Research

BIOINORGANIC CHEMISTRY

1. Late transition metal organometallic complexes

Our research group is interested in the late transition metal organometallic compounds, in particular the design of ruthenium, iridium and rhodium arene complexes. This work has included the modification of the organic ligands, including bidentate N,N, N,O and O,O functionalised ligands, alongside monodentate N-heterocyclic carbenes. We have undertaken chemosensitivity studies to understand the potency of these complexes towards cancerous and normal cells, and in some case we have shown a clear correlation between potency and induction of cell death (apoptosis).

Metals
Dalton Trans. 2016(hot article) and Dalton Trans. 2016
Rh-NHC
J. Organomet. Chem. 2019

Our most prominent work was focused on the design of β-ketoiminate ruthenium and iridium compounds, in which our compounds indicate cellular mechanism of action which are different from that of cisplatin:

(i) more active than cisplatin

(ii) selective towards cancerous cells (when tested against healthy ARPE-19)

(iii) active under hypoxic conditions

(iv) exhibit inhibition of the over-expressed enzyme thioredoxin reductase (Trx-R)

(v) induce significant levels of cancer cell death by apoptosis

(vi) induced significant levels of single-strand DNA breaks (Comet assay)

M-Acnacs
Dalton Trans. 2012, J. Med. Chem. 2015 and Chem. Eur. J. 2019 

2. Late transition metal coordination complexes

Our group is interested in the synthesis of late transition metal coordination compounds, with our most recent work highlighting ruthenium dichloride and ruthenium diiodide complexes which incorporate functionalised picolinamide ligands (N,N and N,O). This work was the first of publication to highlight the importance of isomerisation in metal complexes, and lead us to question “Does geometry matter in the design of anticancer complexes?” We reported ruthenium dichloride complexes which are moderately cytotoxic, but exist as multiple isomers, which are predominately the cis arrangements. Upon a halide exchange to synthesis the ruthenium diiodide complexes, we observed only one isomer was present, and due this was the trans arrangement. The chemosensitivity screening highlighted these complexes to have nanomolar potency, and to be significantly more cytotoxic than the cis ruthenium dichloride complexes. Additionally, trans ruthenium diiodide complexes displayed potent activity against the cisplatin‐resistant human ovarian cancer cell line (A2780cis), with >4-fold higher potency than cisplatin. They also retain their potency when tested under hypoxic conditions, which indicates the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency.

Ru Cl I
Chem. Eur. J. 2017

3. Early transition metal coordination complexes

Our group is interested in the use of functionalised β-diketonate ligands, and their effects on the cytotoxicity of early transition metal compounds. We have shown group IV metal (Ti, Zf, Hf) compounds which have higher potency than that of cisplatin against a range of cancer cell lines, and their potency increases when changing the ancillary ligands from chloride to bromide. We also reported the first hafnium β-diketonate complexes to show potent in vitro cytotoxicity, with an increase in potency down the group IV, Ti < Zr < Hf.

Hf
ChemMedChem 2014

Our most recent work in this field was the synthesis of oxovanadium(IV) β-diketonate complexes. In the hope to reduce costs, limit toxic solvents and to make use of the abundant and cheap early transition metals, we have developed a straightforward, fast, high yielding and environmentally friendly method for the synthesis of oxovanadium(IV) complexes and assessed their potential anti-cancer drugs. These complexes are isolated in moderate to good yields from a simple dry melt reaction. In addition, we observed high cytotoxicity against lung and colorectal cancers, and UV-vis spectroscopy has given evidence that these compounds are stable in biological pH ranges.

Complex Scheme
Chem. Eur. J. 2019

4. Biological Assays

(i) MTT screening – we focus on understanding the chemosensitivity/viability by using the MTT assay, and screen a library on compound in order to gain structure activity relationships (SARs) and highlight new drug leads.

Cancer cells (2)

(ii) cell viability under hypoxic conditions (low oxygen concentrations)

(iii) understand the compounds interactions with proteins and enzymes

(iv) using flow cytometry to determine the compounds interference with the cell cycle and the ability of the compounds to induce cell death (apoptosis)

(v) determining the compounds interactions with DNA through the Comet assay

Comet.png