Targeted Chemotherapy with Metal Complexes

Abstract

Classical chemotherapeutics, such as cisplatin and its analogues, have been highly successful in the clinic, yet improvements can certainly be made, given the significant side effects associated with the killing of healthy cells. Recent advances in the field of chemotherapy include the development of targeted anticancer agents, compounds that are directed towards a specific biomarker of cancer, with the hopes that such targeted therapies might have reduced side effects given their greater selectivity. Here we discuss several transition metal complexes that are tailored towards various biomolecules associated with cancer. Most notably, the success of rhodium metalloinsertors, which specifically bind to nucleic acid base mismatches in DNA, highlight the enormous potential of this exciting new strategy.

Keywords: DNA mismatch repair; bioinorganic; medicinal chemistry.

Figure 1

Chemical structures of classical platinum-based chemotherapeutics.

Figure 2

Chemical structures of targeted chemotherapeutics discussed in this Comment: (top, left to right) The octasporine complex OS1, a potent inhibitor of the protein kinase GSK3α; General architecture of RAPTA cathepsin B inhibitors; Ruthenocene analogues of tamoxifen for the selective targeting of ERα; (bottom, left to right) The first generation rhodium metalloinsertor, [Rh(bpy)₂(chrysi)]³⁺, selectively binds to mismatched and abasic sites in duplex DNA; Structure of mtPt, a cisplatin analogue designed to localize to the mitochondria.

Figure 3

Design of Octasporine complexes as inhibitors of protein kinases (adapted from reference 9). The pyridocarbazole ligand, common to all complexes, binds to the hinge region (where the adenine portion of ATP binds) of the ATP-binding pocket. The remaining A, B, C, and D ligands make up a set of hydrogen-bonding interactions with the glycine-rich loop (where the ribose triphosphate portion of ATP binds) of the ATP binding pocket, each unique to a particular kinase.

Figure 4

(Left) Crystal structure of [Rh(bpy)₂(chrysi)]³⁺, the first generation metalloinsertor, bound to an AC mismatch in duplex DNA. (Right, top) Chemical structure of [Rh(chrysi)(phen)(DPE)]²⁺, a later generation metalloinsertor with enhanced selectivity and potency. (Right, bottom) Cell-selective cytotoxicity of [Rh(chrysi)(phen)(DPE)]²⁺, the complex selectively kills MMR-deficient (red) cells over MMR-proficient (green) cells.

Figure 5

Inhibitory effects of [Rh(DPAE)₂chrysi]³⁺ (bottom, left) and [Rh(PrDPA)₂chrysi]³⁺ (bottom, center) on cellular proliferation in MMR-deficient HCT116O (red) and MMR-proficient HCT116N (green) cells as a function of BrdU incorporation during DNA synthesis (adapted from reference 35). Percent BrdU incorporation is normalized to that of untreated cells. (Bottom, right) Subcellular localization of [Rh(DPAE)₂chrysi]³⁺ (black) and [Rh(PrDPA)₂chrysi]³⁺ (hashed). Mitochondrial rhodium content (left axis) has been normalized to mitochondrial protein content, and nuclear rhodium content (right axis) is expressed as the percentage of cellular rhodium in the nucleus.

Figure 6

NCI-H23 subclones that were uninduced or induced for MLH1 shRNA were treated with either cisplatin (left) or the rhodium metalloinsertor [Rh(chrysi)(phen)(DPE)]²⁺ (right) (adapted from reference 37). Cells were treated at concentrations indicated, and cell viability assessed after 4 days using a Cell Titer-Glo assay. IC₅₀ values are shown below the plots.