New trends for metal complexes with anticancer activity

Abstract

Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side-effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selective delivery and/or activation of cisplatin-related prodrugs and the discovery of new non-covalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in 'metals in medicine'.

Figure 1

Metal-based anticancer drugs that primarily target DNA. (a) Pt(iv) complexes that deliver cisplatin and two equivalents of estradiol (1) and the GST inhibitor ethacrynic acid (2) after activation. (b) Photolabile platinum diazide complexes 4 and 5 demonstrate good cytotoxicity upon irradiation. (c) Typical, cytotoxic examples of the ruthenium- and osmium-arene family of complexes.

Figure 2

New (non-covalent) interactions with DNA. (a) G-quadruplex binding complexes 11 and 12 show high affinity and good (11) to exceptional (12) selectivity for telomeric DNA (centre, 1KF1.pdb). (b) The highly modular TriplatinNC (13) complex binds to DNA via so-called ‘phosphate clamps’ (2DYW.pdb). (c) The saturated iron triple helicate binds to a three-way DNA junction (2ET0.pdb).

Figure 3

The metal as scaffold. (a) Concept: mimicking the protein kinase inhibitor staurosporine with an octahedral ruthenium complex. (b) DW1 (the R enantiomer of the DW1/2 racemic mixture) activates p53 and induces apoptosis in human melanoma cells. (c) The concept is demonstrated by the crystal structure of with the protein kinase Pim-1. (d) The remarkably close match is illustrated by the superimposed cocrystal structures of the organometallic inhibitor (white, 2BZI.pdb) and staurosporine (purple, 1YHS.pdb).

Figure 4

Proteins and enzymes as non-classical targets. This cross-section illustrates the diversity in structure of the complexes and the many organometallic agents being studied. (a) The Au(i)-phosphole complex 14 inhibits hTrxR. The crystal structure shows the two gold binding sites (insets, gold atoms as orange spheres, 2AAQ.pdb). (b) Gold(iii)-porphyrin anticancer agent 15. (c) The cobalt-alkyne (16) and cobalt-marimastat chaperone (17) complexes inhibit COX and MMP, respectively. The cobaltocenium complex (22) carries a nuclear localization signal for directed nuclear delivery. (d) NAMI-A (9) and the RAPTA-ruthenium complexes (18) show antimetastatic activity. (e) Ferrocifen (19) constitutes a prototypical example of a bioorganometallic drug. The nucleotide-appended organometallic iron complexes 20 and 21 show pronounced cytotoxicity.