Tuning Reactivity of Platinum(II) Complexes

transformational pathways that compete for the bioavailability of the drug at the target,
DNA (Figure 1.5).
Figure 1.5: Schematic pathway of a platinum drug in cells showing how sulphur containing
compounds are thought to act as potential drug reserving agents in platinum
chemotherapy. 51
Inside the cell, the active forms of the drug, i.e. Cl/H2O (1) and H2O/H2O (2), do not only
undergo DNA (N-donor) adduct formation, but also can be deactivated by S-donor
biomolecules such as glutathione (0.5-10 mM GSH) and metallothioneins (MT) that are
available in large amounts. 52 This results in accumulation of Pt-S intermediates in vivo
that depletes intracellular concentration of the drug to levels insufficient to inhibit
tumour growth and is responsible for the serious toxic side effects of cisplatin caused by
binding of platinum to the proteins. 10,49,53, The high affinity of sulphur for Pt(II) centre
has led to the development of the so-called “rescue or protective agents” like thiourea
(TU), 2-mercaptoethanesulfonate (mesna) and sodium thiosulphate (STS). These are co-
administered with other drugs to suppress the coordination of platinum to S-containing
proteins which is responsible for severe toxic side effects such as nephrotoxicity
(reduced kidney function and damage), ototoxicity (hearing loss) and myelosuppression
(reduction in bone marrow activity). 49,54 Their protective effect can be attributed to
either prevention from causing unwanted toxic side effects 49,55 or reversals of the Pt-S
9