Tuning the Activity of Platinum(IV) Anticancer Complexes through Asymmetric Acylation

Platinum­(II) anticancer drug cisplatin is one of the
most important
chemotherapeutic agents in clinical use but is limited by its high
toxicity and severe side effects. Platinum­(IV) anticancer prodrugs
can overcome these limitations by resisting premature aquation and
binding to essential plasma proteins. Structure–activity relationship
studies revealed a link between the efficacy of platinum­(IV) complexes
with the nature of their axial ligands, which can be modified to enhance
the properties of the prodrug. The existing paradigm of employing
platinum­(IV) complexes with symmetrical axial carboxylate ligands
does not fully exploit their vast potential. A new approach was conceived
to control properties of platinum­(IV) prodrugs using contrasting axial
ligands via sequential acylation. We report a novel class of asymmetric
platinum­(IV) carboxylates based on the cisplatin template containing
both hydrophilic and lipophilic ligands on the same scaffold designed
to improve their aqueous properties and enhance their efficacy against
cancer cells in vitro.