Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting

Abstract

The five platinum anticancer compounds currently in clinical use conform to structure-activity relationships formulated (M. J. Cleare and J. D. Hoeschele, Bioinorg. Chem., 1973, 2, 187-210) shortly after the discovery that cis-diamminedichloroplatinum(II), cisplatin, has antitumor activity in mice. These compounds are neutral platinum(II) species with two am(m)ine ligands or one bidentate chelating diamine and two additional ligands that can be replaced by water through aquation reactions. The resulting cations ultimately form bifunctional adducts on DNA. Information about the chemistry of these platinum compounds and correlations of their structures with anticancer activity have provided guidance for the design of novel anticancer drug candidates based on the proposed mechanisms of action. This article discusses advances in the synthesis and evaluation of such non-traditional platinum compounds, including cationic and tumor-targeting constructs.

Figure 1

Structures of the platinum compounds currently in clinical use.

Figure 2

New and non-traditional compounds in clinical trials.

Figure 3

Structural frameworks for cationic platinum(II) complexes with antitumor activity.

Figure 4

Three cationic platinum(II) anticancer drug candidates.

Figure 5

Transporters of organic cations in enterocytes of the human small intestine. OCT1 transports cations in either direction depending on the electrochemical potential. In the presence of a normal membrane potential (−60 mV), cation uptake (thick arrows) is preferred. Efflux can occur if the intracellular concentration of the cation is 10 times higher inside the cell than outside the cell.

Figure 6

Sequence alignment of human HMGB4 and human HMGB1. Identical residues are highlighted in black, similar residues are highlighted in grey, and the Phe38, Cys23, and Cys45 residues are underlined.

Scheme 1

Proposed reaction of [(cis-{Pt(NH₃)₂})₂(μ-OH)(μ-pL)]²⁺ with adjacent dG residues.