand to one metal ratio.