Transition Metal Intercalators as Anticancer Agents-Recent Advances

Abstract

The diverse anticancer utility of cisplatin has stimulated significant interest in the development of additional platinum-based therapies, resulting in several analogues receiving clinical approval worldwide. However, due to structural and mechanistic similarities, the effectiveness of platinum-based therapies is countered by severe side-effects, narrow spectrum of activity and the development of resistance. Nonetheless, metal complexes offer unique characteristics and exceptional versatility, with the ability to alter their pharmacology through facile modifications of geometry and coordination number. This has prompted the search for metal-based complexes with distinctly different structural motifs and non-covalent modes of binding with a primary aim of circumventing current clinical limitations. This review discusses recent advances in platinum and other transition metal-based complexes with mechanisms of action involving intercalation. This mode of DNA binding is distinct from cisplatin and its derivatives. The metals focused on in this review include Pt, Ru and Cu along with examples of Au, Ni, Zn and Fe complexes; these complexes are capable of DNA intercalation and are highly biologically active.

Keywords: DNA; DNA binding; cancer; cytotoxicity; intercalate; platinum; transition metals.

Figure 1

Chemical structures of cisplatin, carboplatin and oxaliplatin.

Figure 2

Schematic representation of a metal complex interacting with DNA, resulting in elongation of the double-helix (left, sourced from Protein Data Bank (PDB) file 2MG8 [9] with metal complex inserted manually) and cisplatin covalently binding to DNA, causing the double helix to bend (right, sourced from PDB 1AIO) [10]. Central DNA figure sourced from PDB file 1D86 [11]. Oxygen is orange, phosphorous is yellow, carbon is cream/white and nitrogen is blue/purple. The base pairs are also represented as blue/purple rectangular panels.

Figure 3

Chemical structures of early transition metal intercalators.

Figure 4

General structures of phen, dpq, bpy platinum intercalators. * indicates a stereocentre of the A_L, either S or R. Counter ions have been omitted for clarity.

Figure 5

General structure of platinum complexes incorporating acridine and benz[c]acridine (left) and the acridine complex [PtCl(en)(1-{2-(acridin-9-ylamino)ethyl}-1,3-dimethylthiourea)](NO₃)₂ bound to DNA, as determined through a solution structure (PDB 1XRW) [39]. Counter-ions have been omitted for clarity and en = ethylenediamine. Oxygen is orange, phosphorous is yellow, carbon is cream/white and nitrogen is blue/purple. The base pairs are also represented as blue/purple rectangular panels.

Figure 6

Structures of the luminescent cyclometalated PC, Pt9 and the tetraplatinated porphyrin, Pt10. Counter-ions have been omitted for clarity.

Figure 7

Structures of copper complexes Cu1–4, and the IC₅₀ value of each complex in the SKOV3 human cancer cell line. Blue-coloured atoms are those that coordinate to the copper centre for each L example. Counter-ions have been omitted for clarity.

Figure 8

Structures of complexes Cu5–13. Counter-ions have been omitted for clarity.

Figure 9

Chemical structures of ruthenium polypyridyl complexes Ru1–5 (left) and the X-ray crystal structure of rac-[Ru(phen)₂(dppz)]²⁺ bound to DNA sequence d(ATGCAT)₂ (right). The extended aromatic ligand intercalates and separates the DNA base pairs, here shown with both the ∆ and Λ enantiomers bound. Sourced from PDB file 4JD8 [59]. Blue-coloured atoms are those that coordinate to the ruthenium centre in each L example. Counter-ions have been omitted for clarity. Oxygen is orange, phosphorous is yellow, carbon is cream/white and nitrogen is blue/purple. The base pairs are also represented as blue/purple rectangular panels.

Figure 10

Chemical structures of ruthenium arene complexes Ru6–9. Counter-ions have been omitted for clarity. Ligands with a blue label coordinate at the “L” position of the arene through the blue-coloured oxygen or nitrogen atoms. L_a coordinates at the X₂ position through the red nitrogen.

Figure 11

Structures of the metallointercalators Au1, Fe1, Zn1 and Ni1. Counter-ions have been omitted for clarity.