A cyclometallated IrIII complex conjugated to a coumarin derivative is a potent photodynamic agent against prostate differentiated and tumorigenic cancer stem cells

A cyclometalated IrIII complex conjugated to a far-red-emitting coumarin, IrIII-COUPY (3), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone-refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk, differentiated and prostate, hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of IrIII-COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumorspheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal-based compound is an efficient agent capable of killing even hardly treatable CSC

Fe II metallohelices stabilize DNA G‐quadruplexes and downregulate the expression of G‐quadruplex‐regulated oncogenes

DNA G-quadruplexes (G4s) have been identified within the promoter regions of many proto-oncogenes. Thus, G4s represent attractive targets for cancer therapy, and the design and development of new drugs as G4 binders is a very active field of medicinal chemistry. Here, molecular biophysics and biology methods were employed to investigate the interaction of chiral metallohelices with a series of four DNA G4s (hTelo, c-myc, c-kit1, c-kit2) that are formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT proto-oncogenes. We show that the investigated water-compatible, optically pure metallohelices, which are made by self-assembly of simple nonpeptidic organic components around FeII ions and exhibit bioactivity emulating the natural systems, bind with high affinity to G4 DNA and much lower affinity to duplex DNA. Notably, both enantiomers of a metallohelix containing a m-xylenyl bridge (5 b) were found to effectively inhibit primer elongation catalyzed by Taq DNA polymerase by stabilizing G4 structures formed in the template strands containing c-myc and c-kit2 G4-forming sequences. Moreover, both enantiomers of 5 b downregulated the expression of c-MYC and c-KIT oncogenes in human embryonic kidney cells at mRNA and protein levels. As metallohelices also bind alternative nucleic acid structures, they hold promise as potential multitargeted drugs

Metallohelix vectors for efficient gene delivery via cationic DNA nanoparticles

The design of efficient and safe gene delivery vehicles remains a major challenge for the application of gene therapy. Of the many reported gene delivery systems, metal complexes with high affinity for nucleic acids are emerging as an attractive option. We have discovered that certain metallohelices—optically pure, self-assembling triple-stranded arrays of fully encapsulated Fe—act as nonviral DNA delivery vectors capable of mediating efficient gene transfection. They induce formation of globular DNA particles which protect the DNA from degradation by various restriction endonucleases, are of suitable size and electrostatic potential for efficient membrane transport and are successfully processed by cells. The activity is highly structure-dependent—compact and shorter metallohelix enantiomers are far less efficient than less compact and longer enantiomers

Hetero-Bis-Conjugation of Bioactive Molecules to Half-Sandwich Ruthenium(II) and Iridium(III) Complexes Provides Synergic Effects in Cancer Cell Cytotoxicity

Four bipyridine-Type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2′-bipyridine-4,4′-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes

The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium(ii) arene anticancer complexes

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic OsII complexes [Os(η6-arene)(XY)Z]PF6 where arene = p-cymene or biphenyl, XY = N,N′-chelated phenyliminopyridine or phenylazopyridine derivatives, and Z = Cl or I. The X-ray crystal structure of [Os(η6-p-cym)(Impy-OH)I]PF6·0.5CH2Cl2·H2O (Impy-OH = 4-[(2-pyridinylmethylene)amino]-phenol) is reported. Like the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553–10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1H NMR (−4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism

Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs

This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy

Somatostatin subtype-2 receptor-targeted metal-based anticancer complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl 2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η 6-bip)Os(4-CO 2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η 6-p-cym)RuCl(dap)] + (p-cym = p-cymene) (5), and [(η 6-p-cym)RuCl(imidazole-CO 2H)(PPh 3)] + (6), were synthesized by using a solid-phase approach. Conjugates 3-5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC 50 = 63 ± 2 μ in MCF-7 cells and IC 50 = 26 ± 3 μ in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 ± 2.6 μ in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically. © 2012 American Chemical Society

Os2-Os4 switch controls DNA knotting and anticancer activity

Dinuclear trihydroxido-bridged osmium–arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged OsII–arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity

Triplex metallohelices have enantiomer-dependent mechanisms of action in colon cancer cells

Self-assembled enantiomers of an asymmetric di-iron metallohelix differ in their antiproliferative activities against HCT116 colon cancer cells such that the compound with Λ-helicity at the metals becomes more potent than the Δ compound with increasing exposure time. From concentration- and temperature-dependent 57Fe isotopic labelling studies of cellular accumulation we postulate that while the more potent Λ enantiomer undergoes carrier-mediated efflux, for Δ the process is principally equilibrative. Cell fractionation studies demonstrate that both enantiomers localise in a similar fashion; compound is observed mostly within the cytoskeleton and/or genomic DNA, with significant amounts also found in the nucleus and membrane, but with negligible concentration in the cytosol. Cell cycle analyses using flow cytometry reveal that the Δ enantiomer induces mild arrest in the G1 phase, while Λ causes a very large dose-dependent increase in the G2/M population at a concentration significantly below the relevant IC50. Correspondingly, G2-M checkpoint failure as a result of Λ-metallohelix binding to DNA is shown to be feasible by linear dichroism studies, which indicate, in contrast to the Δ compound, a quite specific mode of binding, probably in the major groove. Further, spindle assembly checkpoint (SAC) failure, which could also be responsible for the observed G2/M arrest, is established as a feasible mechanism for the Λ helix via drug combination (synergy) studies and the discovery of tubulin and actin inhibition. Here, while the Λ compound stabilizes F-actin and induces a distinct change in tubulin architecture of HCT116 cells, Δ promotes depolymerization and more subtle changes in microtubule and actin networks