DNA G-quadruplex-stabilizing metal complexes as anticancer drugs

Abstract

Guanine quadruplexes (G4s) are important targets for cancer treatments as their stabilization has been associated with a reduction of telomere ends or a lower oncogene expression. Although less abundant than purely organic ligands, metal complexes have shown remarkable abilities to stabilize G4s, and a wide variety of techniques have been used to characterize the interaction between ligands and G4s. However, improper alignment between the large variety of experimental techniques and biological activities can lead to improper identification of top candidates, which hampers progress of this important class of G4 stabilizers. To address this, we first review the different techniques for their strengths and weaknesses to determine the interaction of the complexes with G4s, and provide a checklist to guide future developments towards comparable data. Then, we surveyed 74 metal-based ligands for G4s that have been characterized to the in vitro level. Of these complexes, we assessed which methods were used to characterize their G4-stabilizing capacity, their selectivity for G4s over double-stranded DNA (dsDNA), and how this correlated to bioactivity data. For the biological activity data, we compared activities of the G4-stabilizing metal complexes with that of cisplatin. Lastly, we formulated guidelines for future studies on G4-stabilizing metal complexes to further enable maturation of this field.

Keywords: Bioinorganic chemistry; Guanine tetrads; Metallodrugs; Oncology.

Fig. 1

A Generic G-quadruplex forming sequence, the ≠ sign indicates the large variations observed in G4s. B Sequences of G-quadruplex forming sequences mentioned in this review. C Chemical drawing of a guanine tetrad, with the different hydrogen bonding interactions and the centra metal monocation that is required to stabilize the G4 biological nanostructure. Representation of a G4-DNA structure consisting of three stacked G-quartets. D Various conformations of G-quadruplexes that are known to occur in nature. E Structures of biological G4 structures resolved by NMR (left: parallel G-quadruplex [PDB-code: 2M4P]; middle: antiparallel G-quadruplex [PDB-code: 1L34], right: hybrid G-quadruplex [PDB-code: 2JPZ]). Images were generated using YASARA and based on NMR structures of which one representative structure has been displayed out of the 10 lowest energy structures that were deposited. Two common binding modes for G4-stabilizing ligands are shown by the orange sphere in the first two structures: end-on G4 stacking (left) and major groove binding (right)

Fig. 2

Overview of the metal complexes, including metals and ligand structures described in this review. The guanine tetrad that is the target of the ligands is shown in the same proportions as the ligands. The periodic table highlights the transition metals that have occurred in the metal complexes treated in detail in this review

Fig. 3

Structures of G4-binding metalloporphyrins mentioned in this review

Fig. 4

Structures of G4-binding metallophthalocyanins and metallocorroles mentioned in this review

Fig. 5

Structures of G4-binding metallo-salphen complexes mentioned in this review

Fig. 6

Structures of G4-binding metal–phenanthroline complexes mentioned in this review

Fig. 7

Structures of G4-binding metal–terpyridine complexes mentioned in this review

Fig. 8

Structures of G4-binding octahedral ruthenium complexes mentioned in this review

Fig. 9

Structures of G4-binding multinuclear metal assemblies and dimetallic complexes mentioned in this review

Fig. 10

Structures of G4-binding miscellaneous complexes mentioned in this review

Fig. 11

Metal–salphen complexes with Cu (left, CCDC-code 766686) [93], V (middle, CCDC-code 252952) [94], and Zn (right, CDCC code 667235) [95] in top and frontal view (top and bottom, respectively), with emphasis on the metal-dependent deviation from the flat nature of the complex. As the vanadium complex did not meet our criteria for this review, we did not highlight this element in the periodic table of the elements shown in Fig. 2