Strong Cytotoxicity of Organometallic Platinum Complexes with Alkynyl Ligands

The synthesis, spectroscopy, structures, and chemical reactivity of the organometallic complexes [(COD)­Pt­(CCR)₂] and [(COD)­Pt­(CCR)­(R′)] (COD = 1,5-cyclooctadiene, R = Ph, (Me)­Ph (2Me, 3Me, or 4Me), (NO₂)­Ph (2NO₂, 3NO₂, or 4NO₂), (4F)­Ph, (4OMe)­Ph, 2Py (2-pyridyl); R′ = Me (methyl), Neop (neopentyl = 2,2-dimethyl-1-methyl), NeoSi (neosilyl = trimethylsilylmethyl), Bz (benzyl)) has been explored. The crystal structures reveal square-planar surroundings of the Pt atoms with short Pt–C­(alkynyl) bonds (<2 Å) and almost perpendicular orientation of the CC–aryl group to the Pt coordination plane. Nonattractive π–π stacking and C–H···F intermolecular interactions were observed in the crystal structures. Multinuclear (¹H, ¹³C, ¹⁹⁵Pt, and ¹⁹F) NMR spectroscopy reveals structures in solution and Pt–ligand bond strength. The thermal stability in organic solvents, the electrochemical stability, and the reactivity of the complexes in organic or aquatic (water-containing) solution toward the physiologically relevant species glutathione, chloride, and protons was tested, revealing remarkable stability or inertness of the complexes. Cytotoxicity experiments in HT-29 colon carcinoma and MCF-7 breast adenocarcinoma cell lines revealed highly promising activities for selected platinum alkynyl COD complexes

Strong Cytotoxicity of Organometallic Platinum Complexes with Alkynyl Ligands

The synthesis, spectroscopy, structures, and chemical reactivity of the organometallic complexes [(COD)­Pt­(CCR)₂] and [(COD)­Pt­(CCR)­(R′)] (COD = 1,5-cyclooctadiene, R = Ph, (Me)­Ph (2Me, 3Me, or 4Me), (NO₂)­Ph (2NO₂, 3NO₂, or 4NO₂), (4F)­Ph, (4OMe)­Ph, 2Py (2-pyridyl); R′ = Me (methyl), Neop (neopentyl = 2,2-dimethyl-1-methyl), NeoSi (neosilyl = trimethylsilylmethyl), Bz (benzyl)) has been explored. The crystal structures reveal square-planar surroundings of the Pt atoms with short Pt–C­(alkynyl) bonds (<2 Å) and almost perpendicular orientation of the CC–aryl group to the Pt coordination plane. Nonattractive π–π stacking and C–H···F intermolecular interactions were observed in the crystal structures. Multinuclear (¹H, ¹³C, ¹⁹⁵Pt, and ¹⁹F) NMR spectroscopy reveals structures in solution and Pt–ligand bond strength. The thermal stability in organic solvents, the electrochemical stability, and the reactivity of the complexes in organic or aquatic (water-containing) solution toward the physiologically relevant species glutathione, chloride, and protons was tested, revealing remarkable stability or inertness of the complexes. Cytotoxicity experiments in HT-29 colon carcinoma and MCF-7 breast adenocarcinoma cell lines revealed highly promising activities for selected platinum alkynyl COD complexes

A Ruthenocene–PNA Bioconjugate  Synthesis, Characterization, Cytotoxicity, and AAS-Detected Cellular Uptake

Labeling of peptide nucleic acids (PNA) with metallocene complexes is explored herein for the modulation of the analytical characteristics, as well as biological properties of PNA. The synthesis of the first ruthenocene–PNA conjugate with a dodecamer, mixed-sequence PNA is described, and its properties are compared to a ferrocene-labeled analogue as well as an acetylated, metal-free derivative. The synthetic characteristics, chemical stability, analytical and thermodynamic properties, and the interaction with cDNA were investigated. Furthermore, the cytotoxicity of the PNA conjugates is determined on HeLa, HepG2, and PT45 cell lines. Finally, the cellular uptake of the metal-containing PNAs was quantified by high-resolution continuum source atomic absorption spectrometry (HR-CS AAS). An unexpectedly high cellular uptake to final concentrations of 4.2 mM was observed upon incubation with 50 μM solutions of the ruthenocene–PNA conjugate. The ruthenocene label was shown to be an excellent label in all respects, which is also more stable than its ferrocene analogue. Because of its high stability, low toxicity, and the lack of a natural background of ruthenium, it is an ideal choice for bioanalytical purposes and possible medicinal and biological applications like, e.g., the development of gene-targeted drugs

Metallocene-Modified Uracils: Synthesis, Structure, and Biological Activity

A new family of metallocene–uracil conjugates, including [3-(<i>N</i>1-uracilyl)-1-(ferrocenyl)]­propene (<b>2c</b>), [3-(<i>N</i>1-thyminyl)-1-(ferrocenyl)]­propene (<b>3c</b>), [3-(<i>N</i>1-(5-fluorouracilyl))-1-(ferrocenyl)]­propene (<b>4c</b>), and [3-(<i>N</i>1-uracilyl)-1-(ruthenocenyl)]­propene (<b>5c</b>), was obtained in three steps from (3-chloropropionyl)­ferrocene and (3-chloropropionyl)­ruthenocene, respectively. The complexes <b>2c</b>–<b>5c</b> and their intermediates <b>2a</b>–<b>5a</b> and <b>2b</b>–<b>5b</b> were characterized by NMR and infrared spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of the intermediates <b>2b</b> and <b>4a</b> were determined by single-crystal X-ray structure analysis. In the solid state, two molecules of <b>2b</b> or <b>4a</b> form a dimeric structure, which is held together by strong hydrogen bonds. Compounds <b>2c</b>–<b>5c</b> were also studied by cyclic voltammetry (CV). The ferrocenyl–uracil derivatives <b>2c</b>–<b>4c</b> revealed reversible uncomplicated oxidations, whereas the cyclic voltammogram of the ruthenocenyl derivative <b>5c</b> showed an irreversible oxidation. Compounds <b>2c</b>–<b>5c</b> were tested for their antiproliferative activity against human MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells. Compounds <b>3c</b>–<b>5c</b> were moderately active against MCF-7 cancerous cells. Atomic absorption spectroscopy measurements on compound <b>5c</b> revealed that the ruthenocenyl derivative is taken up by HT-29 cells in a time-dependent manner. However, the ruthenium cellular level remains relatively low. Compounds <b>2a</b>–<b>5a</b> were also tested against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA) and Staphylococcus epidermidis bacterial strains. Compound <b>4a</b> showed significant antibacterial activity against all bacterial strains, while compounds <b>2a</b> and <b>3b</b> were only moderately active. No antibacterial activity was found for the ruthenocenyl derivative <b>5a</b>

Results of a docking experiment with 8a in CLK1 (PDB-ID: 1Z57).

<p>A: front view; B: top view; dashed lines: H-bonds and edge to face interaction.</p

In vitro growth inhibition of cancer cell lines by KuWal151 (8c)^a.

<p>In vitro growth inhibition of cancer cell lines by KuWal151 (8c)<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#t002fn001" target="_blank">^a</a>.</p

CLK1 inhibitors described in the literature.

<p>TG003 (<b>1</b>); NCGC00185963 (<b>2</b>), KH-CB19 (<b>3</b>); benzo[<i>b</i>]thiophen-2-carboxamide <b>4</b>; T3 (<b>5</b>); TG693 (<b>6</b>); [1,2,3]triazolo[4,5-<i>c</i>]quinoline <b>7</b>.</p

3-Aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones listed in Table 1.

<p>3-Aryl-6,7-dihydropyrrolo[3,4-<i>g</i>]indol-8(1<i>H</i>)-ones listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196761#pone.0196761.t001" target="_blank">Table 1</a>.</p

Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2‑Pyridyl-2-pyrimidine-4-carboxylic Acid

A great majority of the Ru complexes currently studied in anticancer research exert their antiproliferative activity, at least partially, through ligand exchange. In recent years, however, coordinatively saturated and substitutionally inert polypyridyl Ru­(II) compounds have emerged as potential anticancer drug candidates. In this work, we present the synthesis and detailed characterization of two novel inert Ru­(II) complexes, namely, [Ru­(bipy)₂(Cpp-NH-Hex-COOH)]²⁺ (<b>2</b>) and [Ru­(dppz)₂(CppH)]²⁺ (<b>3</b>) (bipy = 2,2′-bipyridine; CppH = 2-(2′-pyridyl)­pyrimidine-4-carboxylic acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)­pyrimidine-4-carboxamido)­hexanoic acid; dppz = dipyrido­[3,2-<i>a</i>:2′,3′-<i>c</i>]­phenazine). <b>3</b> is of particular interest as it was found to have IC₅₀ values comparable to cisplatin, a benchmark standard in the field, on three cancer cell lines and a better activity on one cisplatin-resistant cell line than cisplatin itself. The mechanism of action of <b>3</b> was then investigated in detail and it could be demonstrated that, although <b>3</b> binds to calf-thymus DNA by intercalation, the biological effects that it induces did not involve a nuclear DNA related mode of action. On the contrary, confocal microscopy colocalization studies in HeLa cells showed that <b>3</b> specifically targeted mitochondria. This was further correlated by ruthenium quantification using High-resolution atomic absorption spectrometry. Furthermore, as determined by two independent assays, <b>3</b> induced apoptosis at a relatively late stage of treatment. The generation of reactive oxygen species could be excluded as the cause of the observed cytotoxicity. It was demonstrated that the mitochondrial membrane potential in HeLa was impaired by <b>3</b> as early as 2 h after its introduction and even more with increasing time

Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2‑Pyridyl-2-pyrimidine-4-carboxylic Acid

A great majority of the Ru complexes currently studied in anticancer research exert their antiproliferative activity, at least partially, through ligand exchange. In recent years, however, coordinatively saturated and substitutionally inert polypyridyl Ru­(II) compounds have emerged as potential anticancer drug candidates. In this work, we present the synthesis and detailed characterization of two novel inert Ru­(II) complexes, namely, [Ru­(bipy)₂(Cpp-NH-Hex-COOH)]²⁺ (<b>2</b>) and [Ru­(dppz)₂(CppH)]²⁺ (<b>3</b>) (bipy = 2,2′-bipyridine; CppH = 2-(2′-pyridyl)­pyrimidine-4-carboxylic acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)­pyrimidine-4-carboxamido)­hexanoic acid; dppz = dipyrido­[3,2-<i>a</i>:2′,3′-<i>c</i>]­phenazine). <b>3</b> is of particular interest as it was found to have IC₅₀ values comparable to cisplatin, a benchmark standard in the field, on three cancer cell lines and a better activity on one cisplatin-resistant cell line than cisplatin itself. The mechanism of action of <b>3</b> was then investigated in detail and it could be demonstrated that, although <b>3</b> binds to calf-thymus DNA by intercalation, the biological effects that it induces did not involve a nuclear DNA related mode of action. On the contrary, confocal microscopy colocalization studies in HeLa cells showed that <b>3</b> specifically targeted mitochondria. This was further correlated by ruthenium quantification using High-resolution atomic absorption spectrometry. Furthermore, as determined by two independent assays, <b>3</b> induced apoptosis at a relatively late stage of treatment. The generation of reactive oxygen species could be excluded as the cause of the observed cytotoxicity. It was demonstrated that the mitochondrial membrane potential in HeLa was impaired by <b>3</b> as early as 2 h after its introduction and even more with increasing time