Metallodrugs

Functionalized Platinum(IV) Anticancer Compounds

One strategy to reduce toxicities and side-effects is to improve drug delivery by using targeting methods to enhance the selectivity. At the molecular level, platinum(IV) carboxylate complexes represent suitable scaffolds, since they can be readily derived from classical platinum(II) drugs without altering the pharmacophore. Upon cell entry, they are reduced by intracellular biomolecules such as glutathione, to yield cytotoxic platinum(II) moieties while releasing the axial ligands. The general strategy to prepare these complexes is shown below.

Preparation of platinum(IV) carboxylates from platinum(II) drugs

The nature of the ligand sphere affects the reduction potential of the complexes and can be tuned to achieve optimal release of the platinum(II) moiety. An orally-active platinum(IV) prodrug, satraplatin, is currently undergoing phase III clinical trials for hormone refractory prostate cancer. Other platinum(IV) compounds with functionalised ligands have also been harnessed to defeat glutathione-transferase mediated drug resistance, target estrogen receptor-positive breast cancer and for photochemotherapy.

Highly hydrophobic platinum(IV) carboxylates

Functionalized Organometallic Ruthenium Scaffolds

The development of ruthenium-based anticancer drugs represents one of the most prominent areas in metallopharmaceuticals for chemotherapy. The main motivation for using ruthenium is its lower toxicity, in comparison to platinum, and the ease of accessing ruthenium compounds given its rich coordination and redox chemistry. Recently, two ruthenium(III)-based compounds, namely KP1019 and NAMI-A, successfully completed Phase 1 clinical trials and are scheduled to enter Phase 2 trials in the near future. In particular, KP1019 is transported by serum protein transferrin into cells, where it is reduced to Ru(II) species and induces oxidative DNA damage resulting in apoptosis.

Another class of ruthenium complexes that have been actively pursued as anticancer agents contains the organometallic [(η6-arene)Ru] fragment. From a structural perspective, the organometallic ruthenium scaffold is particularly intriguing because it resembles a "piano-stool". By altering either "stool-top" or the "stool-legs", a range of structurally-diverse complexes can be easily prepared as targeted chemotherapeutic agents. Using this strategy, a wide variety of organometallic ruthenium complexes have investigated as anticancer drug candidates and some were found to exhibit favourable pharmacological and cytotoxic profiles for further development.

Organometallic ruthenium-based enzyme inhibitor