DNA Intercalating Research Articles

The Intercalator Ethidium Bromide Generates Covalent Adducts at Apurinic/Apyrimidinic Sites in DNA.

Ethidium bromide was first described as a DNA intercalator 60 years ago and, over the ensuing years, may be the most widely used fluorescent DNA stain in molecular biology, biochemistry, and histology. Noncovalent DNA binding by ethidium has been well characterized, but to date, there have been no reports of covalent DNA adduct formation by ethidium bromide. This report describes the characterization of covalent adducts generated by the reaction of ethidium with apurinic/apyrimidinic (AP) sites in DNA. Adduct formation proceeds via the reaction of the amino group(s) on ethidium with the ring-opened aldehyde residue of the AP site in DNA to yield an imine. Ethidium-AP adducts may form under a variety of circumstances due to the ubiquitous occurrence of AP sites in cellular and synthetic DNA.

An enzyme-responsive double-locked amonafide prodrug for the treatment of glioblastoma with minimal side effects.

Amonafide (ANF), a topoisomerase II inhibitor and DNA intercalator, has exhibited promise in phase II trials but faces significant limitations due to adverse side effects. Here, we have developed a novel enzyme-triggered fluorogenic prodrug, AcKLP, that incorporates dual-locked enzyme activation, ensuring that the prodrug remains inactive until it confronts the unique enzymatic environment of glioblastoma cells. This approach minimizes premature activation and reduces toxicity to normal cells, with an IC50 > 100 μM for human umbilical vein endothelial cells (HUVEC) and ∼2.3 μM for human glioblastoma cells (U87). Upon activation of AcKLP by two distinct enzymes prevalent in glioblastoma cells, amonafide is released and emits a fluorescence signal response, facilitating treatment and the monitoring of real-time drug distribution. Mechanistic studies indicate that AcKLP mainly induces autophagic cell death in U87 cells. Moreover, three-dimensional multicellular U87 tumor spheroid assays and in vivo experiments confirm the potent antiproliferative activity of AcKLP against glioblastoma cells. This work demonstrates a novel de-caging strategy to improve the selectivity and efficacy of amonafide for cancer therapy.

Antiproliferative Activity of Cephalotaxus Esters: Overcoming Chemoresistance.

Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1). In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells. Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via caspase 3 cleavage, leading to apoptosis. Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

The arylbipyridine platinum (II) complex increases the level of ROS and induces lipid peroxidation in glioblastoma cells.

Here we present the biological properties of the arylbipyridine platinum (II) complex (arylbipy-Pt) and describe the potential mechanism of its antitumor action which differs from that of the well-known cisplatin. Leading to the oxidative stress and lipid peroxidation, the arylbipyridine platinum (II) complex showcases the significant cytotoxicity against the glioblastoma cells as shown by the MTT test. Using the 5-ethyl-2-deoxyuridine we study the proliferative activity of glioblastoma cells to affirm that arylbipyridine platinum (II) complex does not impede cell division or DNA replication. Staining by the MitoCLox dye and 2',7'-dichlorodihydrofluorescein diacetate demonstrates that the glioblastoma cells treated with arylbipy-Pt exhibit a strong increase of the lipid peroxidation and the stimulation of the reactive oxygen species formation. The hypothesis that arylbipy-Pt promotes oxidative death of tumor cells is confirmed by control experiments using N-acetyl-L-cysteine as an antioxidant. Further evidence for the oxidative mechanism of action is provided by real-time PCR, which shows high expression levels for genes associated with the heat shock proteins HSP27 and HSP70, which can be used as markers of tumor cell ferroptosis. To elucidate the chemical nature of the arylbipy-Pt complex activity, we perform 195Pt NMR spectroscopy and cyclic voltammetry measurements under biologically relevant conditions. The results obtained clearly indicate the structural transformation of the arylbipy-Pt complex in the DMSO-saline mixture, which is crucial for its further antitumor activity via the oxidative pathway. The found correlation between the molecular structure of arylbipy-Pt and its effect on the tumor cell cycle paves the way for the rational design of Pt complexes possessing the alternative mechanism of antitumor activity as compared to DNA intercalation, providing possible solutions to the major problems such as toxicity and drug resistance.

8-Hydroxyquinoline Series Exerts Bactericidal Activity against Mycobacterium tuberculosis Via Copper-Mediated Toxicity.

New drugs and mechanisms of action targeting Mycobacterium tuberculosis are urgently needed to solve the global pandemic of tuberculosis. We previously demonstrated that the 8-hydroxyquinoline series has rapid bactericidal activity against M. tuberculosis. In this work, we determined that the activity of the 8HQ series is potentiated by copper ions and that the activity is dependent on copper since activity was reduced when copper was depleted from the medium. We determined that exposure to 8HQs led to an increase in intracellular copper. The increase in copper ions was specific since we saw no changes for other metal cations (zinc, iron, magnesium, manganese, or calcium). We observed the transient generation of reactive oxygen species after 8HQ exposure which disappeared by 24 h. Inhibition of growth could be partially relieved by scavenging hydroxyl radicals. We excluded the possibility that 8HQs are toxic by DNA intercalation. We screened a panel of hypomorph strains and identified sensitized strains. The pattern of sensitized strains did not suggest a specific target, but metalloenzymes, proteins with Fe-S clusters, and cell envelope biosynthetic enzymes were highlighted. These data suggest that 8HQs do not have a specific intracellular target, but act as copper ionophores, and that the mode of action is via copper-dependent toxicity.

Synthesis, cytotoxicity, docking, MD simulation, drug-likeness, ADMET prediction and multi spectroscopic studies of some novel quinoline-4-carboxamide derivatives as DNA intercalating and anticancer agents

In this study, some new quinoline-carboxamide derivatives possessing a flexible (dimethylamino) ethylcarboxamide side chain were synthesized as DNA intercalating agents. Synthesized compounds displayed potent cytotoxic activities against three human cancer cell lines including colorectal adenocarcinoma cancer cells (HT-29), breast cancer cells (MCF-7) and lung cancer cells (A549). Compound 3d showed promisingantiproliferative activity (IC50= 3.97 to 6.67 µM) against cancer cells. The simplest compound (compound 3a) without substitution displayed the weakest cytotoxic effects ranging from 24.6 to 42.3 μM. The interaction of the most cytotoxic compound 3d with calf thymus DNA (ctDNA) was evaluated by fluorescence, UV absorption, resonance light scattering (RLS), melting studies, viscosity measurements, circular dichroism (CD) spectroscopy, molecular docking and molecular dynamic (MD). Generally, studies displayed a combined quenching via intercalating binding mode of compound 3d to ctDNA.

Cobaltabis(dicarbollide) Interaction with DNA Resolved at the Atomic Scale.

Boron neutron capture therapy represents a promising avenue for cancer treatment that requires nontoxic drugs with a high boron content efficiently distributed into cancerous cells. The metallacarborane o-cobaltabis(dicarbollide) ([COSAN]-) fulfills these requirements and constitutes an attractive candidate. Nevertheless, the interaction of this promising drug with nucleic acids, the assumed target of the biological damage, is poorly understood since contradictory results are reported in the literature. This work establishes the DNA/[COSAN]- interaction strength, mechanism, and time scale at the atomistic level by using a combination of microsecond-molecular dynamics and hybrid quantum mechanics/molecular mechanics simulations and by quantifying the absolute binding free energy. Results show that the DNA/[COSAN]- interaction is highly dependent on the ionic strength of the medium. A relatively weak DNA major groove binding (ΔGbind= -2.49 kcal/mol) driven mostly by dihydrogen B-H···H-N bonding is observed in the simulations only at a high NaCl concentration, whereas DNA intercalation mode is deemed highly unlikely.

2-Ferrocene-4-amine-1H-benzo[d]imidazole and their derivatives: Synthesis, biological and docking study

An organometallic series based on 2-ferrocene-4-amine-1H-benzo[d]imidazole derivative has been synthesized and characterized through FTIR, H/CNMR, and LCMS. Their antimicrobial activity was assessed by testing them against B. subtills, Staphylococcus aureus, E. faecalis, S. marcescens, E. coli, K. pneumoniae, C. albicans, A. niger, Mucor sp. where they showed good zone of inhibition (ZOI) as compared to standards. The cytotoxicity of synthesized compounds was tested against Hela (cervical) and MCF-7 (breast) cancer cell lines where compound 5a and 5b displayed equivalent potency to the standard while 5e demonstrated highest cytotoxicity against both cell lines. Their comparative docking analysis with DNA suggested that docking score of 5e was −7.4 kcal/mol versus −6 kcal/mol of ethidium bromide, indicating that our designed compound acts via DNA intercalation.

Quinoline-based compounds can inhibit diverse enzymes that act on DNA.

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a key epigenetic process. Developing non-nucleoside inhibitors to cause DNA hypomethylation is crucial for treating various conditions without the toxicities associated with existing cytidine-based hypomethylating agents. This study characterized fifteen quinoline-based analogs, particularly compounds with additions like a methylamine (9) or methylpiperazine (11), which demonstrate similar low micromolar inhibitory potency against human DNMT1 and Clostridioides difficile CamA. These compounds (9 and 11) intercalate into CamA-bound DNA via the minor groove, causing a conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation. Additionally, some quinoline-based analogs inhibit other DNA-interacting enzymes, such as polymerases and base excision repair glycosylases. Finally, compound 11 elicits DNA damage response via p53 activation in cancer cells.

DNA-Intercalating Supramolecular Hydrogels for Tunable Thermal and Viscoelastic Properties.

Polymeric supramolecular hydrogels (PSHs) leverage the thermodynamic and kinetic properties of non-covalent interactions between polymer chains to govern their structural characteristics. As these materials are formed via endothermic or exothermic equilibria, their thermal response is challenging to control without drastically changing the nature of the chemistry used to join them. In this study, we introduce a novel class of PSHs utilizing the intercalation of double-stranded DNA (dsDNA) as the primary dynamic non-covalent interaction. The resulting dsDNA intercalating supramolecular hydrogels (DISHs) can be tuned to exhibit both endothermically or exothermically driven binding through strategic selection of intercalators. Bifunctional polyethylene glycol (MW~2000 Da) capped with intercalators of varying hydrophobicity, charge, and size (acridine, psoralen, thiazole orange, and phenanthridine) produced DISHs with comparable moduli (500-1000 Pa), but unique thermal viscoelastic responses. Notably, acridine-based cross-linkers displayed invariant and even increasing relaxation times with temperature, suggesting an endothermic binding mechanism. This methodology expands the set of structure-properties available to biomass-derived DNA biomaterials and promises a new material system where a broad set of thermal and viscoelastic responses can be obtained due to the sheer number and variety of intercalating molecules.

Enantioselectively generating imidazolone dIz by the chiral DNA intercalating and “light-switching” Ru(II) polypyridyl complex via a novel flash-quench method

The 2-aminoimidazolone is a major and ubiquitous in vitro product of guanine oxidation. The flash-quench method, combining spectroscopy and product analysis, offers a novel and tunable approach to study guanine oxidation on double helical DNA. Herein we found that imidazolone dIz (2-amino-5-[(2-deoxy-β-D-erythro-pentofuranosyl)amino]-4H-imidazole-4-one) and dZ (2,2-diamino-5-[2-deoxy-β-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone) were the major oxidation products of double-strand DNA from the visible-light irradiation of the well-known DNA intercalating and light-switching Ru(OP)2dppz2+ (OP = 1,10-phenanthroline, dppz = dipyrido [3,2-a:2′,3′-c]phenazine) in the presence of a typical quencher methyl viologen (MV2+). Using ESR spin-trapping method, the radical intermediate MV•+ with typical hyperfine pattern was detected which indicated the successful formation of the corresponding Ru3+ intercalated oxidant. The formation of dIz and dZ decreased markedly with the addition of nitrotetrazolium blue chloride (NBT), a typical O2•- reactant. With a more specific and highly sensitive O2•- probe CT02-H, its ESR signal decayed rapidly in the presence of Ru(OP)2dppz2+ and MV2+, suggesting that O2•- was indeed produced. More interestingly, enantio-selective generation of oxidation products from dsDNA was observed with the two chiral forms of Ru(OP)2dppz2+. This represents the first report that the flash-quench technique with MV2+ as the quencher can oxidize dsDNA effectively to form dIz and dZ via the Ru3+/O2•- mediated mechanism. Our new findings provide a novel method to generate two radicals simultaneously, G (-H)• and O2•-, in close proximity to one another in dsDNA.

The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer

The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.

Photostimulated Anticancer Activity of Mitochondria Localized Rhenium(I) Tricarbonyl Complexes Bearing 1H-imidazo[4,5-f][1,10]phenanthroline Ligands Against MDA-MB-231 Cancer Cells.

We have introduced Re(I) tricarbonyl complexes (ReL1 - ReL6) [Re(CO)3(N^N)Cl] where N^N = extensive π conjugated imidazo-[4,5-f]1,10-phenanthroline derivatives that helps in strong DNA intercalation, enhanced photophysical behavior, increase the 3π-π* character of T1 state for PDT and high value of lipophilicity for cell membrane penetration. These complexes exhibited prominent intraligand/ligand-centered (π - π*/ 1LC) absorption bands at λ 260 - 350 nm and relatively weak metal-to-ligand charge-transfer (1MLCT) bands within the λ 350 - 550 nm range. Among the six synthesized complexes, [(CO)3ReICl(K2-N,N-2-(4-(1-benzyl-1H-tetrazol-5-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline] (ReL6) exhibited outstanding potency (IC50 ~ 6 µM, PI > 9) under yellow light irradiation compared to dark conditions. Importantly, extremely lipophilic complex ReL6 showed effective penetration through the cell membrane and localized primarily in mitochondria (Pearson's correlation coefficient, PCC = 0.918) of MDA-MB-231 cells. Complex ReL6 exhibited more than 9 times higher photo-toxicity in normoxic and hypoxic environment of tumor by inducing 1O2 generation (type II PDT), radical generation triggered by NADH oxidation (type I PDT). This complex is a promising candidate for TNBC treatment in hypoxic tumors, with efficacy comparable to photofrin and have demonstrated CO release ability under UV light irradiation.

Novel platinum therapeutics induce rapid cancer cell death through triggering intracellular ROS storm

Induction of reactive oxygen species (ROS) production in cancer cells plays a critical role for cancer treatment. However, therapeutic efficiency remains challenging due to insufficient ROS production of current ROS inducers. We designed a novel platinum (Pt)-based drug named “carrier-platin” that integrates ultrasmall Pt-based nanoparticles uniformly confined within a poly(amino acids) carrier. Carrier-platin dramatically triggered a burst of ROS in cancer cells, leading to cancer cell death as quick as 30 min. Unlike traditional Pt-based drugs which induce cell apoptosis through DNA intercalation, carrier-platin with superior ROS catalytic activities induces a unique pattern of cancer cell death that is neither apoptosis nor ferroptosis and operates independently of DNA damage. Importantly, carrier-platin demonstrates superior anti-tumor efficacy against a broad spectrum of cancers, particularly those with multidrug resistance, while maintaining minimal systemic toxicity. Our findings reveal a distinct mechanism of action of Pt in cancer cell eradication, positioning carrier-platin as a novel category of anti-cancer chemotherapeutics.

Exploring the antibiofilm potential of chitosan nanoparticles by functional modification with chloroquine and deoxyribonuclease

Planktonic bacteria tend to form sessile community architectures to shield resident bacteria from various environmental stresses. The formed biofilm leads to the failure of conventional antimicrobial therapy. Extracellular macromolecules, including extracellular DNA (eDNA), proteins, lipids, and polysaccharides, crosslink into gel-like structures through electrostatic forces in the mature biofilm matrix. The stereo-structural integrity and chemical inertia of the extracellular polymeric matrix result in comprehensive antimicrobial resistance to antibacterial polysaccharides. Herein, an ionic gelation method was employed to functionalize cationic chitosan nanoparticles (CSNPs) with chloroquine and deoxyribonuclease. The modification involved shifting eDNA chirality through a DNA-intercalating agent, chloroquine, and hydrolyzing an eDNA scaffold with deoxyribonuclease. The antibiofilm activity was assessed against a standard Staphylococcus aureus strain and clinical subtype isolates. Functional modifications targeting eDNA improved the chitosan anti-biofilm efficiency (residual biomass decreased from 74.2 to 90.3 % to 16.7–24.6 %) by disrupting the biofilm matrix. The functional CSNPs worked as a sensitizer prodrug, contributing to a bactericidal process of chitosan itself (cell wall damage increased from 11.38–18.16 % to 55.2–61.4 %) by dispersing the biofilm-enclosed bacteria. In vivo, the bacterial burden of infected mouse joints was reduced by 4.1 lg CFU/mL. Our results indicate the potential of this chitosan-based anti-infection strategy in biofilm-related infections.

Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells.

The phenotypic plasticity of cancer cells has recently emerged as an important factor of treatment failure. The mechanisms of phenotypic plasticity are not fully understood. One of the hypotheses is that the degree of chromatin accessibility defines the easiness of cell transitions between different phenotypes. To test this, a method to compare overall chromatin accessibility between cells in a population or between cell populations is needed. We propose to measure chromatin accessibility by fluorescence signal from nuclei of cells stained with DNA binding fluorescent molecules. This method is based on the observations that small molecules bind nucleosome-free DNA more easily than nucleosomal DNA. Thus, nuclear fluorescence is proportional to the amount of nucleosome-free DNA, serving as a measure of chromatin accessibility. We optimized the method using several DNA intercalators and minor groove binders and known chromatin-modulating agents and demonstrated that chromatin accessibility is increased upon oncogene-induced transformation and further in tumor cells.

Force-enhanced sensitive and specific detection of DNA-intercalative agents directly from microorganisms at single-molecule level.

Microorganisms can produce a vast array of bioactive secondary metabolites, including DNA-intercalating agents like actinomycin D, doxorubicin, which hold great potential for cancer chemotherapy. However, discovering novel DNA-intercalating compounds remains challenging due to the limited sensitivity and specificity of conventional activity assays, which require large-scale fermentation and purification. Here, we introduced the single-molecule stretching assay (SMSA) directly to microbial cultures or extracts for discovering DNA-intercalating agents, even in trace amounts of microbial cultures (5 μl). We showed that the unique changes of dsDNA incontour length and overstretching transition enable thespecific detection of intercalators from complex samples without the need forextensive purification. Applying force to dsDNA also enhanced the sensitivity by increasing both the binding affinity Ka and the quantity of ligands intercalation, thus allowing thedetection of weak intercalators, which are often overlooked using traditional methods. We demonstrated the effectiveness of SMSA,identified two DNA intercalator-producing strains: Streptomyces tanashiensis and Talaromyces funiculosus, and isolated three DNA intercalators: medermycin, kalafungin and ligustrone B. Interestingly, both medermycin and kalafungin, classified as weak DNA intercalators (Ka ∼103 M-1), exhibited potent anti-cancer activity against HCT-116 cancer cells, with IC50 values of 52±6and 70±7 nM, respectively.

DNA Damage-Inducing 10-Methoxy-canthin-6-one (Mtx-C) Promotes Cell Cycle Arrest in G2/M and Myeloid Differentiation of Acute Myeloid Leukemias and Leukemic Stem Cells.

Synthetic 10-methoxy-canthin-6-one (Mtx-C), an alkaloid derivative, exhibits cytotoxic effects against acute myeloid cells (AMLs) and leukemic stem cells (LSCs) at a concentration of approximately 60 μM. However, the antitumor mechanism of Mtx-C in AMLs and LSCs remains elusive. Using Mtx-C at concentrations with low cytotoxicity (2-4 μM) for 72 h, we observed cell arrest with the accumulation of cells in the G2/M phase of the cell cycle. This effect was controlled by cyclin B1 expression and induction of the DNA damage cascade characterized by ATM, ATR, Chk1/2, p53, and H2A.X phosphorylation. Molecular docking analysis confirmed Mtx-C as a DNA intercalator. Moreover, the expression of inhibitors of cyclin-dependent kinases, including p21 (Cip1) and p27 (Kip1), increased. In addition, several miRNAs that are considered oncosuppressors were regulated by Mtx-C in Kasumi-1 cells. Finally, concomitant with cell cycle arrest, the underlying molecular mechanisms of Mtx-C in AML cells include myeloid differentiation, as evidenced by the increased expression of PU.1, myeloperoxidase, CD15, CD11b, and CD14 in the AML and LSC populations with the participation of p38 mitogen-activated protein kinase. Thus, we showed that Mtx-C simultaneously induced cell cycle arrest and myeloid differentiation in AML lineages and in the LSC population, providing insights into new therapeutic alternatives for the treatment of AML based on naturally occurring molecules.

Biomolecular Interactions and Anticancer Mechanisms of Ru(II)-Arene Complexes of Cinnamaldehyde-Derived Thiosemicarbazone Ligands: Analysis Combining In Silico and In Vitro Approaches.

Our study focuses on synthesizing and exploring the potential of three N-(4) substituted thiosemicarbazones derived from cinnamic aldehyde, alongside their Ru(II)-(η6 -p-cymene)/(η6-benzene) complexes. The synthesized compounds were comprehensively characterized using a range of analytical techniques, including FT-IR, UV-visible spectroscopy, NMR (1H, 13C), and HRMS. We investigated their electronic and physicochemical properties via density functional theory (DFT). X-ray crystal structures validated structural differences identified by DFT. Molecular docking predicted promising bioactivities, supported by experimental observations. Notably, docking with EGFR suggested an inhibitory potential against this cancer-related protein. Spectroscopic titrations revealed significant DNA/BSA binding affinities, particularly with DNA intercalation and BSA hydrophobic interactions. RuPCAM displayed the strongest binding affinity with DNA (Kb = 6.23 × 107 M-1) and BSA (Kb = 9.75 × 105 M-1). Assessed the cytotoxicity of the complexes on cervical cancer cells (HeLa), and breast cancer cells (MCF-7 and MDA-MB 231), revealing remarkable potency. Additionally, selectivity was assessed by examining MCF-10a normal cell lines. The active complexes were found to trigger apoptosis, a vital cellular process crucial for evaluating their potential as anticancer agents utilizing staining assays and flow cytometry analysis. Intriguingly, complexation with Ru(II)-arene precursors significantly amplified the bioactivity of thiosemicarbazones, unveiling promising avenues toward the creation of powerful anticancer agents.

Benzoquinone Ligand-Enabled Ruthenium-Catalyzed Deaminative Coupling of 2-Aminoaryl Aldehydes and Ketones with Branched Amines for Regioselective Synthesis of Quinoline Derivatives.

The catalytic system generated in situ from the cationic Ru-H complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1) with 2,3,4,5-tetrachloro-1,2-benzoquinone (L1) was found to be highly effective for promoting the deaminative coupling reaction of 2-aminoaryl aldehydes with branched amines to form 2-substituted quinoline products. The analogous deaminative coupling reaction of 2-aminoaryl ketones with branched amines led to the regioselective formation of 2,4-disubstituted quinoline products. A number of biologically active quinoline derivatives including graveolinine and a triplex DNA intercalator have been synthesized by using the catalytic method.