The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

Abstract

Cancer is rapidly becoming the top killer in the world. Most of the FDA approved anticancer drugs are organic molecules, while metallodrugs are very scarce. The advent of the first metal based therapeutic agent, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design. Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anti-cancer agents that serve as alternatives to cisplatin and its derivertives. Ruthenium(iii) complexes have successfully been used in clinical research and their mechanisms of anticancer action have been reported in large volumes over the past few decades. Ruthenium(ii) complexes have also attracted significant attention as anticancer candidates; however, only a few of them have been reported comprehensively. In this review, we discuss the development of ruthenium(ii) complexes as anticancer candidates and biocatalysts, including arene ruthenium complexes, polypyridyl ruthenium complexes, and ruthenium nanomaterial complexes. This review focuses on the likely mechanisms of action of ruthenium(ii)-based anticancer drugs and the relationship between their chemical structures and biological properties. This review also highlights the catalytic activity and the photoinduced activation of ruthenium(ii) complexes, their targeted delivery, and their activity in nanomaterial systems.

Fig. 1

Three ruthenium(III) compounds in clinical trials.

Fig. 2

Conmmon cellular uptake mechanisms of drugs. Reproduced with permission from ref. . Copyright 2012, Royal Society of Chemistry.

Fig. 3

The schematic description of the anticancer effect of the nucleic targeting complex [Ru(bpy)(phpy)dppz]⁺. Reproduced with permission from ref. . Copyright 2015, American Chemical Society.

Fig. 4

Representation of Ru(II) compounds that accumulate in mitochondria. Bottom image:fluorescence confocal microscopy images of HeLa cells incubated with 1a with commercial dyes. Reproduced with permission from ref. . Copyright 2015, American Chemical Society.

Fig. 5

Representation of Ru(II) compounds that target DNA. Left-hand fluorescence image: the nuclear DNA staining of 2a in PFA-fxed HeLa cells, as evident by red luminescence, with co-staining by nuclear DNA dye DAPI. Right-hand fluorescence image: the nuclear DNA staining of the dinuclear 2b in MCF-7 cells, as evident by the red luminescence, with co-staining SYTO-9 (green). Reproduced with permission from ref. ^and , respectively. Copyright 2015, Nature Publishing Group.

Fig. 6

Representation of Ru(II) compounds that target proteins as enzymes inhibitors. Right-bottom image: caging strategy for comound 3h as photoinduced cysteine protease inhibitors. Reproduced with permission from ref. . Copyright 2015, American Chemical Society.

Fig. 7

Schematic representation of the work-flow used in the metallodrug pull-down experiments performed by Hartinger et al. Reproduced with permission from ref. . Copyright 2012, Royal Society of Chemistry.

Fig. 8

General representation of the main targets and proposed mechanisms of action of ruthenium compounds as anticancer drugs.

Fig. 9

Common structures of [(η⁶-arene)Ru(X](Y)(Z)].

Fig. 10

Common structures of arene Ru(II) compounds with N,N-chelating ligands.

Fig. 11

The N,N- ligands arene Ru(II) compounds with good photoactivity.

Fig. 12

Ru(II) arene complexes bearing N,O- chelating ligands.

Fig. 13

0,O- ligands arene Ru(II) complexes with different monodentate ligands.

Fig. 14

C,N-cyclometalated (η⁶-p-cymene) Ru(II) complexes.

Fig. 15

(A) The structures of PTA, RAPTA-C, RAPTA-T and RAPTA-B. (B) Growth curve of A2780 tumors with respect to RAPTA-C treatment. (C) Images show representative tumors from the vehicle treated (CTRL) and RAPTA-C (0.2 mg kg-1) treated CAMs. (D) Representative images of the immunohistochemical staining of the endothelial cell marker CD31 (in brown) showing reduced microvessel density per mm2 in tumors treated with RAPTA-C normalized to the tumor surface area and provided as a % of the control (E) and Ki-67 positive nuclei (in blue) (D) and quantification of the percentage of the tumor surface area staining positive for Ki-67 (as a % of CTRL) (F). Black bar in the right image of (D) represents 500 mm and is valid for both images. Reproduced with permission from ref. . Copyright 2012, Royal Society of Chemistry.

Fig. 16

Curcuminate complexes derived from the RAPTA structure.

Fig. 17

Chemical structures and nucleosomal adducts of RAPTA-C and RAED-C by X-ray. Reproduced with permission from ref. . Copyright 2015, Nature Publishing Group.

Fig. 18

(A), (B), (C) and (D) The structures of selective dinuclear and tetranuclear arene Ru(II) complexes.

Fig. 19

Cellular localization of Λ- and Δ-11 in MDA-MB-231 cells. Reproduced with permission from ref. . Copyright 2015, American Chemical Society.

Fig. 20

The structures of selective Ru(II) polypyridyl compounds as anticancer drugs.

Fig. 21

The structures of the selective cyclothenated compounds used in anticancer durgs.

Fig. 22

The structures of the selective Ru(II) compounds used in PDT

Fig. 23

The Ru(II) compounds used for two-photon-PDT in Chao’s group, and the schematic description of 15c used for two-photon-PDT. Reproduced with permission from ref. . Copyright 2015, Wiley-VCH.

Fig. 24

(A) The diagrammatic figure of FA-SeNPs and the structure of RuPOP. (B) The method for the synthesis of the Ru-SeNPs. (C) The structure of the Ru-MUA@Se. Reproduced with permission from ref. ^{, and} , respectively. Copyright 2015, Elsevier.

Fig. 25

(A) Schematic illustration of the photothermal efficiency of Ru@AuNPs under two-photon luminescence. (B) The structure of AuNRs@Ru and AuNTs@Ru, and the schematic illustration of photothermal treatment on mice. Reproduced with permission from ref. (Copyright 2015, Elsevier) and 287 (Copyright 2012, Royal Society of Chemistry), respectively.

Fig. 26

(A) Graphical representation for the assembly of mechanized MSNPs. (B) Schematic model and TEM image of UCNP@mSiO₂ nanoparticles (1), the schematic illustrationof the drug release from DOX-UCNP@mSiO₂-Ru nanoparticles (2). (C) Synthetic scheme for the pSiNP–Ru–PEG–Man. (D) The reaction pathways for the construction of the materials RuPOP@MSNs. Reproduced with permission from ref. (Copyright 2015, American Chemical Society), 291, 292 (Copyright 2012, Royal Society of Chemistry) and 293 (Copyright 2015, Wiley-VCH), respectively.

Fig. 27

(A) The design and radiosensitization action mechanisms of the RuPOP@MWCNTs nanosystem. (B) Schematic Design of Ru@SWCNTs for bimodal photothermal therapy and two-photon photodynamic therapy with 808 nm Irradiation, and the presentative photographs of HeLa tumors in mice Ru@SWCNTs treatments. Reproduced with permission from ref. ^and , respectively. Copyright 2015, American Chemical Society.

Fig. 28

Schematic designof cHSA-PEO-TPP-Ru for PDT. Reproduced with permission from ref. . Copyright 2015, American Chemical Society.

Fig. 29

Uncaging reactions of allyloxycarbonyl (alloc) protected amines under (a) biologically relevant conditions and (b) within living human cells with ruthenium(II) complexes reported by Meggers et al. Reproduced with permission from ref. . Copyright 2015, Elsevier.

Fig. 30

The Ru(II) catalytic reactions reported by Sadler group. Reproduced with permission from ref. (Copyright 2008, National Academy of Sciences.) and 326 (Copyright 2015, Nature Publishing Group), respectively.

Fig. 31

Spatiotemporal resolution of the sequential actions performed by Rotello’s nanobots. Reproduced with permission from ref. . Copyright 2015, Nature Publishing Group.

Scheme 1

The reaction rate of [(η⁶-C₆H₅)Ru(en)Cl]⁺ family with cGMP and their cytotoxicity towards A2780 cells. Data originate from ref. ^and .

Scheme 2

Ru(II) arene complexes bearing O,O-chelating ligands, and their cytotoxicity towards A2780 cells. Data originate from ref. .