Antiproliferative activity and inhibition of cancer cell migration by a cisplatin-based Pt(IV) bifunctional prodrug containing perillic acid

The discovery of the anticancer properties of cisplatin in the late ’60s originated an enormous interest in the medicinal chemistry of Pt compounds. Unfortunately, like many other single-target drugs, cisplatin fails or underperforms because of redundant pathways in cancer cells, so that the inhibition of one of them has no significant effect on the global outcome. One approach to overcome this problem is the conjugation of two distinct pharmacophores together to create single molecule, dual-targeting therapeutics.

Octahedral Pt(IV) complexes are an attractive platform to develop such a class of molecules. The rationale behind their development was that the nontoxic Pt(IV) prodrugs, upon entry into the reducing environment of the tumor tissue, would be activated by a two-electron reduction, to form a Pt(II) active metabolite with concomitant loss of the two axial ligands. If such positions are occupied by a second anticancer agent/pharmacophore, the complex will release two kinds of molecules: the Pt(II) moiety will enter the nucleus where it will react with DNA inducing apoptosis, whereas the axial ligands will interact with their own target. This approach allows the bifunctional molecule to aim at multiple targets simultaneously and often synergistically, achieving a greater therapeutic advantage over single-targeting agents.

In this framework, two Pt(IV) complexes containing perillic acid were synthesized and tested in vitro on several human tumor cell lines. In particular, the complex [PtCl₂(NH₃)₂(perillato)₂] exhibited excellent antiproliferative and anti-migration (antimetastatic) activity on A-549 lung tumor cells at nanomolar concentrations.