Tuning Heavy Metal Compounds for Anti-Tumor Activity: Is Diversity the Key to Ruthenium’s Success?

Page, Simon M.; Boss, Sally R.; Barker, Paul D.

doi:10.4155/fmc.09.25

Cited by 19 publications

(6 citation statements)

References 102 publications

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“…Ruthenium is one of the most promising metals in anticancer drug candidates [54–57], with two Ru-compounds even in clinical trials [58–62]. Surprisingly however, its potential in antibacterial research has not been explored so far.…”

Section: Discussionmentioning

confidence: 99%

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

Albada¹,

Chiriac²,

Wenzel³

et al. 2012

Beilstein J. Org. Chem.

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SummaryA series of small synthetic arginine and tryptophan containing peptides was prepared and analyzed for their antibacterial activity. The effect of N-terminal substitution with metallocenoyl groups such as ferrocene (FcCO) and ruthenocene (RcCO) was investigated. Antibacterial activity in different media, growth inhibition, and killing kinetics of the most active peptides were determined. The toxicity of selected derivatives was determined against erythrocytes and three human cancer cell lines. It was shown that the replacement of an N-terminal arginine residue with a metallocenoyl moiety modulates the activity of WRWRW-peptides against Gram-positive and Gram-negative bacteria. MIC values of 2–6 µM for RcCO-W(RW)2 and 1–11 µM for (RW)3 were determined. Interestingly, W(RW)2-peptides derivatized with ferrocene were significantly less active than those derivatized with ruthenocene which have similar structural but different electronic properties, suggesting a major influence of the latter. The high activities observed for the RcCO-W(RW)2- and (RW)3-peptides led to an investigation of the origin of activity of these peptides using several important activity-related parameters. Firstly, killing kinetics of the RcCO-W(RW)2-peptide versus killing kinetics of the (RW)3 derivative showed faster reduction of the colony forming units for the RcCO-W(RW)2-peptide, although MIC values indicated higher activity for the (RW)3-peptide. This was confirmed by growth inhibition studies. Secondly, hemolysis studies revealed that both peptides did not lead to significant destruction of erythrocytes, even up to 500 µg/mL for (RW)3 and 250 µg/mL for RcCO-W(RW)2. In addition, toxicity against three human cancer cell lines (HepG2, HT29, MCF7) showed that the (RW)3-peptide had an IC50 value of ~140 µM and the RcW(RW)2 one of ~90 µM, indicating a potentially interesting therapeutic window. Both the killing kinetics and growth inhibition studies presented in this work point to a membrane-based mode of action for these two peptides, each having different kinetic parameters.

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Section: Discussionmentioning

confidence: 99%

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

Albada¹,

Chiriac²,

Wenzel³

et al. 2012

Beilstein J. Org. Chem.

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“…Besides, metal complexes can exhibit different geometry and coordination index, so this kind of chemistry offers a huge structural diversity to develop and design different drugs. 1 The breaking point in bioinorganic chemistry and in the use of metal complexes for cancer treatment started with the discovery of cisplatin and, later, with the second-or third-generation drugs such as carboplatin (paraplatin) and oxaliplatin (eloxatin) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Selective cytotoxicity of cyclometalated gold(III) complexes on Caco-2 cells is mediated by G2/M cell cycle arrest

et al. 2021

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New cyclometalated gold(III) complexes with a general structure [Au(C^N)(SR)2] or [Au(C^N)Cl(SR)] where C^N is biphenyl ligands such as 2-(p-tolyl)pyridinate (tpy), 2-phenylpyridinate (ppy) and 2-benzylpyridinate (bzp) (SR = Spym, S(Me)2pym, 2-thiouracil and thiourea); and also with ethynyl moieties of the type [Au(C^N)(C≡C-Ar)2] (Ar = p-toluene and 2-pyridine) have been synthesized. All of them have been characterized, including X-ray studies of complex [Au(bzp)Cl(Spym)], and these studies have permitted to elucidate that leaving chloride ligand is trans located to CAr atom. After the full characterization, physicochemical properties were measured by evaluating drug-likeness water solubility and cell permeability (partition coefficient). All these experiments pointed that our complexes present adequate properties to be used as anticancer drugs. Although not all the complexes showed antiproliferative effects on Caco-2 cells, those that did, were more cytotoxic than cisplatin, and complex [Au(tpy)Cl(2-Thiouracil)] is even more active than auranofin. In addition to this effectiveness, not evidence of cytotoxic effects was observed on considered normal cells (with the exception of [Au(bzp)Cl(2-Thiouracil)]. Further mechanistic studies were performed using these selective complexes, showing cell cycle arrest on the G2/M phase, a proapoptotic behaviour and also the modification of some genes involved in tumorigenesis. Thus, as a result of this investigation, we present a new family of seventeen cyclometalated complexes, being six of them selective and possible candidates to be used against colon cancer.

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“…Ruthenium complexes are rich in chemistry and the side-effects of the ruthenium complexes are low compared to platinum-derived drugs because of the selective activation to cytotoxic species in solid tumor tissues (28). Ruthenium complexes display relatively low ligand exchange rates in comparison to platinum complexes (29). Slow ligand exchanges ensure that a drug reaches its biological target without prior modification.…”

Section: Introductionmentioning

confidence: 99%

“…Slow ligand exchanges ensure that a drug reaches its biological target without prior modification. In addition, the various oxidation states (II, III and IV) of ruthenium are all accessible under physiological conditions (29). In these complexes, the ruthenium center is primarily hexacoordinated with octahedral geometry in contrast to square planar geometry of platinum (II) (30).…”

Section: Introductionmentioning

confidence: 99%

Anticancer activities of the ruthenium carboxylato, amido and pyridine complexes

Srivastava

Fronczek²,

Perkins³

et al. 2010

Int J Oncol

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Abstract. Ruthenium complexes [1][2][3] with oxalato, amido and pyridine ligands have been synthesized and characterized. Biological tests showed that the ruthenium complexes 2 and 3 have modest cytotoxicity on both murine cell line NIH3T3 and human cancer colon cell lines HCT116 and HT29 while complex 1 has no obvious growth defect. We further tested why complexes 2 and 3 exhibit modest cytotoxicity. Gel electrophoresis analysis demonstrates that complex 3 has the ability to cleave double-stranded DNAs in a dose-dependent manner. In contrast, complex 2 does not have detectable DNA cleavage activity. Additionally, real-time PCR analysis suggests that the observed cell growth inhibition or death could be due to the altered gene expression in the processes of cell cycle and apoptosis/necrosis caused by the addition of complexes 2 and 3. Furthermore, cell death by DNA fragmentation assay indicates that the addition of these two complexes may cause cell necrosis rather than apoptosis.

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Tuning Heavy Metal Compounds for Anti-Tumor Activity: Is Diversity the Key to Ruthenium’s Success?

Cited by 19 publications

References 102 publications

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

Selective cytotoxicity of cyclometalated gold(III) complexes on Caco-2 cells is mediated by G2/M cell cycle arrest

Anticancer activities of the ruthenium carboxylato, amido and pyridine complexes

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