Intern
Prof. Dr. U. Schatzschneider

Bioactive Metal Complexes

Medicinal Inorganic Chemistry

Since the introduction of cisplatin as an important agent in the chemotherapy of cancer, there has been a steadily increasing interest in the exploration of metal-inherent properties for therapeutic applications in human medicine.
In fact, today, organometal and coordination compounds can be developed in a way totally in line with standard procedures of medicinal chemistry, and offer access to a significantly expanded chemical space due to a wide range of coordination geometries, facile variation of the coligand sphere, and tunable ligand exchange kinetics.
In addition to a traditional focus on anticancer agents, in recent years, more and more research has also been directed at the development of novel metal-based antimicrobial and antiviral agents, due to the urgent need to overcome antibiotics resistance to common agents and the threat of neglected tropical diseases (NTDs) as well as targeting of emerging viral infections.

Antiviral activity of (organo)metal complexes

Since late 2019, the COVID-19 pandemic has had a world-wide impact on public health and economy. In addition to vaccination, antiviral drugs might also contribute to fight the virus and provide a treatment option to persons already infected. As most of the SARS-CoV-2 viral proteins have now been isolated and characterized at the molecular level, the search is on for novel protein inhibitors. In a joint effort with many colleagues, we have started a research program that aims at the identification of metal complexes as inhibitors of the two key viral cysteine proteases 3CLpro and PLpro. In particular, we use a HPLC-based assay to study model protein degradation and organometal inhibitors of the relevant proteases.

The coordination of ketoconazole to a Mn(I) tricarbonyl moiety leads to increased activity on Trypanosoma brucei, the causative agent of African Sleeping Sickness.

Antimicrobial activity of (organo)metal complexes

Increasing bacterial resistance to established antibiotics and very limited treatment options for neglected tropical diseases such as malaria and trypanosomiasis call for the development of new lead compounds. In that context, metal complexes have not been explored to their full potential so far, with the notable exception of ferroquine, an organometallic antimalarial drug candidate in advanced clinical trials. Thus, the Schatzschneider group has prepared a number of organometal complexes and identified a number of compounds with sub-micromolar biological activity in some cases:

Anticancer activity of metal complexes and bioorganometallic compounds

In addition to cisplatin, a surprisingly wide range of other metal-coligand combinations also give rise to promising anticancer activity. Compounds evaluated in the group include rhodium(III) metalloinsertors, ruthenium(II) polypyridyl complexes, and molybdenum(II) allyl dicarbonyl compounds:

Anticancer activity of organometal peptide and dendrimer conjugates

The cellular uptake and intracellular distribution of bioactive metal complexes can be modulated by conjugation to bio(macro)molecular carrier systems such as cell-penetrating peptides (CPPs) or dendrimers. We have extensively studied the anticancer activity of organometal compounds attached to such carrier peptides and obtained interesting results which raise the question of what is actually the carrier and what the cargo, the metal complex or the peptide?

The intracellular distribution of a metal-carbonyl complex in living cells was investigated with confocal Raman microspectroscopy.

Bioimaging of metal complex distribution in living cells

The inherent spectroscopic signature of metal complexes, for example prominent M(C-O) bands in metal-carbonyl complexes, in a spectral window where the absorbance of cells and tissues is negligible, allowed us to image the biodistribution of such compounds with high spatial resolution in living human cells without fixation: