Inorganic chemical biology
Coordination or organometallic compounds employing a platinum group transition metal centre (Ru, Rh, Pd, Os, Ir or Pt) and bio-active organic ligands possess several advantageous properties in chemical biology and medicinal chemistry. These include coordination numbers greater than carbon’s limit of 4, well-developed synthetic pathways, luminescence compatible with optical microscopy and a metal atom identifiable by mass spectrometry. Biomolecule binding and organelle targeting can be chemically controlled while screening compounds for specific cellular responses (phenotypes) can then isolate candidates for further investigation. We are developing compounds compatible with cell imaging techniques that interfere with cell-cycle processes. Examples include a Ru(II)-Pt(II) bimetallic complex that upregulates the KIP1 inhibitor p27 to prevent entry into S phase (Chemistry - A European Journal, 2015, 21, 9185) and a Ru(II) complex that interferes with chromosome stability during mitosis (Chemical Science, 2018, 9, 841). These new molecules are of use as cell imaging agents, tools for molecular biology and represent new therapeutic leads.
Metallodrugs in combination therapy
Ruthenium(II) polypyridyl complexes (RPCs) that bind DNA by metallo-intercalation can stall DNA replication forks in cells (Scientific Reports, 2016, 6, 31973 and Chemical Science, 2018, 9, 841). This results in replication stress without high levels of genotoxic DNA double-strand break (DSB) damage generated, a mechanistic difference to current DNA-damaging anti-cancer drugs. A consequence of RPC replication fork stalling is that cancer cells are rendered hypersensitive to PARP (poly ADP ribose polymerase) inhibitors such as Olaparib, with a 300-fold increase in efficacy of Olaparib chemically induced by an RPC in triple-negative breast cancer cells (ACS Chemical Biology, 2020, 15, 378). This drug synergy presents the opportunity to include RPCs within the highly successful anticancer strategy of combination therapy and to aims to extend the use of clinically approved PARP inhibitors beyond BRCA deficient cancers (ChemMedChem, 2020).