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Three Schiff base Cu(II) complexes, (N,N’-bis(acetylacetone)propylenediimine) copper(II) complex, [Cu(acac2pn)] (1), (N,N'-bis-(benzoylacetone) propylenediimine)copper(II) complex, [Cu(phacac2pn)] (2) and (N,N’-bis- -(trifluoroacetylacetone)propylenediimine)copper(II) complex, [Cu(tfacac2pn)] (3), were used to investigate the interactions with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) using the electronic absorption and spectroscopic fluorescence methods. UV–Vis absorption studies showed that studied complexes interact with DNA molecule and exhibit moderate binding affinity. Fluorescence studies of complexes 1–3 also showed a possibility for DNA intercalation as well as a relatively high binding ability toward BSA. Among the tested complexes, the highest affinity for DNA and BSA molecules was shown by complex 1. Cytotoxic analyses, performed on human colorectal carcinoma HCT-116 and healthy lung fibroblast MRC-5 cell lines, showed that complex 2 exhibited activity on both cell lines, while complexes 1 and 3 did not show any activity.

The antimicrobial and antioxidant activities, as well as the DNA-binding of four square-planar Pd(II) complexes, [Pd(terpy)Cl]+ (C1), [Pd(en)Cl2] (C2), [Pd(DMEAImiPr)Cl2] (C3) and [Pd(dach)Cl2] (C4) (terpy = 2,2′:6′,2′′- -terpyridine, en = ethylenediamine, dach = trans-1,2-diaminocyclohexane and DMEAImiPr = N2-((1,3-dihydro-1,3-diisopropyl-4,5-dimethyl)-2H-imidazol-2- ylidene)-N1,N1-dimethyl-1,2-ethanediamine are reported. The antimicrobial activities of the Pd(II) complexes with the appropriate ligands were tested using the microdilution method against 18 strains of microorganisms, whereby the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC) were determined. The antibiofilm activity of [Pd(terpy)Cl]+ and the corresponding ligand were determined on a formed biofilm. The intensity of antimicrobial activity varied depending on the type of microorganism and the tested compound. The C1 complex with the corresponding ligand demonstrated significantly greater overall antimicrobial activity than C2, C3 and C4. The antibacterial activity of the C1 complex was better than its antifungal activity that was overall greater than that of the positive control, fluconazole. The greatest sensitivity for C1 and L1 was with Penicillium italicum (MIC < 0.49 μg mL-1) among the fungi, and with Proteus mirabilis ATCC 12453 (MIC = 0.98 μg mL-1) among the tested bacteria. The tested compounds show low and moderate antibiofilm activity. The complexes showed weak antioxidant properties when tested using the DPPH (1,1-diphenyl-2- -picrylhydrazyl) method. The interaction of the metal complexes C1–C4 with calf thymus DNA (CT-DNA) was further examined by absorption (UV–Vis) and emission spectral studies (EthBr displacement studies). Overall, the investigated complexes exhibited good DNA interaction ability. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172011 and Grant no. 173032]

This paper presents optimization of matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometer (MS) instrumental parameters for the analysis of chloro(2,2'',2"-terpyridine)palladium(II) chloride dihydrate complex applying design of experiments methodology (DoE). This complex is of interest for potential use in the cancer therapy. DoE methodology was proved to succeed in optimization of many complex analytical problems. However, it has been poorly used for MALDI-TOF-MS optimization up to now. The theoretical mathematical relationships which explain the influence of important experimental factors (laser energy, grid voltage and number of laser shots) on the selected responses (signal to noise – S/N ratio and the resolution – R of the leading peak) is established. The optimal instrumental settings providing maximal S/N and R are identified and experimentally verified. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172052 and Grant no. 172011]

This study investigates the potential of using ionic liquids as cosolvents to enhance the solubility and activity of poorly soluble rhodium(III) complexes, particularly those with diene, pyridine derivatives, and camphor-derived bis-pyrazolylpyridine ligands, in relation to 5'-GMP, CT-DNA, and HSA as well as their biological activity. Findings indicate that ionic liquids significantly increase the substitution activity of these complexes toward 5'-GMP while only marginally affecting DNA/HSA binding affinities with molecular docking, further confirming the experimental results. Lipophilicity assessments indicated good lipophilicity. Notably, cytotoxicity studies show that Rh2 is selectively effective against HeLa cancer cells, with IL1 and IL10 modulating the cytotoxic effects. Redox evaluations indicate that rhodium complexes induce oxidative stress in cancerous cells while maintaining redox balance in noncancerous cells. By elucidating the role of ionic liquids in modulating these effects, the study proposes a promising avenue for augmenting the efficacy and selectivity of cancer treatments, thus opening new horizons in cancer therapeutics.

A series of mono- and heteronuclear platinum(II) and zinc(II) complexes with 4,4',4″-tri- tert -butyl-2,2':6',2″-terpyridine ligand were synthesized and characterized. The DNA and protein binding properties of [ZnCl 2 (terpy t Bu )] ( C1 ), [{ cis -PtCl(NH 3 ) 2 ( μ -pyrazine)ZnCl(terpy t Bu )}](ClO 4 ) 2 ( C2 ), [{ trans -PtCl(NH 3 ) 2 ( μ -pyrazine)ZnCl(terpy t Bu )}](ClO 4 ) 2 ( C3 ), [{ cis -PtCl(NH 3 ) 2 ( μ -4,4'-bipyridyl)ZnCl(terpy t Bu )}](CIO 4 ) 2 ( C4 ) and [{ trans -PtCl(NH 3 ) 2 ( μ -4,4'-bipyridyl)ZnCl(terpy t Bu )}](CIO 4 ) 2 ( C5 ) (where terpy t Bu = 4,4',4″-tri- tert -butyl-2,2':6',2″-terpyridine), were investigated by electronic absorption, fluorescence spectroscopic, and molecular docking methods. Complexes featuring transplatin exhibited lower K b and K sv constant values compared to cisplatin analogs. The lowest K sv value belonged to complex C1, while C4 exhibited the highest. Molecular docking studies reveal that the binding of complex C1 to DNA is due to van der Waals forces, while that of C2 - C5 is due to conventional hydrogen bonds and van der Waals forces. The tested complexes exhibited variable cytotoxicity toward mouse colorectal carcinoma (CT26), human colorectal carcinoma (HCT116 and SW480), and non-cancerous mouse mesenchymal stem cells (mMSC). Particularly, the mononuclear C1 complex showed pronounced selectivity toward cancer cells over non-cancerous mMSC. The C1 complex notably induced apoptosis in CT26 cells, effectively arrested the cell cycle in the G0/G1 phase, and selectively down-regulated Cyclin D.

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5'-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1β, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.

Four new complexes of copper(II) with S,O-tetradentate ligands, derivatives of thiosalicylic acid, encompassing an ethylene-, propylene-, butylene- and pentylene- bridge, were synthesized and characterized by microanalysis, molecular conductance and infrared (IR) spectra. The structures were assumed based on the previously mentioned analyses and confirmed with the results of electron paramagnetic resonance (EPR) spectra. The reactivity of complexes towards L-methionine (L-Met), L-cysteine (L-Cys) and guanosine-5'-monophosphate (5'-GMP) was also examined. Complex C1 ([Cu(S,O-ethylene-thiosalicylic acid)(H 2 O) 2 ]) containing two inert methylene groups in the side chain of ligand shows the highest reactivity, while the least reactive is complex C4 ([Cu(S,O-pentylene-thiosalicylic acid)(H 2 O) 2 ]) with five methylene groups. All complexes showed the highest reactivity towards L-Met and the lowest reactivity towards 5'-GMP. The interactions of complexes C1-C4 with calf thymus DNA (ct-DNA) were examined by ultraviolet-visible (UV-Vis) absorption and fluorescence spectral studies, revealing good DNA interaction abilities. All synthesized complexes C1-C4 show to interact with human serum albumin (HSA) with high values of binding constants. Complexes interaction with DNA/HSA was also confirmed using molecular docking simulations. All synthesized complexes reduce viability of human colon, breast and lung cancer cells, evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric technique. The complex [Cu(S,O-pentylene- thiosalicylic acid)(H 2 O) 2 ] showed the highest binding affinity constants to DNA/HSA and highest cytotoxicity, thus presenting a good candidate for further pharmacological research in the field of colon, breast and lung cancer therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to RNA transcripts and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization driven, whereas differential expression events are more common and driven by other mechanisms (including spurious experimental variation). We further evaluated the performance of in silico screens for off-target splicing events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate (FDR) of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR of 90%. Despite these large improvements in performance, this approach does not detect the majority of events at an FDR <99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs, and experimental screening by RNA-seq should be the preferred approach.

Background: Over the years, transition metal complexes have exhibited significant antimicrobial and antitumor activity. It all started with cisplatin discovery, but due to the large number of side effects it shows, there is a growing need to find a new metal-based compound with higher selectivity and activity on more tumors., Objectives: Two novel trans-palladium(II) complexes with organoselenium compounds as ligands, [Pd(L1) 2 Cl 2 ] (L1 = 5-(phenylselanylmethyl)-dihydrofuran-2(3H)-one) and [Pd(L2) 2 Cl 2 ] (L2 = 2- methyl-5-(phenylselanylmethyl)- tetrahydrofuran) were synthesized, in the text referred to as Pd-Se1 and Pd-Se2. Also, a structurally similar trans-palladium(II) complex, [Pd(L3) 2 Cl 2 ] (L3= 2,2- dimethyl-3-(phenylselanylmethyl)-tetrahydro-2H-pyran) was synthesized according to an already published work and is referred to as Pd-Se3. The interaction of synthesized complexes with DNA and bovine serum albumin was observed. Also, antimicrobial activity and in vitro testing, cell viability, and cytotoxic effects of synthesized ligands and complexes on human epithelial colorectal cancer cell line HCT-116 were studied. Molecular docking simulations were performed to understand better the binding modes of the complexes reported in this paper with DNA and BSA, as well as to comprehend their antimicrobial activity., Methods: The interactions of the synthesized complexes with DNA and bovine serum albumin were done using UV-Vis and emission spectral studies as well as docking studies. Antimicrobial activity was tested by determining the minimum inhibitory concentrations (MIC) and minimum microbicidal concentration (MMC) using the resazurin microdilution plate method. Cytotoxic activity on cancer cells was studied by MTT test., Results: The Pd(II) complexes showed a significant binding affinity for calf thymus DNA and bovine serum albumin by UV-Vis and emission spectral studies. The intensity of antimicrobial activity varied with the complexes Pd-Se1 and Pd-Se3, showing significantly higher activity than the corresponding ligand. The most significant activity was shown on Pseudomonas aeruginosa. Under standardized laboratory conditions for in vitro testing, cell viability and cytotoxic effects of synthesized ligands and complexes were studied on human epithelial colorectal cancer cell line HCT-116, where Pd-Se2 showed some significant cytotoxic effects., Conclusion: The newly synthesized complexes have the potential to be further investigated as metallodrugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The synthesis and structural characterization of a newly synthesized mononuclear rhodium(iii) complex, Rhtrz, with a ligand (2,2,6-bis((4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine) and a ligand of 1,2,4-triazole, are presented in this paper. The kinetic interactions of the Rhtrz complex with essential biomolecules such as 5-GMP, L-Met, and GSH were examined. The study of the biological interactions was focused on the binding properties of the Rhtrz complex with CT-DNA and serum albumin. These interactions were investigated using UV-vis spectrophotometry, fluorescence spectroscopy, viscosity measurements, thermal denaturation studies, and electrophoresis. Fluorescence competition experiments with site-markers for BSA were used to locate the binding site of the Rhtrz-complex to the BSA. Molecular docking studies were carried out to obtain detailed binding information of the complex with CT-DNA, BSA, and HSA. Furthermore, the apparent distance between the donor (HSA) and acceptor (Rhtrz) was determined using fluorescence resonance energy transfer (FRET). The thermodynamic properties and relative stabilities of the Rhtrz complex were examined, constructing the two model equation by DFT calculations (B3LYP(CPCM)/LANL2DZp). In vitro cytotoxicity and redox status on the human epithelial colorectal cancer cell line (HCT-116) and healthy human fibroblast cell line (MRC-5) were also investigated.

Two novel rhodium(III) complexes, namely, [Rh III (X)Cl 3 ] (X = 2 2,6-bis((4 S,7 R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine or 2,6-bis((4 S,7 R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine), were synthesized from camphor derivatives of a bis(pyrazolylpyridine), tridentate nitrogen-donor chelate system, giving [Rh III (H 2 L*)Cl 3 ] (1a) and [Rh III (Me 2 L*)Cl 3 ] (1b). A rhodium(III) terpyridine (terpy) ligand complex, [Rh III (terpy)Cl 3 ] (1c), was also synthesized. By single-crystal X-ray analysis, 1b crystallizes in an orthorhombic P2 1 2 1 2 1 system, with two molecules in the asymmetric unit. Tridentate coordination by the N,N,N-donor localizes the central nitrogen atom close to the rhodium(III) center. Compounds 1a and 1b were reactive toward l-methionine (l-Met), guanosine-5'-monophosphate (5'-GMP), and glutathione (GSH), with an order of reactivity of 5'-GMP > GSH > l-Met. The order of reactivity of the Rh III complexes was: 1b> 1a > 1c. The Rh III complexes showed affinity for calf thymus DNA and bovine serum albumin by UV-vis and emission spectral studies. Furthermore, 1b showed significant in vitro cytotoxicity against human epithelial colorectal carcinoma cells. Since the Rh III complexes have similar coordination modes, stability differences were evaluated by density functional theory (DFT) calculations (B3LYP(CPCM)/LANL2DZp). With (H 2 L*) and (terpy) as model ligands, DFT calculations suggest that both tridentate ligand systems have similar stability. In addition, molecular docking suggests that all test compounds have affinity for the minor groove of DNA, while 1b and 1c have potential for DNA intercalation.

Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands i.e. [Pd(DMEAIm iPr )Cl 2 ] (1) (DMEAIm iPr , 2-(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine), [Pd(DACH(Im iPr) 2 )Cl 2 ] (2) (DACH(Im iPr) 2 , N,N'-(cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)) and [Pt(DMEAIm iPr )Cl 2 ] (3), are evaluated here as potential cytotoxic and anticancer agents. An acceptable solution behaviour was found for the three study compounds in terms of solubility and stability. Notably, the three metal complexes demonstrated moderate to high cytotoxic properties in selected cancer cell lines (liquid and solid tumor). To gain deeper mechanistic insight, the reactivity of the study complexes with model DNA oligos and protein molecules was investigated through spectrometric and spectroscopic methods; in both cases adduct formation was clearly documented by ESI-MS measurements. The binding of these metal complexes to calf thymus DNA (CT-DNA) was further examined by absorption (UV-Vis) and emission spectral studies (Ethidium bromide displacement studies, EtBr). Overall, the studied complexes 1-3 exhibited a remarkable DNA binding ability that might be linked to the observed cytotoxic effects. Interestingly our results revealed that DNA binding, as well as anticancer activity of 1-3 follows the order 2>3>1. The implications of these findings are discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A series of novel Pd(ii) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands were synthesized. The crystal structures of [Pd(DMEAIm(iPr))Cl2] and [Pd(DPENIm(iPr))Cl2] were determined by X-ray diffraction analysis. The reactivity of the six Pd(ii) complexes, namely, [Pd(en)Cl2], [Pd(EAIm(iPr))Cl2], [Pd(DMEAIm(iPr))Cl2], [Pd(DPENIm(iPr))Cl2], [Pd(BL(iPr))Cl2] and [Pd(DACH(Im(iPr))2)Cl2], were investigated. Spectrophotometric acid-base titrations were performed to determine the pKa values of the coordinated water molecules in [Pd(en)(H2O)2](2+), [Pd(EAIm(iPr))(H2O)2](2+), [Pd(DMEAIm(iPr))(H2O)2](2+), [Pd(DPENIm(iPr))(H2O)2](2+), [Pd(BL(iPr))(H2O)2](2+) and [Pd(DACH(Im(iPr))2)(H2O)2](2+). The substitution of the chloride ligands in these complexes by TU, l-Met, l-His and Gly was studied under pseudo-first-order conditions as a function of the nucleophile concentration and temperature using stopped-flow techniques; the sulfur-donor nucleophiles have shown better reactivity than nitrogen-donor nucleophiles. The obtained results indicate that there is a clear correlation between the nature of the imidazolin-2-imine ligands and the acid-base characteristics and reactivity of the resulting Pd(ii) complexes; the order of reactivity of the investigated Pd(ii) complexes is: [Pd(en)Cl2] > [Pd(EAIm(iPr))Cl2] > [Pd(DMEAIm(iPr))Cl2] > [Pd(DPENIm(iPr))Cl2] > [Pd(BL(iPr))Cl2] > [Pd(DACH(Im(iPr))2)Cl2]. The solubility measurements revealed good solubility of the studied imidazolin-2-imine complexes in water, despite the fact that these Pd(ii) complexes are neutral complexes. Based on the performed studies, three unusual features of the novel imidazolin-2-imine Pd(ii) complexes are observed, that is, good solubility in water, very low reactivity and high pKa values. The coordination geometries around the palladium atoms are distorted square-planar; the [Pd(DMEAIm(iPr))Cl2] complex displays Pd-N distances of 2.013(2) and 2.076(2) Å, while the [Pd(DPENIm(iPr))Cl2] complex displays similar Pd-N distances of 2.034(4) and 2.038(3) Å. The studied systems are of interest because little is known about the substitution behavior of imidazolin-2-imine Pd(ii) complexes with bio-molecules under physiological conditions.

A brief overview of mechanistic studies on the reactions of different Pt(II) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for substitution reactions of mono-functional Pt(II) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(II) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(II) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(II) complexes as potential anti-tumour drugs in the human body.

The kinetics and the mechanism of the substitution reactions of the complex [(TL(tBu))PdCl](+), where TL(tBu) is 2,6-bis[(1,3-di-tert-butylimidazolin-2-imino)methyl]pyridine, with nucleophiles (guanosine-5'-monophosphate (5'-GMP), l-Methionine (l-Met) and l-Histidine (l-His)) were studied using variable-temperature stopped-flow techniques in aqueous 0.1 M NaClO(4) with 10 mM NaCl at 298 K. The order of reactivity is: l-Met > 5'-GMP > l-His. The formation equilibria of [(BL(iPr))Pd(H(2)O)(2)](2+), where BL(iPr) is 1,2-bis(1,3diisopropyl-4,5-dimethylimidazolin-2-imino)ethane, and [(TL(tBu))Pd(H(2)O)](2+) with some biologically relevant ligands (l-Met, 5'-GMP and l-His) were also studied. The stoichiometry and stability constants of the newly formed complexes are reported, and the concentration distribution of the various complex species has been evaluated as a function of pH. Comparing the values of logβ(1,1,0) for 5'-GMP, l-His and l-Met complexes, the most stable complex is with 5'-GMP followed by l-His and l-Met for both complexes, [(BL(iPr))Pd(H(2)O)(2)](2+) and [(TL(tBu))Pd(H(2)O)](2+). The crystal structures of [(TL(tBu))PdCl]ClO(4) and [(BL(iPr))PdCl(2)] were determined by X-ray diffraction. The coordination geometries around the palladium atoms are distorted square-planar, with the Pd-N1 distance to the central nitrogen atom of the TL(tBu) ligand, 1.944(2) Å, being shorter than those to the other two nitrogen atoms of TL(tBu), viz. 2.034(3) and 2.038(2) Å. The BL(iPr) complex displays similar Pd-N distances of 2.031(2) and 2.047(2) Å., (This journal is © The Royal Society of Chemistry 2011)