High Binding Constants Research Articles

In Vitro Cytotoxicity and Mechanistic Investigation of Quinazolin-4(1H)-One Linked Coumarin as a Potent Anticancer Agent.

Quinazolinone-coumarin conjugates synthesized through Late-Stage Functionalization approach are evaluated for their invitro biological activity for 60 human cancer cell lines representing nine different cancer types. Among the synthesized compounds, eight displayed significant growth inhibitory activity across a spectrum of cancer types, with compound 23 demonstrating particularly notable cytotoxicity. Further investigation involved a five-dose assay of compound 23 against NCI-60 cancer cell lines, revealing its efficacy at different concentrations. Additionally, binding studies elucidated its interaction with Human Serum Albumin (HSA) and DNA. The results indicated a strong binding affinity of 23 with HSA, evidenced by a high binding constant (2.26 × 105 M-1). Moreover, its interaction with DNA occurred via intercalation, specifically between the base pairs of DNA strands, with a binding constant of 5.51 × 104 M-1. This suggests that compound 23 has the ability to bind to both DNA and transport proteins, making it a promising pharmacophore with potential therapeutic applications.

Selective Chromogenic Chemosensors for Arsenite Anion: A Facile Approach to Analyzing Arsenite in Honey, Milk, and Water Samples.

In this study, two chemosensors, N5R1 and N5R2, based on 5-(4-nitrophenyl)-2-furaldehyde, with varying electron-withdrawing groups, were synthesized and effectively employed for the colorimetric selective detection of arsenite anions in a DMSO/H2O solvent mixture (8 : 2, v/v). Chemosensors N5R1 and N5R2 exhibited a distinct color change upon binding with arsenite, accompanied by a spectral shift toward the near-infrared region (Δλmax exceeding 200 nm). These chemosensors established stability between a pH range 6-12. Among them, N5R2 displayed the lowest detection limit of 17.63 ppb with a high binding constant of 2.6163×105 M-1 for arsenite. The binding mechanism involved initial hydrogen bonding between the NH binding site and the arsenite anion, followed by deprotonation and an intramolecular charge transfer (ICT) mechanism. The mechanism was confirmed through UV and 1H NMR titrations, cyclic voltammetric studies, and theoretical calculations. The interactions between the sensor and arsenite anions were further analyzed using global reactivity parameters (GRPs). Practical applications were demonstrated through the utilization of test strips and molecular logic gates. Real water samples, honey, and milk samples were successfully analyzed by both chemosensors for the sensing of arsenite.

Enhancing recovery of gold(III) from hydrochloric acid solutions using gemini surfactant microemulsions: The effect of spacer group

The recovery of precious metals from waste has garnered significant attention owing to their non-renewable nature and essential role in the burgeoning information industry. However, enhancing the extraction efficiency of microemulsions remains a significant challenge. In this study, three water-in-oil microemulsions were formulated using gemini surfactants with different spacers (14-OH-14, 14-SO4-14, and 14-3-14) as emulsifiers, supplemented with n-butanol as a cosurfactant, n-heptane as the oil phase, and NaCl aqueous solution as the internal aqueous phase. These microemulsions were employed for the extraction of gold(III) from hydrochloric acid solutions. The results illustrate that all three microemulsions effectively extracted gold(III) through a spontaneous, exothermic, enthalpy-driven anion-exchange mechanism, achieving notable extraction efficiency. In contrast to 14-3-14, incorporating –OH into the spacer significantly augments the positive electrostatic potential through the cationization of –OH in an HCl solution, resulting in a higher binding constant (2.43) and thereby improving the extraction efficiency. However, the presence of −SO4 diminishes the positive electrostatic potential through partial neutralization, resulting in a lower binding constant (1.17), which is detrimental to the extraction process. Response surface optimization revealed that concentrations of C(14-OH-14) and V(1-butanol) significantly influence extraction efficiency and exhibit pronounced interaction. At optimal conditions (C(14-OH-14) = 0.09 mol·L−1, V(1-butanol) = 47.41 %, R=20, and C(NaCl) = 1.57 mol·L−1), over 95.54 % of gold(III) can be extracted from actual e-waste solutions. This study offers an alternative approach for designing or selecting surfactants in microemulsion-based extraction of gold(III) from e-waste.

Colorimetric sensors for discriminatory detection of arsenite ions: Application in milk, honey and water samples and molecular logic gates

Millions of people are exposed to dangerous arsenic levels in drinking water, highlighting the urgent need for affordable, continuous on-site arsenic monitoring methods. It is crucial to specifically detect arsenite among inorganic arsenic anions because it is more poisonous than arsenate. Addressing these concerns, the present study developed 5-(4-nitrophenyl)-2-furaldehyde based two colorimetric chemosensors, N5R3 and N5R4, with different signaling groups for the selective detection of arsenite anions over arsenate in DMSO/H2O (6:4, v/v). The red-shift in the UV–Vis absorption spectra supported the distinct color changes of sensors N5R3 and N5R4 displayed upon binding with arsenite. Sensors demonstrated stability over a pH range of 6 to 12 and exhibited stability over a considerable time period. Among the chemosensors, N5R3 exhibited the lowest detection limit of 7.41 ppb with a high binding constant of 2.9976 × 106 M−1 for arsenite. The 1:1 binding interactions between the chemosensors and arsenite were confirmed using B-H plot and Job’s plot analysis. The intramolecular charge transfer (ICT) mechanism for detecting arsenite was proposed through UV and 1H NMR titrations, electrochemical studies, mass spectral analysis and DFT calculations. The interactions between the sensor and arsenite anions were further analyzed using global reactivity parameters (GRPs). Practical applications were demonstrated through the utilization of test strips and molecular logic gates. Both chemosensors efficiently recognized arsenite in real water, honey, and milk samples.

Supercritical CO2 Fluid Extraction and Microencapsulation of Oil from Anchovy (Engraulis mordax) By-Products.

Fish by-products are discarded as waste, which has a significant impact on the environment. They have no economic value, but there are many opportunities to turn them into high value products. Due to significant quantities generated internationally and the continuous expansion of the market for ω-3 and ω-6 fatty acids as nutraceuticals, innovative technological approaches are needed to transform this waste into marketable products with added value, while limiting the risk of environmental pollution. In this study, two temperatures (40 and 60 °C) at a constant pressure during the extraction of anchovy by-products with supercritical CO2 fluid were used to determine extraction yield, fatty acid, tocopherol and phytosterol composition, followed by microencapsulation with two matrices based on the transglutaminase-mediated crosslinking reaction between whey protein isolates and casein. Before microencapsulation, the binding parameters were estimated using quenching studies. The results showed a higher content of total fatty acids when extracted at 40 °C, resulting in two fractions on a dry mass basis of (712±12) mg/g in the fraction obtained in the separator with code S40 and (732±10) mg/g in the fraction obtained in the separator with code S45, respectively. The monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs) accounted for 40-44 %. The extracts showed a higher mass fraction of eicosapentaenoic acid ((28.7±1.0) mg/g) in fraction S45 when extracted at 60 °C. A minimum inhibitory and bactericidal concentration of 0.66 μg/mL against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923 was found for all fractions. Higher binding constants were found for palmitoleic and oleic acids than for palmitic acid. The control variant, without crosslinking, enabled the microencapsulation of a higher amount of fatty acids, while in both powders the sum of MUFAs and PUFAs was 40 %. The approaches used in our study open up new opportunities for adding value to the fish by-products through extraction and microencapsulation, extending their potential use to food, cosmetics and nutraceuticals.

New Cu (II) and Zn (II) metal chelates derived from azo‐Schiff bases: Synthesis, DNA/BSA binding, anticancer activity and molecular docking studies

In this study, new Cu (II) and Zn (II) chelates (3–6) of 3‐/or 4‐ethyl and azo chromophore groups (NN) containing Schiff base ligands (2‐{(E)‐[(4‐ethylphenyl)imino]methyl}‐4‐[(E)‐phenyldiazenyl]phenol, HL1 (1) and 2‐{(E)‐[(3‐ethylphenyl)imino]methyl}‐4‐[(E)‐phenyldiazenyl]phenol, HL2 (2) were prepared and characterized by the analytical and spectroscopic methods. Crystal structures of chelates 3, 4 and 6 were determined by single‐crystal X‐ray diffraction studies. The ligands behaved as bidentates, coordinating through the nitrogen atom of the azomethine group (CHN) and the oxygen atom of the α‐hydroxyl group (OH). The metal:ligand ratio in the prepared copper (II) and zinc (II) chelates was found to be 1:2 by analytical and spectral analysis. The bands in the infrared spectra of the metal chelates in the region of 522–504 cm−1 and 467–455 cm−1 are attributed to ν(MO) and ν(MN) vibrations, respectively. When the DNA binding activities of the compounds were examined, it was determined that compound 4 had the highest binding constant. Fluorescence and viscosity data showed that the compounds interact with DNA through minor grove binding mode. Furthermore, anticancer properties of the compounds were investigated. Ligand 2 was found to be highly effective against the HepG2 cell with an IC50 of 0.31 μM. In addition, structural analysis, frontier molecular orbitals, molecular electrostatic potential maps, Hirshfeld surface analysis of the synthesized compounds using computational chemistry methods and anticancer activity studies were carried out by molecular docking.

A General Strategy for Enhanced Photodynamic Antimicrobial Therapy with Perylenequinonoid Photosensitizers Using a Macrocyclic Supramolecular Carrier.

Perylenequinonoid natural products are a class of photosensitizers (PSs) that exhibit high reactive oxygen species (ROS) generation and excellent activity for Type I/Type II dual photodynamic therapy. However, their limited activity against gram-negative bacteria and poor water solubility significantly restrict their potential in broad-spectrum photodynamic antimicrobial therapy (PDAT). Herein, a general approach to overcome the limitations of perylenequinonoid photosensitizers (PQPSs) in PDAT by utilizing a macrocyclic supramolecular carrier is presented. Specifically, AnBox·4Cl, a water-soluble cationic cyclophane, is identified as a universal macrocyclic host for PQPSs such as elsinochrome C, hypocrellin A, hypocrellin B, and hypericin, forming 1:1 host-guest complexes with high binding constants (≈107 m -1) in aqueous solutions. Each AnBox·4Cl molecule carries four positive charges that promote strong binding with the membrane of gram-negative bacteria. As a result, the AnBox·4Cl-PQPS complexes can effectively anchor on the surfaces of gram-negative bacteria, while the PQPSs alone cannot. In vitro and in vivo experiments demonstrate that these supramolecular PSs have excellent water solubility and high ROS generation, with broad-spectrum PDAT effect against both gram-negative and gram-positive bacteria. This work paves a new path to enhance PDAT by showcasing an efficient approach to improve PQPSs' water solubility and killing efficacy for gram-negative bacteria.

Eco-friendly Fluorescent Sensor for Sensitive and Selective Detection of Zn2+ and Fe3+ Ions: Applications in Human Hair Samples.

A new eco-friendly sensor, 3-((6-((4-chlorobenzylidene)amino)pyridin-2-yl)imino)indolin-2-one (CBAPI) was synthesized and well characterized. The CBAPI sensor was employed for detecting Zn2+ and Fe3+ ions. It exhibited a low limit of detection at pH 6.0, with values of 2.90, for Zn2+ and 3.59nmol L-1 for Fe3+ ions. The sensor demonstrated high selectivity over other interfering cations. Additionally, the high binding constants reflect the great affinity of sensor towards Zn2+ and Fe3+ ions. To further validate its quantification ability for Zn2+ ions, the synthesized CBAPI sensor was used to determine Zn levels in human hair samples, and the results were confirmed using atomic absorption spectroscopy (AAS). The AGREE metric tool was used to assess the method's environmental impact and practical applicability. These positive outcomes indicated that the new method for detecting Zn2+ and Fe3+ ions is environmentally friendly and safe for humans. The developed CBAPI sensor represents a potential development in metal ion detection, combining sensitivity, selectivity, and rapidity.

Design, synthesis, molecular docking and anti-proliferative activity of novel phenothiazine containing imidazo[1,2-a]pyridine derivatives against MARK4 protein.

A series of novel phenothiazine-containing imidazo[1,2-a]pyridine derivatives were designed and synthesized under metal-free conditions in excellent yield. These derivatives were effectively transformed further into N-alkyl, sulfoxide, and sulfone derivatives. Derivatives were deployed against human microtubule affinity regulating kinase (MARK4), some molecules play crucial roles in cell-cycle progression such as G1/S transition and regulator of microtubule dynamics. Hence, molecules have shown excellent MARK4 inhibitory potential. Molecules with excellent IC50 values were selected for further studies such as ligand interactions using fluorescence quenching experiments for the binding constant. The highest binding constant was calculated as K = 0.79 × 105 and K = 0.1 × 107 for compounds 6a and 6h, respectively. Molecular docking, cell cytotoxicity, mitochondrial reactive oxygen species measurement and oxidative DNA damage were also studied to understand the mechanism of action of the molecules on cancer cells. It was found that the designed and synthesized compounds played anti-cancer roles by binding and inhibiting MARK4 protein.

Anion Binding Interaction Enhances the Robustness of Iodide for High-Performance Perovskite Solar Cells.

Owing to the ionic bond nature of the Pb-I bond, the iodide at the interface of perovskite polycrystalline films was easily lost during the preparation process, resulting in the formation of a large number of iodine vacancy defects. The presence of iodine vacancy defects can cause nonradiative recombination, provide a pathway for iodide migration, and be harmful to the power conversion efficiency (PCE) and stability of organic-inorganic hybrid perovskite solar cells (HPSCs). Here, in order to increase the robustness of iodides at the interface, a strategy to introduce anion binding effects was developed to stabilize the perovskite films. It was demonstrated that the N,N'-diphenylurea (DPU), characterized by high anionic binding constants and a Y-shaped structure, provides a relatively strong hydrogen bond donor site to effectively reduce the iodine loss during film preparation and inhibits iodide migration in the device working condition. As expected, the reduced iodine loss considerably improves the quality of the perovskite films and suppresses nonradiative recombination. The performance of the device after DPU modification was significantly increased, with the PCE rising from 23.65 to 25.01% with huge stability enhancement as well.

Design and synthesis of simple quinoline-based organic molecules as dual/multifunctional chemosensors for the detection of Cu2+/Fe3+ ions

The current research deals with the sensitivity of a turn-on-off fluorescence chemosensor using the probe, namely (E)-2-(((2‑hydroxy-5-methylphenyl) imino)methyl) quinolin-8-ol (HQ-AMP) as a selective detection of Cu2+/Fe3+ ions in DMSO: H2O (1:1, v/v). The probe HQ-AMP was synthesized using a simple acid catalyst, Schiff base condensation, which involves the reaction between aldehyde and amine. This probe shows a significant fluorescence response towards Cu2+ and Fe3+ ions among the other alkaline earth metal ions. The HQ-AMP forms a 1:1 stoichiometry complex with a high binding constant for Cu2+ and Fe3+ ions with a low detection limit of 34 nM and 47 nM, respectively. Due to their strong intermolecular charge transfer properties, the probe HQ-AMP shows intense fluorescence at 488 nm upon excitation at 350 nm. The selective fluorescence quenching of probe HQ-AMP with Cu2+/Fe3+ ions shows static/dynamic quenching and their quenching constant of 1.93 × 10−8 and 2.06 × 10−8, respectively. Also, the probe shows the highest selectivity towards Cu2+/Fe3+ ions over the other tested metal ions.

Ciprofloxacin Metal Complexes–Silica Nanoparticles: Characterization, Spectroscopic Study, DNA Interaction and Biological Activity

Ciprofloxacin (CIPH) was classified as one of the most effective quinolone antibiotics, which is commonly used to cure a wide range of infections resulting from Gram-negative and Gram-positive microorganisms. The complexes which formed due to the interaction of Ni(II), Zn(II), Cu(II), Gd(III) and Sm(III) with ciprofloxacin were characterized by CHN% analysis, conductivity, FTIR, electronic spectra, fluorescence measurements, and magnetic susceptibility, besides studying the complex–DNA interaction. Meanwhile, the molar conductance values (0.001 mol·L−1 in DMSO) revealed the electrolytic behavior of the complexes and could be designated with the A−B+ formula. In addition, the geometry of the compounds was confirmed from the electronic transitions as well as the μeff values as octahedral for all complexes. The postulated formula could be generally assigned as [M(CIP)a(CIPH)b(H2O)c](NO3)(H2O)n(C2H5OH)m. Moreover, the interaction between metal complexes and DNA revealed that the Cu complex had the highest binding constant. Nanotechnology was applied to synthesized compounds using silica nanoparticles (SiNPs), which were prepared using a sol–gel process. The silica nanoparticles were chemically functionalized for binding the ligand and its metal complexes; this enables the as-prepared compounds to enhance their features as a drug delivery platform. Meanwhile, the antimicrobial activity was tested for the free complexes and SiNPs composites. Collectively, Sm complex gave the largest zone of inhibition, while the Cu(II)–SiNPs composite showed the strongest potential to reduce the bacterial activity. Furthermore, the fluorescence data of CIPH, ligand–metal mixture and the effect of silica nanoparticles on them were studied.

Mixed N‐heterocyclic carbene and benzyl‐, phenethyl‐, and biphenylamine coordinated Pd complexes: Anticancer activities and stereo‐electronic effects

A series of mixed N‐heterocylic carbene (NHC) palladium complexes bearing C^N bidentate ligands derived from benzylamine, phenethylamine, and biphenylamine were prepared and fully characterized by NMR spectroscopy, ESI‐MS spectrometry, and X‐ray diffraction analyses. The complexes were potent in inhibiting proliferation of HepG2 and Caco2 cancer cells, and a SAR (structure–activity relationship) study revealed C^N ligands with stronger electron donation and moderate steric hindrance are more cytotoxic. DNA binding study through UV–vis absorption titration indicated that such complexes bound stronger to CT‐DNA molecules with higher binding constants. Additional molecular docking of the best performer suggested a groove binding mode through hydrogen bonding and π‐π stacking interactions. The apoptosis induced by the two best performers of α,α‐dimethylbenzylamine and S‐α‐methylbenzylamine ligated complexes was further analyzed by morphology change, cell cycle distribution, ROS production, and mitochondrial membrane potential studies.

Spectroscopic investigation and structural simulation in human serum albumin with hydroxychloroquine/Silybum marianum and a possible potential COVID-19 drug candidate.

In this study, the interaction between human serum albumin (HSA) and the hydroxychloroquine/Silybum marianum (HCQ/SM) mixture was investigated using various techniques. The observed high binding constant (Kb) and Stern-Volmer quenching constant (KSV) indicate a strong binding affinity between the HCQ/SM mixture and HSA. The circular dichroism (CD) analysis revealed that HCQ/SM induced conformational changes in the secondary structure of HSA, leading to a decrease in the α-helical content. UV-Vis analysis exhibited a slight redshift, indicating that the HCQ/SM mixture could adapt to the flexible structure of HSA. The experimental results demonstrated the significant conformational changes in HSA upon binding with HCQ/SM. Theoretical studies were carried out using molecular dynamics simulation via the Gromacs simulation package to explore insights into the drug interaction with HSA-binding sites. Furthermore, molecular docking studies demonstrated that HCQ/SM-HSA exhibited favorable docking scores with the receptor (5FUZ), suggesting a potential therapeutic relevance in combating COVID-19 with a value of -6.24 kcal mol-1. HCQ/SM exhibited stronger interaction with both SARS-CoV-2 virus main proteases compared to favipiravir. Ultimately, the experimental data and molecular docking analysis presented in this research offer valuable insights into the pharmaceutical and biological properties of HCQ/SM mixtures when interacting with serum albumin.

Rim-Based Binding of Perfluorinated Acids to Pillararenes Purifies Water.

Per- and polyfluoroalkyl substances (PFAS) pose a rapidly increasing global problem as their widespread use and high stability lead worldwide to water contamination, with significant detrimental health effects.[1] Supramolecular chemistry has been invoked to develop materials geared towards the specific capture of PFAS from water,[2] to reduce the concentration below advisory safety limits (e.g., 70 ng/L for the sum of perfluorooctane sulfonic acid, PFOS and perfluorooctanoic acid, PFOA). Scale-up and use in natural waters with high PFAS concentrations has hitherto posed a problem. Here we report a new type of host-guest interaction between deca-ammonium-functionalized pillar[5]arenes (DAF-P5s) and perfluoroalkyl acids. DAF-P5 complexes show an unprecedented 1 : 10 stoichiometry, as confirmed by isothermal calorimetry and X-ray crystallographic studies, and high binding constants (up to 106 M-1) to various polyfluoroalkyl acids. In addition, non-fluorinated acids do not hamper this process significantly. Immobilization of DAF-P5s allows a simple single-time filtration of PFAS-contaminated water to reduce the PFOS/PFOA concentration 106 times to 15-50 ng/L level. The effective and fast (<5 min) orthogonal binding to organic molecules without involvement of fluorinated supramolecular hosts, high breakthrough capacity (90 mg/g), and robust performance (>10 regeneration cycles without decrease in performance) set a new benchmark in PFAS-absorbing materials.

Rim‐Based Binding of Perfluorinated Acids to Pillararenes Purifies Water

AbstractPer‐ and polyfluoroalkyl substances (PFAS) pose a rapidly increasing global problem as their widespread use and high stability lead worldwide to water contamination, with significant detrimental health effects.[1] Supramolecular chemistry has been invoked to develop materials geared towards the specific capture of PFAS from water,[2] to reduce the concentration below advisory safety limits (e.g., 70 ng/L for the sum of perfluorooctane sulfonic acid, PFOS and perfluorooctanoic acid, PFOA). Scale‐up and use in natural waters with high PFAS concentrations has hitherto posed a problem. Here we report a new type of host–guest interaction between deca‐ammonium‐functionalized pillar[5]arenes (DAF−P5s) and perfluoroalkyl acids. DAF−P5 complexes show an unprecedented 1 : 10 stoichiometry, as confirmed by isothermal calorimetry and X‐ray crystallographic studies, and high binding constants (up to 106 M−1) to various polyfluoroalkyl acids. In addition, non‐fluorinated acids do not hamper this process significantly. Immobilization of DAF−P5s allows a simple single‐time filtration of PFAS‐contaminated water to reduce the PFOS/PFOA concentration 106 times to 15–50 ng/L level. The effective and fast (&lt;5 min) orthogonal binding to organic molecules without involvement of fluorinated supramolecular hosts, high breakthrough capacity (90 mg/g), and robust performance (&gt;10 regeneration cycles without decrease in performance) set a new benchmark in PFAS‐absorbing materials.

Mononuclear η6-arene ruthenium(II) complexes with pyrazolyl-pyridazine ligands: synthesis, CT-DNA binding, reactivity towards glutathione, and cytotoxicity.

Organometallic η6-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η6-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV-Visible absorption spectra in PBS buffer or DMSO over 24h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV-Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 104M-1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC50 values in the range of 59.2-39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes.

Exploring therapeutic potential of Rutin by investigating its cyclin-dependent kinase 6 inhibitory activity and binding affinity

Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (Ka = 7.6 × 105M−1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC50 value of 3.10 μM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6.

New Fluorescent Dye for the Detection of Zn2+ in Living Cells and Fixed Sections of the Rat Pancreas.

We report the synthesis and characterization of a new 4-methoxyphenyl-2,2'-bipyridine-based ligand, such as 12, bearing dipicolylaminomethyl core as a receptor unit, as a probe for the fluorescence "turn-on" detection of Zn2+. Thus, in the presence of Zn2+ the probe 12 exhibited a fluorescence enhancement with a Stokes shift of ~ 180nm and photoluminescence quantum yields value of ~ 1.0. In addition, 12 exhibited higher binding constant for Zn2+ (~ 2 × 105M-1) with the LOD reaching the nanomolar level (~ 0.1 × 10-9M) compare to the previously reported probe 1. The stoichiometry and structure of the [Zn(12)]2+ and [Zn(1)]2+ complexes were supported by XRD analysis, DFT calculations and 1H NMR experiments. It was postulated that, as a result of binding of Zn2+, the sample exhibited a bright "on" state via the PET-ICT processes. Molecular docking studies and confocal fluorescence microscopy experiments demonstrated that the probe 12 could be used for the fluorescence detection of Zn2+ not only in artificially enriched with zinc salts live cells, but also in fixed tissues with cations are in a bound state. The high binding constant of compound 12 to Zn2+ cation allows it to be used for the accurate localization of pancreatic beta cells (islets of Langerhans).

Bacterial cell death to overcome drug resistance with multitargeting bis-naphthalimides as potent antibacterial agents against Enterococcus faecalis.

The increasing frequency of drug-resistant pathogens poses serious health issues to humans around the globe, leading to the development of new antibacterial agents to conquer drug resistance and bacterial infections. In view of this, we have synthesized a series of bis-naphthalimides to respond to awful drug resistance. Bioactivity assay and structure-activity relationship disclosed that compounds 5d and 5o exhibit potent antibacterial activity against E. faecalis, outperforming the marketed antibiotics. These drug candidates not only inhibit the biofilm formation of E. faecalis but also display rapid bactericidal properties, thus delaying the development of drug resistance within 20 passages. To explore the mechanism of antibacterial activity against E. faecalis, biofunctional examination was carried out which unveiled that 5d and 5o effectively disrupt bacterial cell membranes, causing the leakage of cytoplasmic contents and metabolic activity loss. Concurrently, 5d and 5o effectively intercalate with DNA to block DNA replication, causing the build-up of excessive reactive oxygen species and inhibiting the glutathione activity, ultimately leading to oxidative damage of E. faecalis and cell death. In addition, these compounds readily bind with HSA with a high binding constant, indicating that these drug candidates could be easily delivered to the target site. The above finding manifested that these newly synthesized bis-naphthalimides with multitargeting antibacterial properties offer a new prospect to overcome drug resistance.