Search Results (196)

The search for new anticancer agents with improved efficacy and reduced toxicity has intensified interest in metal-based compounds. In this study, two novel palladium(II) complexes, synthesized from Schiff base ligands derived from 5-chloro-salicylaldehyde and p-hydroxybenzylamine or tyramine, were chemically characterized and biologically evaluated. Both complexes exhibited significant cytotoxic activity against the MCF-7 breast cancer cell line in a dose- and time-dependent manner, with Pd2 showing slightly higher potency. Morphological analysis of treated cells indicated that apoptosis is the predominant mechanism of cell death. To gain deeper insight into the potential mechanisms underlying the observed anticancer activity, several biologically relevant targets were investigated. Enzyme kinetics revealed that the complexes act as uncompetitive inhibitors of liver catalase, suggesting a possible role in the induction of oxidative stress. Fluorescence studies demonstrated that Pd2 interacts with CT-DNA through combined intercalative and minor groove binding modes and exhibits significant binding affinity toward human serum albumin, predominantly at Sudlow’s site I. Molecular docking analysis further supported favorable interactions with catalase, estrogen receptor α, and B-form DNA, providing structural insight into the experimentally observed biological effects. Overall, the study explores multiple potential mechanisms of anticancer action, underscoring the promising therapeutic potential of these palladium(II) complexes, while antitumor activity has been initially assessed using a MCF-7 cell line as a preliminary model. Full article

The structural characterization of GG-rich DNA sequences in presence of metal ions provides essential insight into quadruplex stability and ion-dependent conformational specifics. We report the crystal structure of the GG-quadruplex formed by the sequence GGGGTTTTGGGG in the presence of Zn²⁺, K⁺, and Na⁺. It was deposited in the RCSB Protein Data Bank under the accession code 9FTA. The structure was determined by single-crystal X-ray diffraction at a resolution of 2.49 Å in the space group P2₁2₁2₁. It reveals a parallel-stranded, two-G-tetrad stabilized by K⁺ ions within the central channel, while Na⁺ and Zn²⁺ occupy peripheral and groove-associated sites. Zn²⁺ ions are engaged in noncanonical coordination interactions with phosphate oxygens and structured water molecules, contributing to lattice stabilization and subtle adjustments in groove dimensions. The T4 loop forms a compact, ordered motif that contributes to crystal packing rather than intramolecular G4 stabilization. The presence of mixed cations produces a sole lattice architecture mediated by ions that provides structural insight into how bivalent and monovalent metals mutually modulate G-quadruplex topology. These results suggest a basis for understanding the specific ion effects on G4 structures and may direct the design of metal open DNA architectures. Full article

The leishmaniases are a group of neglected tropical diseases caused by kinetoplastid protozoa of the genus Leishmania, transmitted by phlebotomine sandflies. In the absence of a human vaccine, current chemotherapeutic options remain suboptimal due to limited target selectivity, high cost, restricted availability in endemic low-resource regions, and escalating parasite resistance. This review highlights recent advances in rational drug design directed at the kinetoplast—a distinctive mitochondrial organelle critical for parasite viability. Different targets (e.g., kDNA, G-quadruplex, topoisomerases) and innovative approaches employing mitochondrion-targeted small molecules are discussed, as well as ligand-functionalized nanoparticle delivery systems that can transport bioactive agents to the parasite’s mitochondrial microenvironment. These strategies highlight the kinetoplast’s strong translational relevance as a selective antileishmanial target. By exploiting its unique molecular machinery, these strategies may offer improved parasite selectivity, although potential mitochondrial liabilities in host cells must be carefully evaluated. Full article

Cisplatin’s chemotherapy is hindered by drug resistance and toxicity, making copper complexes a potential alternative. A novel copper(II) complex, [CuLBr], was synthesized from a tetradentate vicinal dioxime ligand (H₂L) and characterized. [CuLBr] features a distorted square pyramidal geometry with a CuN₄Br chromophore. DFT calculations showed a narrowed HOMO-LUMO gap and increased electrophilicity, enhancing its chemical reactivity. [CuLBr] exhibited potent biomimetic catalytic activity, functioning as an efficient superoxide dismutase mimic and catalase mimic. Biophysical studies (UV-Vis, fluorescence, and viscosity) demonstrated a strong, spontaneous affinity of [CuLBr] for calf thymus DNA and Human Serum Albumin, suggesting groove-binding and static quenching mechanisms. In vitro assays revealed superior anticancer activity against HepG-2, HCT-116, and MDA-MB-231 cell lines, with greater selectivity than the free ligand and doxorubicin. Molecular docking studies reveal a high binding affinity of [CuLBr] with key proteins, including ferredoxin-1 and VEGF. This may suggest potential dual mechanisms of action, involving the induction of cuproptosis and the inhibition of tumor angiogenesis. These findings position [CuLBr] as an effective multi-metal-based anticancer agent with advantageous selectivity. Full article

The complexes cis-[Ru(dmbpy)₂Cl(bpy)](PF₆) (Rubpy) and cis-[Ru(dmbpy)₂Cl(bpe)](PF₆) (Rubpe) (dmbpy = 4,4′-Dimethyl-2,2′-dipyridyl, bpy= 4,4′-dipyridyl and bpe = 1,2-bis(4-pyridyl)ethane) were synthesized and spectroelectrochemically characterized. Both Ru(II) complexes exhibited absorption bands assigned to intraligand and metal-to-ligand charge transfer (MLCT) transitions, and their spectral stability in PBS buffer (pH 7.4) supports their suitability for biological studies involving biomolecules or living cells. Fluorescence quenching assays revealed strong interactions with bovine serum albumin (BSA), with binding constants (K_b) values were 2.89 × 10⁵ M⁻¹ for Rubpy and 1.97 × 10⁵ M⁻¹ for Rubpe, and a stoichiometry of one binding site per albumin molecule. DNA-binding studies demonstrated non-covalent interactions with ss-DNA, evidenced by a hyperchromic effect in the MLCT bands, suggesting a partial intercalation or groove-binding mechanism. Cellular uptake assays indicated moderate incorporation of both complexes in tumor cells, with uptake levels of 52% (Rubpy) and 47% (Rubpe) in HeLa cells, and 42% (Rubpy) and 32% (Rubpe) in MDA-MB-231 cells. Despite the similar uptake profiles, cytotoxicity assays showed that Rubpe is approximately 2.4 times more potent than Rubpy, with IC₅₀ values of 9 μM (HeLa) and 12 μM (MDA-MB-231), compared to 22 μM and 29 μM for Rubpy, respectively. These results highlight the relevance of these Ru(II) complexes as molecular platforms for exploring structure–activity relationships in anticancer agents. Full article

Tuberculosis (TB) remains a global health issue exacerbated by spreading drug resistance and lengthy treatment regimens. Targeting bacterial DNA-repair pathways, particularly those counteracting host-generated genotoxic stress, represents a promising strategy to sensitize Mycobacterium tuberculosis to existing antibiotics. Through structure-based virtual screening of a compound library, we identified novel small-molecule inhibitors of M. tuberculosis uracil–DNA glycosylase (MtbUng), an enzyme essential for the repair of DNA damage inflicted by macrophage-produced reactive nitrogen species. Experimental validation revealed that four derivatives of usnic acid, a lichen-derived metabolite, significantly inhibited MtbUng activity, with the most potent compound, OL10-88-1, exhibiting IC₅₀ 26 ± 7 µM. Molecular docking suggests that OL10-88-1 inhibits MtbUng by occupying both the active site and the DNA-binding groove, thereby disrupting multiple steps of uracil recognition. The compounds also showed variable inhibitory activity against uracil–DNA glycosylases from Escherichia coli, humans, and vaccinia virus. Our findings establish that the compound could potentially be used in combination therapies to enhance the efficacy of current anti-TB drugs by exploiting the vulnerability of DNA-repair-deficient mycobacteria. Full article

Background: Silver(I) complexes with aromatic heterocyclic ligands are well known for their broad antimicrobial potential, largely attributed to their ability to interact with biomolecular targets. Results and Discussion: In this study, a new polynuclear silver(I) complex with N-(3′-phenylpropyl)quinoxaline-2-carboxamide (pqx-2ca), [Ag(NO₃)(pqx-2ca)]_n, was synthesized. Its structure was confirmed by single-crystal X-ray diffraction and comprehensively characterized using NMR, IR, and UV–Vis spectroscopy, while its behavior in solution was further elucidated through density functional theory (DFT) calculations combined with spectral simulations. The complex demonstrated significantly enhanced antimycobacterial activity compared with the free ligand when tested against the avirulent Mycobacterium tuberculosis H37Ra, fast-growing model organisms M. smegmatis and M. aurum, as well as the nontuberculous species M. avium and M. kansasii. Experimental and docking studies confirmed stable binding of the complex to subdomain III of bovine serum albumin (BSA) and to the minor groove of DNA. Furthermore, docking to validated mycobacterial targets revealed inhibitory potential toward the InhA and MmpL3 proteins, with binding affinities comparable to those of standard inhibitors. Conclusions: These results highlight [Ag(NO₃)(pqx-2ca)]_n as a promising candidate for the development of silver-based antimycobacterial agents with a dual mechanism of action involving both DNA and protein targets. Full article

The urgent need for effective therapies against cancer and antimicrobial-resistant pathogens motivates the development of novel metal-based complexes. Herein, we report the synthesis and characterization of four novel cobalt(II) complexes with biologically relevant β-diketo ester ligands. The complexes were characterized via UV-Vis, FTIR, mass spectrometry, and elemental analysis. Their biological activities were evaluated through antimicrobial and cytotoxic assays. Complex B1 exhibited the strongest antimicrobial activity, with minimum inhibitory concentrations (MICs) of 0.23 mg/mL against Staphylococcus aureus and Proteus mirabilis, and 0.01 mg/mL against Mucor mucedo, exceeding the performance of ketoconazole. Cytotoxicity studies on SW480 colorectal cancer cells and HaCaT normal keratinocytes identified B3 as the most potent anticancer agent (IC₅₀ = 11.49 µM), selectively targeting tumor cells. Morphological analysis indicated apoptosis as the primary mode of cell death. Mechanistic studies were performed to elucidate interactions with biomolecules. UV-Vis and fluorescence spectroscopy, viscosity measurements, and molecular docking revealed that B3 binds strongly to calf thymus DNA via hydrophobic interactions and groove binding, and exhibits selective binding to bovine serum albumin (site II, subdomain IIIA). These results highlight the potential of cobalt(II) complexes as multifunctional agents with significant antimicrobial and antitumor activities and provide detailed insight into their molecular interactions with DNA and serum proteins. Full article

A new series of styryl hemicyanine dyes featuring substituted N-phenylpiperazine end groups was synthesized using an environmentally friendly procedure. The photophysical properties of the dyes were systematically investigated in organic solvents of varying polarity and when bound to DNA, using a combination of spectroscopic techniques. The dyes show strong negative solvatochromism and exhibit fluorescence quenching upon DNA binding. The dyes are definitely halochromic, exhibiting pronounced fluorescent acidochromism, accompanied by a photoinduced electron transfer (PET) effect. Titration with acid of the dye–DNA complexes restores fluorescence, indicating suppression of the PET and, at the same time, rigidizing of the chemical structure. UV/VIS and fluorescence titration, circular dichroism spectroscopy, and molecular docking methods were used to investigate the interaction mode between the dyes and DNA. Density functional theory (DFT) and time-dependent density functional theory (TDDFT) quantum chemical calculations were employed in deciphering the observed spectroscopic behavior and PET-related effects. The obtained results suggest the dyes’ potential as pH-responsive fluorescent probes for nucleic acid environments. Full article

G-quadruplexes (G4s) are four-stranded DNA or RNA structures formed by guanine-rich sequences. They occur in functional regions of the genomic material, including the promoter part of genes, regulatory region, and telomeric threads. G4s play a key role in various biological processes, including transcription, replication, and telomere maintenance. Guanidine-containing derivatives can bind to G-quadruplexes, either by intercalating into the structure or by interacting with the grooves or loops. The binding can stabilize the G-quadruplex, potentially affecting its biological function. In this paper, the ability of guanidinium-containing hordatines to interact with G4 was evaluated. Analogues lacking the guanidinium group or showing the benzofuran system instead of the dihydrobenzofuran core were prepared and tested as well. NMR titration and docking calculations were used to probe the binding of the compounds to G4 of c-MYC oncogene. Spectroscopic analyses were consistent with a significant interaction of benzofurans 3 and 4 at the 5′-end and 3′-end tetrads and with the formation of ligand/G-quadruplex complexes with a 2:1 stoichiometry. The resulting data were supported by docking simulations. Cytotoxic activity was evaluated on a model of U2OS osteosarcoma (ATCC HTB-96) and breast cancer (MDA-MB-231) cell lines, further highlighting the key role of the guanidinium fragment and the benzofuran core in the G-quadruplex stabilization. Full article

By imposing finite order constraints on Fibonacci anyon braid relations, we construct the finite quotient $G={\mathbb{Z}}_5⋊2I$, where $2I$ is the binary icosahedral group. The Gröbner basis decomposition of its $SL(2,\mathbb{C})$ character variety yields elliptic curves whose L-function derivatives $L^{\prime }(E,1)$ remarkably match fundamental biological structural ratios. Specifically, we demonstrate that the Birch–Swinnerton-Dyer conjecture’s central quantity: the derivative $L^{\prime }(E,1)$ of the L-function at 1 encodes critical cellular geometries: the crystalline B-DNA pitch-to-diameter ratio ($L^{\prime }(E,1)=1.730$ matching $34\AA /20\AA =1.70$), the B-DNA pitch to major groove width ($L^{\prime }=1.58$) and, additionally, the fundamental cytoskeletal scaling relationship where $L^{\prime }(E,1)=3.570\approx 25/7$, precisely matching the microtubule-to-actin diameter ratio. This pattern extends across the hierarchy ${\mathbb{Z}}_5⋊2P$ with $2P\in \{2O,2T,2I\}$ (binary octahedral, tetrahedral, icosahedral groups), where character tables of $2O$ explain genetic code degeneracies while $2T$ yields microtubule ratios. The convergence of multiple independent mathematical pathways on identical biological values suggests that evolutionary optimization operates under deep arithmetic-geometric constraints encoded in elliptic curve L-functions. Our results position the BSD conjecture not merely as abstract number theory, but as encoding fundamental organizational principles governing cellular architecture. The correspondence reveals arithmetic geometry as the mathematical blueprint underlying major biological structural systems, with Gross–Zagier theory providing the theoretical framework connecting quantum topology to the helical geometries that are essential for life. Full article

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor. Due to its aggressive nature and resistance to conventional treatments, there is a pressing need to develop novel and more effective therapies for this deadly malignancy. Here, we explored the therapeutic potential of the DNA minor groove binders trabectedin (TRB) and lurbinectedin (LUR) for the treatment of iCCA using cell lines, spheroids, cancer-associated fibroblasts (CAFs), patient-derived tumor organoids (PDOs), and the chicken chorioallantoic membrane (CAM) in vivo model. TRB and, more substantially, LUR, significantly inhibited cell growth in iCCA cell lines, spheroids, CAFs, and PDOs at very low nanomolar concentrations. Specifically, the two drugs significantly reduced proliferation, triggered apoptosis, and caused DNA damage in iCCA cells. At the metabolic level, TRB and LUR decreased mitochondrial respiration and glycolysis. At the molecular level, the two compounds effectively downregulated the mammalian target of rapamycin complex 1 (mTORC1) and Hippo/YAP pathways and suppressed the expression of yes-associated protein 1 (YAP1), cellular myelocytomatosis oncogene (c-Myc), E2F transcription factor 1 (E2F1), Bromodomain-containing protein 4 (BRD4), TEA domain transcription factor 4 (TEAD4), and cluster of differentiation 7 (CD7) proto-oncogenes. Furthermore, LUR significantly restrained the in vivo growth of iCCA cells in the CAM model. Our data indicate that TRB and LUR possess strong anti-proliferative and pro-apoptotic activities and could represent promising therapeutic agents for the treatment of iCCA. Full article

I-motifs are non-canonical, cytosine-rich DNA structures stabilized by hemiprotonated C•C⁺ base pairs, whose formation is highly pH-dependent. While certain chemical modifications can enhance i-motif stability, modifications at the sugar moiety often disrupt essential inter-strand contacts. In this study, we examine the structural and thermodynamic impact of incorporating 2′-fluoro-ribocytidine (2′F-riboC) into i-motif-forming sequences derived from d(TCCCCC). Using a combination of UV, ¹H NMR, and ¹⁹F NMR spectroscopy, we demonstrate that full substitution with 2′F-riboC strongly destabilizes i-motif, whereas partial substitutions (one or two substitutions per strand) support well-folded structures at acidic pH (pH 5). High-resolution NMR structures reveal well-defined i-motif architectures with conserved C•C⁺ pairing and characteristic interstrand NOEs. Sugar conformational analysis reveals a predominant North pucker for cytosines, which directs the fluorine substituent toward the minor groove of the i-motif. ¹⁹F NMR further confirms slow exchange between folded and unfolded species, enabling the simultaneous detection of both under identical experimental conditions and, consequently, highlighting the utility of fluorine at the 2′ sugar position as a spectroscopic probe. These findings provide insights into fluorine-mediated modulation of i-motif stability and further extend the utility of ¹⁹F NMR in nucleic acid research. Full article

Schiff base ligands prepared from salicylaldehyde and 2-, 3- and 4-methoxybenzylamine were used to prepare copper(II) complexes, characterized by spectral methods, elemental analysis and X-ray crystallography in the case of complex 4a derived from 2-methoxybenzylamine. The DNA cleavage activity of the prepared complexes was exceptional, with best activities of over 95% one-strand cleavage for 4c at 3 mM and full double-strand cleavage for complex 4a at 5 mM. Absorption titration studies with ct-DNA revealed good binding constants (at 10⁵ M⁻¹) with a decrease of up to 56% light absorption. Meanwhile, the EB–DNA displacement method and viscosity studies revealed groove binding as a possible binding mode. For BSA binding studies, all three complexes showed K_BSA values in the optimal range for reversible BSA binding (10⁴ M⁻¹). The copper(II) complexes showed significant cytotoxic effects (67–96% at 1 mM) in mitochondrial activity monitoring assays. Cytotoxicity was confirmed against cancer cell lines (A549 and HepG2) and HEL cells. The complexes 4a and 4c exhibited high activity against HepG2 cancer cells (IC50 < 22 μM), comparable to cisplatin. The radical scavenging activity was determined by the INT method with the best IC50 for 4c (189 ± 11 μM). Overall, complexes 4a and 4c with a methoxy group in the ortho and para positions show high potential in most determined activities, but mainly as DNA cleavers and as cytotoxic agents with selectivity against HepG2 cells. Full article

The rise of multidrug-resistant pathogens has become a serious health concern, creating an urgent need for novel therapeutic approaches. Among the compounds explored, AMPs have emerged as promising candidates due to their broad-spectrum activity and low propensity for resistance development. However, their clinical implementation is limited by improper size, in vivo instability, and toxicity. Here, we designed short analogs of CeHS-1 via (1) truncation of intact CeHS-1, (2) amino acid substitution, (3) end-tagging, and (4) C-terminal amidation. The results showed that short analogs fused with an RWW stretch exhibited stronger antibacterial activity than the parent analogs, without inducing hemolysis in human red blood cells. Among the tested AMPs, mechanistic studies revealed membrane-disruptive activity of certain peptides against Staphylococcus aureus. In silico analyses also suggested that the analogs bind DNA by aligning parallel to its grooves, where the RWW stretch is believed to contribute to interactions between arginine and tryptophan residues and nitrogenous bases through electrostatic, hydrogen bonding, and hydrophobic interactions. The short CeHS-1 analogs established here may serve as potential alternative antimicrobial agents, which should be tested in clinical trials in the future. Full article