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Ru(ii)arene(N^N bpy/phen)-based RAPTA complexes for in vitro anti-tumour activity in human glioblastoma cancer cell lines and in vivo toxicity studies in a zebrafish model.

ABSTRACT: Herein, we have introduced a series of half-sandwich Ru(ii)arene(N^N bpy/phen)-based RAPTA complexes for brain cancer therapy. Among all the synthesized complexes, [(η⁶-p-cymene)Ru^II(κ²-N,N-4,7dimethyl phenanthroline)(PTA)]·2PF₆ (4c) and [(η⁶-p-cymene)Ru^II(κ²-N,N-4,7diphenyl phenanthroline)(PTA)]·2PF₆ (4d) showed outstanding potency against the T98G, LN229 and U87MG cancer cells. The antiproliferative activity of these complexes was reinforced by neurosphere, DNA intercalation, agarose gel electrophoresis, cell cycle analysis and time-dependent ROS detection assays. The real-time reverse transcription (RT)-polymerase chain reaction (PCR) study showed that complex 4c inhibited the TNF-α-induced NF-κB phosphorylation in glioma cells. Moreover, the in vivo biodistribution of complex 4c in different organs and the morphological patterns of widely used zebrafish embryos due to toxic effects have been evaluated.

SUBMITTER: P K A

PROVIDER: S-EPMC9241057 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Arene-Ru(II)-chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells.

Project description:The complexes [Ru(eta(6)-p-cymene)(CQ)Cl(2)] (1), [Ru(eta(6)-benzene)(CQ)Cl(2)] (2), [Ru(eta(6)-p-cymene)(CQ)(H(2)O)(2)][BF(4)](2) (3), [Ru(eta(6)-p-cymene)(en)(CQ)][PF(6)](2) (4), [Ru(eta(6)-p-cymene)(eta(6)-CQDP)][BF(4)](2) (5) (CQ = chloroquine base; CQDP = chloroquine diphosphate; en = ethylenediamine) interact with DNA to a comparable extent to that of CQ and in analogous intercalative manner with no evidence for any direct contribution of the metal, as shown by spectrophotometric and fluorimetric titrations, thermal denaturation measurements, circular dichroism spectroscopy and electrophoresis mobility shift assays. Complexes 1-5 induced cytotoxicity in Jurkat and SUP-T1 cancer cells primarily via apoptosis. Despite the similarities in the DNA binding behavior of complexes 1-5 with those of CQ the antitumor properties of the metal drugs do not correlate with those of CQ, indicating that DNA is not the principal target in the mechanism of cytotoxicity of these compounds. Importantly, the Ru-CQ complexes are generally less toxic toward normal mouse splenocytes and human foreskin fibroblast cells than the standard antimalarial drug CQDP and therefore this type of compound shows promise for drug development.

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Binding of Ru(bpy)2(eilatin)2+ to matched and mismatched DNA.

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Binding mechanisms of half-sandwich Rh(III) and Ru(II) arene complexes on human serum albumin: a comparative study.

Project description:Various half-sandwich ruthenium(II) arene complexes and rhodium(III) arene complexes have been intensively investigated due to their prominent anticancer activity. The interaction of the organometallic complexes of Ru(η6-p-cymene) and Rh(η5-C5Me5) with human serum albumin (HSA) was studied in detail by a combination of various methods such as ultrafiltration, capillary electrophoresis, 1H NMR spectroscopy, fluorometry and UV-visible spectrophotometry in the presence of 100 mM chloride ions. Binding characteristics of the organometallic ions and their complexes with deferiprone, 2-picolinic acid, maltol, 6-methyl-2-picolinic acid and 2-quinaldic acid were evaluated. Kinetic aspects and reversibility of the albumin binding are also discussed. The effect of low-molecular-mass blood components on the protein binding was studied in addition to the interaction of organorhodium complexes with cell culture medium components. The organometallic ions were found to bind to HSA to a high extent via a coordination bond. Release of the bound metal ions was kinetically hindered and could not be induced by the denaturation of the protein. Binding of the Ru(η6-p-cymene) triaqua cation was much slower (ca. 24 h) compared to the rhodium congener (few min), while their complexes interacted with the protein relatively fast (1-2 h). The studied complexes were bound to HSA coordinatively. The highly stable and kinetically inert 2-picolinate Ru(η6-p-cymene) complex bound in an associative manner preserving its original entity, while lower stability complexes decomposed partly or completely upon binding to HSA. Fast, non-specific and high-affinity binding of the complexes on HSA highlights their coordinative interaction with various types of proteins possibly decreasing effective drug concentration.

| S-EPMC6682546 | biostudies-literature

Design, Synthesis, DNA/HSA Binding, and Cytotoxic Activity of Half-Sandwich Ru(II)-Arene Complexes Containing Triarylamine-Thiosemicarbazone Hybrids.

Project description:Organoruthenium complexes are potent alternatives for platinum-based complexes because of their superior anticancer activity. In this investigation, a series of new Ru(II)-arene complexes with triarylamine-thiosemicarbazone hybrid ligands with higher anticancer activity than cisplatin are reported. The molecular structure of the ligands and complexes was confirmed spectroscopically and supported by single-crystal X-ray crystallography. These complexes adopted a three-leg piano stool geometry. All the Ru(II)-arene complexes were systematically investigated for their in vitro cytotoxicity against human cervical (HeLa S3), lung (A549) cancer, and human normal lung (IMR-90) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Interestingly, a pyrrolidine-attached Ru(II)-benzene complex exhibited superior activity against cancer cells with low IC50 values, and colony formation study showed complete inhibition at 5 and 10 μM concentration. Furthermore, morphological changes assessed by acridine orange and propidium iodide staining revealed that the cell death occurred by apoptosis. In addition, the interaction between synthesized Ru(II)-arene complexes and DNA/protein was explored by absorption and emission spectroscopy methods. These synthesized new organoruthenium complexes can be used for developing new metal-based anticancer drugs.

| S-EPMC6682138 | biostudies-literature

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