Medicinal Applications of Metal Complexes Binding to Biological Macromolecules

Abstract

Summary: Biological macromolecules present in living organisms, like proteins, DNA, have many metal-binding sites. As a consequence, coordination compounds can react with such cellular components, displaying possible toxic effects, or they also may have beneficial applications. So metal ions and compounds not only are essential for life in e.g. dioxygen transport, or biocatalysis, but they can also be used for controlled toxicity in medicinal applications. Well-known examples are the application of gold compounds in arthritis treatment, bismuth compounds for ulcer healing, and silver compounds for open skin protection. However, only in a few cases details of the mechanist are known, and if so, the biological macromolecules play a key role. Transition-metal coordination compounds that have metal-ligand exchange rates comparable to cell-division processes, i.e. in particular Pt and Ru, often appear to be highly active in killing cancers, as seen from the study of several cancer cell lines. Classical examples, like cisplatin, and new examples of Pt and Ru compounds will be discussed in some detail, with a focus on their binding to the DNA biomacromolecule. The classical compound cis-diamminedichloridoplatinum(II), often abbreviated as cisplatin, and its first-generation derivatives are known to bind to several biomacromolecules in a specific way, and eventually bind at DNA. Four important examples are shown in the figure. However, on its way to DNA other cellular components, like proteins and peptides might be intermediates before the final target is reached. Other metal-containing drugs, like Ru compounds, that show anti-cancer activity have a less well-known mode of action. Molecular-based mechanistic studies may result in improved clinical administration protocols.

Contrasting cellular uptake pathways for chlorido and iodido iminopyridine ruthenium arene anticancer complexes

“…Ruthenium arene anticancer complexes are being widely studied as potential alternatives to platinum chemotherapeutics, [1][2][3][4][5][6][7][8][9] especially because acquired resistance to platinum-based drugs represents a major clinical drawback for compounds such as cisplatin (CDDP) 10,11 and oxaliplatin (OXA). 12,13 This type of resistance usually develops as a consequence of impaired cellular accumulation that can be caused by lower cellular uptake or increased cellular efflux.…”

Studies on the cytotoxic, apoptotic and antitumoral effects of Au(III) and Pt(II) complexes of 1, 10-phenanthroline on V79 379A and A549 cell lines

“…Caspase-3 assay showed that induction of apoptosis occurred in V79 379A and A549 cells via mitochondrial pathway ( Figure 5). Chemotherapy was based on apoptotic cell death mechanism and some cancer cells were killed by including Pt(II) and Au(III) compounds via apoptosis like cisplatin 32 . The results of researches about cancer have demonstrated, that these metal complexes are really appropriate drug materials for treatment of various cancer types because apoptosis and cytotoxicity are closely related with chemotherapy.…”

Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461

“…Specifically, we demonstrate the efficacy of Cu 2+ and Zn 2+ in promoting the solubility of CX5461 (Figure ), a first‐in‐class anticancer candidate. These metal ions are particularly appropriate to this method since: (i) they exhibit high ligand exchange rates, (ii) they are relatively non‐toxic biological species, and (iii) they allow comparison of redox‐inert (Zn 2+ ) and redox‐active (Cu 2+ ) metal ions …”

“…This addresses ak ey challenge in medicinal chemistry,w hich is the limiteda queous solubility of many promising pharmaceuticals. These metal ions are particularly appropriate to this method since:( i) they exhibit high ligand exchange rates, [4] (ii)they are relativelyn on-toxic biological species, [5] and (iii) they allow comparison of redox-inert (Zn 2 + )a nd redox-active (Cu 2 + )m etal ions. [3] Our approach is broadly applicable to hydrophobicm oleculesw ith common metal-coordinating groups, such as amines.…”