Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure-Activity Relationship and Application as Orally Available Prodrugs.

Platinum(IV) bis-carboxylates are highly versatile prodrug scaffolds with different axial ligands that can be functionalized while keeping the platinum(II) pharmacophore intact. Using a sequential acylation strategy, we developed a class of PtIV prodrugs of cisplatin with contrasting lipophilic and hydrophilic ligands. We investigated their stability, reduction rates, lipophilicity, aqueous solubility, and antiproliferative efficacies, and assessed for correlations among the parameters that could be useful in drug design. We showed that compounds with high lipophilicity result in better antiproliferative effects in vitro and in vivo, with one of the three compounds tested showing better efficacy than satraplatin against an animal model of colorectal cancer, owing to its higher solubility and lower reduction rates. Our asymmetric PtIV prodrugs may pave the way for a highly predictable, fine-tuned class of orally available PtIV prodrugs for the treatment of colorectal cancer.