Recognition and mechanistic investigation of anion sensing by ruthenium(II) arene complexes and bio-imaging application.

In this work, four new ruthenium complexes [Ru(η6-p-cymene)(L1)Cl] 1, [Ru(η6-p-cymene)(L2)Cl] 2, [Ru(η6-p-cymene)(L3)Cl] 3 and [Ru(η6-p-cymene)(L4)Cl] 4 [HL1 = (2-cyanophenyl)glycine; HL2 = (5-chloro-2-cyanophenyl)glycine; HL3 = (2-cyano-3-fluorophenyl)glycine; HL4 = (4-cyanophenyl)glycine] were synthesized and well characterized by several spectroscopic and analytical techniques. Complexes 1 and 3 were found to be fluorescent in most of the solvents; however, 2 and 4 were found to be fluorescent mostly in EtOAc, DMF and ethanol. Amongst these four complexes, 3 has shown selective sensing against CO32- and SO42- anions by quenching of fluorescence. The LOD values are found to be in the sub-micromolar range. Investigations of the sensing mechanism performed by computation and NMR studies indicate a possible adduct formation between the NH group of the ligand and the anion(s) through hydrogen bond formation, which ultimately might lead to proton transfer to the bi-negative anion. The quantum yield of the complex 3 was found to decrease on addition of CO32- and SO42- anions from 0.46 to 0.13 and 0.12, respectively. The Job's plot indicates the binding between the probe and anion in a 1 : 1 ratio for both CO32- and SO42- anions. Along with that, all the complexes were found to be biocompatible when tested against several cell lines showing very high IC50 values. It can also be observed that 1 is capable of penetrating within the cells and can act as a cell imaging agent showing fluorescence, and thus can be used for bio-imaging purposes.

Ruthenium(ii)-arene complexes as anti-metastatic agents, and related techniques.

With the discovery of cisplatin, a vast area of applications of metallodrugs in cancer treatment was opened but due to the side effects caused by the cisplatin complexes, researchers began to look for alternatives with similar anticancer properties but fewer side effects. Ruthenium was found to be a promising candidate, considering its significant anticancer properties and low side effects. Several ruthenium complexes, viz. NAMI-A, KP1019, KP1339, and TLD1433, have entered clinical trials. Some other arene ruthenium complexes such as RM175 and RAPTA-C have also entered clinical trials but very few of them have shown anti-metastatic properties. Herein, we provide information and probable mechanistic pathways for ruthenium(ii)-arene complexes that have been studied, so far, for their anti-metastatic activities. Also, we discuss the techniques and their significance for determining the anti-metastatic effects of the complexes.

Selective anticancer activities of ruthenium(II)-tetrazole complexes and their mechanistic insights.

Ruthenium-based metallotherapeutics is an interesting alternative for platinum complexes acting as anticancer agents after the entry of KP1019, NAMI-A, and TLD1339 in clinical trials. Herein, we have synthesized three new arene ruthenium(II)-tetrazole complexes viz. [Ru2(η6-p-cymene)2(2-pytz)2Cl2] (1), [Ru2(η6-p-cymene)2(3-pytz)Cl3] (2), [Ru2(η6-p-cymene)2(4-pytz)Cl3] (3) [2-pytzH = 2-pyridyl tetrazole; 3-pytzH = 3-pyridyl tetrazole; 4-pytzH = 4-pyridyl tetrazole] which have been characterized by different analytical techniques. To aid the understanding of the complex formation, reactions of the arene ruthenium(II) dimer with tetrazoles were investigated using the first principles-based Density Functional Theory (DFT) B3LYP method. Electronic structures, equilibrium geometries of the reactants and products with the first-order saddle points, reactions mechanism, the changes of enthalpy (∆H) and free energy (∆G), chemical stability, and reaction barriers of the complexes were computed using the B3LYP DFT approach. The in vitro cytotoxicity of these complexes was investigated by MTT assay on different cancer cell lines which reveal complex 2 as the most significant cytotoxic agent toward the HeLa cell line. The complexes have also shown a strong binding affinity towards CT-DNA and albumin proteins (HSA and BSA) as analyzed through spectroscopic techniques. Investigation of the mechanism of cell death by complex 2 was further performed by various staining techniques, flow cytometry, and gene expression analysis by RT-PCR. Inhibition of cell migration study has been also revealed the possibility of complex 2 to act as a prospective anti-metastatic agent.

Mechanistic Insight for Targeting Biomolecules by Ruthenium(II) NSAID Complexes.

With the enormous progress in ruthenium complexes as promising anticancer agents after the entry of KP1019, KP1339, and NAMI-A in clinical trials, herein three arene ruthenium(II) NSAID (nonsteroidal anti-inflammatory drugs) complexes viz. [Ru(η6-p-cymene)(mef)Cl] (1), [Ru(η6-p-cymene)(flu)Cl] (2), and [Ru(η6-p-cymene)(dif)Cl] (3) are synthesized, characterized, and reported. Density functional theory (DFT) calculations were performed in support of the obtained experimental results by computing the equilibrium geometries, reactions pathways, relative Gibbs free energy, stability, and reactions barriers of the complexes. The present theoretical study shows that all the proposed structures of the complexes are energetically stable and favorable, and the results obtained are in close accordance with the experiment. Further, the in vitro cytotoxicity of the complexes was explored through MTT assay on MCF-7, Hela, A549, and HEK cell lines. It was found the complex 1 and 2 are significantly cytotoxic toward the MCF-7 cell line. These complexes have also shown a strong affinity toward CT-DNA and proteins (HSA and BSA) as analyzed through spectroscopic techniques. Further investigation of the mechanism of cell death of selected complexes was carried out by various staining, flow cytometry, and gene expression analysis obtained by RT-PCR.

Novel Approach to Generate a Self-Deliverable Ru(II)-Based Anticancer Agent in the Self-Reacting Confined Gel Space.

Finding the most effective method for cancer treatment is one of the thought-provoking tasks. Drug delivery by collapsing of metallogel to the cancer cell is an appealing way out. Cancer cells have an acidic environment due to excessive accumulation of lactic acid. In this work, the novel G5 gelator with a strategically free carboxylic acid arm has been designed and fabricated and characterized by several spectroscopic and microscopic techniques. These experiments suggest the formation of an ordered supramolecular gel with clover-leaf-like morphology. Mechanical properties from rheological measurements suggest the viscoelastic nature of the gel. Furthermore, we have obtained crystals of G5 from the pure dimethyl sulfoxide solution, whereas gelation gets induced by addition of water. This G5 gelator loses its gelation capability once the carboxylate is esterified by layering with methanol, which furnished the crystals of Me-G5' (G5' = G5-H). Further, the G5 gelator is used for the formation of ruthenium metallogel. Interestingly, we obtained the monomeric species [Ru(G5')(η6-p-cymene)Cl] [Ru(II)G5] only in confined gel space upon addition of a [Ru2(η6-p-cymene)2Cl4] dimer to G5. The Ru(II)G5 metallogel has an inherent anticancer property with an IC50 value of 10.53 µM for the A549 cancer cell line. Treatment of the Ru(II)G5 metallogel by lactic acid for mimicking the acidic environment of the malignant cell results in collapsing of the gel by releasing the ruthenium metal ion. This released ruthenium ion binds with the lactic acid derivative making the gelator G5 free and producing a new compound Ru(II)L, which has also shown the anticancer property. The molecular docking study revealed that the released G5 could interact with a monocarboxylate transporter to disrupt the lactate transport chain, which might induce apoptosis.

Cobalt Metallogel Interface for Selectively Sensing l-Tryptophan among Essential Amino Acids.

The development of metallogels widens the span of sensing activity as it opens new opportunities to develop chemosensors through metal-ligand interactions. Herein, a new nitrile-substituted 1,3,5-tricarboxamide-based gelator G4 has been fabricated and shows aggregate-induced enhanced emission (AIEE) after gelation in the presence of water. A dimethylformamide (DMF) solution of the gelator shows rapid crystallization, but addition of water to a DMF solution of gelator G4 leads to gelation at room temperature. In addition, gelator G4 was used for the formation of metallogels, and among them, the cobalt metallogel has been found to be effective for sensing l-tryptophan in the gel state through the quenching of AIEE. Interestingly, the gel is also effective in sensing bovine serum albumin protein at the nanomolar level, which contains an l-tryptophan residue. The limit of detection of Co(II)G4 for selective sensing of tryptophan has been found to be 2.4 × 10-8 M. To the best of our knowledge, there have been no reports to date of a metallogel being utilized to discriminate and selectively sense an amino acid and a protein. The gelation properties of the organic gelator molecule and metallogels have been explored through various spectroscopic tools and physicochemical experiments.

Discotic Organic Gelators in Ion Sensing, Metallogel Formation, and Bioinspired Catalysis.

Two organogelators G2 and G3 with a carboxamide group have been synthesized and characterized with different spectroscopic tools. Dimethylformamide or dimethyl sulfoxide solutions of both the compounds upon the addition of a minute quantity of water show the tendency to form gels. Supramolecular self-assembly for gel formation paves the way for aggregation-induced emission enhancement (AIEE) phenomena for both the gelator molecules. Introduction of metal ions in organogels strengthens the gel property without much affecting the fluorescence behavior. However, the introduction of Ag+, Fe2+, and Fe3+ ions in the G2 organogel separately results in total quenching of AIEE, making it possible to sense that particular cation in the gel state. The G3 organogel shows a similar behavior with the Fe2+ ion. Remarkably, other metallogels such as Ni(II)G2 and Co(II)G2 can sense sulfide ion and Cu(II)G2 can sense iodide ion by switching off the fluorescence even in multianalyte conditions. Furthermore, the copper-based metallogel Cu(II)G2 can be utilized as a catalyst and reaction medium for aerobic oxidation of catechol to quinone. To the best of our knowledge, this is the first attempt known so far to utilize a metallogel material for bioinspired catalysis such as catechol oxidation.