Groove Binding Research Articles

Molecular Docking Study of Binding of Perylene Di-imide to a Bio Molecular Human Telomeric G-quadruplex

Human telomeres are comprised of d(TTAGGG) repeats involved in the formation of G-quadruplex DNA structures. Ligands stabilizing these G-quadruplex DNA structures are potential inhibitors of the cancer cell-associated enzyme telomerase. In human cells , telomerase adds multiple copies of the 5’-GGTTAG-3’ motif to the end of the G-strand of the telomere and in the majority of tumor cells it results over-expressed. Several structural studies have revealed a diversity of topologies for telomeric quadruplexes, which are sensitive to the nature of the cations present, to the flanking sequences, and probably also to concentration, as confirmed by the different conformations deposited in the Protein Data Bank (PDB). The existence of different polymorphism in the DNA quadruplex and the absence of a uniquely precise binding site give rise to check docking approach . As target we have selected six different experimental models of the human telomeric sequence d[AG3(T2AG3)3] based on three G-tetrads and as ligands the perylene di-imide . We checked out molecular docking simulation of binding of perylene di-imide to a slected G-quadruplex using dock 6.9 to examine whether or not to reproduced the loop binding mode of perylene di-imide. The simulation gave the two highest rank docking pose of perylene di-imide and the binding mode were external stacking on the terminal guanine tetrade and the groove binding.

Recent advances on the DNA interaction properties of Schiff bases and their metal complexes

Cancer has become the second leading reason for death in the world. Cell biology states that the bulk of anti‐cancer medications focuses on DNA. A study of how complexes of metals interact with DNA is crucial in creation of the effective chemotherapy drugs. The interactions of DNA with Schiff base and their metal complexes are a thrust area for many researchers, and many papers have reported on them. An amino molecule reacts with carbonyl group to form a variety of chemicals called Schiff bases. Many studies have shown that Schiff bases have compounds that affect biological processes. Due to their potential use as novel reagents for biotechnology and medicine, the research of interactions between transition metal complexes and nucleic acids has grown significantly during the past few decades. It was shown that several metal Schiff base complexes may intercalate DNA. Small molecules can attach themselves to DNA through different ways, such as intercalation and groove binding. The main method to measure nuclease activity was gel electrophoresis, and the ligand alone had much lower activity than the complex. To set the stage for this analysis, a brief overview of Schiff bases and their complexes is provided. Further, this review provides an overview of the DNA interactions brought forth by Schiff base metal complexes. It also draws attention to new developments in the study of Schiff bases and their metal complexes and their prospective use as a bioactive core for DNA cleavage and binding.

Higher-order G-quadruplex structures and porphyrin ligands: Towards a non-ambiguous relationship

Herein, we evaluated the interaction of the tetracationic porphyrin H2TCPPSpm4 with three distinct DNA G-quadruplex (G4) models, i.e., the tetramolecular G4 d(TGGGGT)4 (Q1), the 5′-5′ stacked G4-dimer [d(CGGAGGT)4]2 (Q2), and a mixture of 5′-5′ stacked G-wires [d(5′-CGGT-3′-3′-GGC-5′)4]n (Qn). The combined data obtained from UV–Vis, CD, fluorescence, PAGE, RLS, AFM, NMR, and HPLC-SEC experiments allowed us to shed light on the binding mode of H2TCPPSpm4 with the three G4 models differing for the type and the number of available G4 ending faces, the length of the G4 units, and the number of stacked G4 building blocks. Specifically, we found that H2TCPPSpm4 interacted with the shortest Q1 as an end-stacking ligand, whereas the groove binding mode was ascertained in the case of the Q2 and Qn G4 models. In the case of the interaction with Q1 and Qn, we found that H2TCPPSpm4 induces the formation of supramolecular aggregates at porphyrin/G4 ratios higher than 2:1, whereas no significant aggregation was observed for the interaction with Q2 up to the 5:1 ratio. These results unambiguously demonstrated the suitability of porphyrins for the development of specific G4 ligands or G4-targeting diagnostic probes, being H2TCPPSpm4 capable to distinguish between different G4s.

In-vitro and in-silico analysis and antitumor studies of novel Cu(II) and V(V) complexes of N-p-Tolylbenzohydroxamic acid

Copper(L2Cu) and vanadium(L2VOCl) complexes of N-p-tolylbenzohydroxamic acid (LH) ligand have been investigated for DNA binding efficacy by multiple analytical, spectral, and computational techniques. The results revealed that complexes as groove binders as evidenced by UV absorption. Fluorescence studies including displacement assay using classical intercalator ethidium bromide as fluorescent probe also confirmed as groove binders. The viscometric analysis too supports the inferences as strong groove binders for both the complexes. Molecular docking too exposed DNA as a target to the complexes which precisely binds L2Cu, in the minor groove region while L2VOCl in major groove region. Molecular dynamic simulation performed on L2Cu complex revealing the interaction of complex with DNA within 20 ns time. The complex stacked into the nitrogen bases of oligonucleotides and the bonding features were intrinsically preserved for longer simulation times. In-vitro cytotoxicity study was undertaken employing MTT assay against the breast cancer cell line (MCF-7). Potential cytotoxic activities were observed for L2Cu and L2VOCl complexes with IC50 values of showing 71 % and 74 % of inhibition respectively.

Structure-based drug design of DNA minor groove binders and evaluation of their antibacterial and anticancer properties

Antimicrobial and chemotherapy resistance are escalating medical problem of paramount importance. Yet, research for novel antimicrobial and anticancer agents remains lagging behind. With their reported medical applications, DNA minor groove binders (MGBs) are worthy of exploration. In this study, the approach of structure-based drug design was implemented to generate 11 MGB compounds including a novel class of bioactive alkyne-linked MGBs. The NCI screening protocol was utilized to evaluate the antitumor activity of the target MGBs. Furthermore, a variety of bactericidal, cytopathogenicity, MIC90, and cytotoxicity assays were carried out using these MGBs against 6 medically relevant bacteria: Salmonella enterica, Escherichia coli, Serratia marcescens, Bacillus cereus, Streptococcus pneumoniae and Streptococcus pyogenes. Moreover, molecular docking, molecular dynamic simulations, DNA melting, and isothermal titration calorimetry (ITC) analyses were utilized to explore the binding mode and interactions between the most potent MGBs and the DNA duplex d(CGACTAGTCG)2. NCI results showed that alkyne-linked MGBs (26 & 28) displayed the most significant growth inhibition among the NCI-60 panel. In addition, compounds MGB3, MGB4, MGB28, and MGB32 showed significant bactericidal effects, inhibited B. cereus and S. enterica-mediated cytopathogenicity, and exhibited low cytotoxicity. MGB28 and MGB32 demonstrated significant inhibition of S. pyogenes, whereas MGB28 notably inhibited S. marcescens and all four minor groove binders significantly inhibited B. cereus. The ability of these compounds to bind with DNA and distort its groove dimensions provides the molecular basis for the allosteric perturbation of proteins-DNA interactions by MGBs. This study shed light on the mechanism of action of MGBs and revealed the important structural features for their antitumor and antibacterial activities, which are important to guide future development of MGB derivatives as novel antibacterial and anticancer agents.

Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China.

The aim of this study was to investigate the frequency distribution of the cytochrome P450 (CYP450) enzymes, CYP2D6 and CYP2C19, and the form of tamoxifen metabolisation in premenopausal patients with breast cancer in the Han and Uygur ethnic groups of Xinjiang to guide rational clinical drug use. A total of 125 Han patients and 121 Uygur patients with premenopausal hormone-receptor-positive breast cancer treated at the Xinjiang Uygur Autonomous Region Cancer Hospital between 1 June 2011 and 1 December 2013 were selected. The common mutation sites in CYP450 were analysed using TaqMan® minor groove binder technology. Genetic testing was performed to determine other metabolic types of tamoxifen, and the genotypes and metabolic types were compared using a Chi-squared test. Between the Han and Uygur groups, there were significant differences in the frequencies of the CYP2D6 (*10/*10) and CYP2C19 (*1/*1) genotypes, with P-values of 0.002 and 0.015, respectively. Genotypes of CYP2D6 (*1/*1), CYP2D6 (*1/*5), CYP2D6 (*5/*5), CYP2D6 (*5/*10) and CYP2C19 (*3/*3) were expressed in the two patient groups, and the difference was not statistically significant (P > 0.05). In the Han patients, the proportions of extensive, intermediate and poor metabolisers of tamoxifen were 72, 24 and 4%, respectively, whereas those in the Uygur patients were 76.9, 17.4 and 5.7%, respectively, with no significant difference (P > 0.05). In conclusion, There were partial differences in the CYP2D6 and CYP2C19 gene polymorphisms of CYP450 between the Han and Uygur patients with premenopausal breast cancer, but there was no significant difference between the CYP2D6 and CYP2C19 phenotypes. Further research is needed to determine the relationship between the enzyme genetic differences of CYP450 and the pharmacokinetics and efficacy of tamoxifen. Although there were some differences in genotypes, these did not result in differences in the predicted tamoxifen metabolisation phenotype between the Han and Uygur patients with breast cancer. Therefore, the doses should be adjusted according to the individual genotype data.

Fabrication, physicochemical characterization and theoretical studies of some new mixed ligands complexes based on N-(1H-benzimidazol-2-yl)-guanidine and 1, 10-phenanthroline: DNA interaction, biological applications and molecular docking approach

The fabrication and structural identification of mixed ligand chelates resulting from 1-(1H-benzimidazol-2-yl) guanidine (BIG = main ligand) and 1,10-Phenanthroline (phen) (secondary ligand). The tested compounds were investigated using TGA, CHN, spectra analysis (FT-IR, Mass spectra, NMR), melting point, magnetic moments, molar conductance, Ultraviolet–Visible spectroscopy as well computational studies. The conductance results showed that the tested Pd(II), VO(II) and Ag(I) chelates have electrolytes in fresh solutions of DMSO lies in the range 38.12–118.87 Ω−1 cm2 mol−1 except, Cu(II) chelate is a non-electrolyte it is value equal 15.16 Ω−1 cm2 mol−1. FT-IR spectrum displays that the tested main ligand is coordinated with metal ions in a bi-dentate behavior with N, N donor sites of the HN=C and C=N. While the second ligand coordinated with metal ions through its N2 atom in the pyridine ring. Moreover, the obtained analytical data regarding complexation in solution, molar ratio and continuous variation methods suggest 1M: 1 L molar ratio. Also the stability constant of tested complexes was identified in solution state and the formation constants (Kf) were evaluated by applying continuous-variation method. Stability of complexes was arranged by BIGPAg > BIGPVO > BIGPCu > BIGPPPd in agreement with Kf values. The pH profile revealed that the wide range of pH stability of the tested complexes is at pH = 4- 10 in most of them. Magnetic and electronic spectra are applied to deduce the coordinating ability of the tested ligands and the geometric structure of the studied chelates. That data of magnetic susceptibility for ternary mixed chelates are locked to an octahedral geometry for Cu(II) & VO(II) chelates due to the data of (μeff = 1.8 and 1.83 B.M) respectively and Pd(II) and Ag(I) chelates are diamagnetic with square planar and tetrahedral geometry, respectively. The TGA study of these studied complexes displays that the hydrated H2O, acetate, nitrate, and acetylacetonate anions are removed in the first (45°C-180°C) and second degradation steps followed directly by degradation of the studied ligands in the following stages. The thermodynamic factors, like ΔS*, ΔH*, E*, A and ΔG* are evaluated from the TGA curves and explained. The DFT/B3LYP computation method was applied for the estimation of the MEP, (HUMO & LUMO) energy for the studied compounds. In-silico assay was executed by two different approaches over compounds to evaluate their biological behavior and degree of interaction with biological systems, before practical application. BIGPPd complex displayed priority in interaction with various protein. In-vitro assay was then carried out for compounds against different microbes and BIGPPd showed high antimicrobial activity with inhibition zones are established to be 45.75 ± 0.10 and 41.95 ± 0.05 mm against B. Cereus and G. Candidum at 25 µg/mL. Also, their cytotoxic behavior was examined against MCF-7, HepG2 and HCT-116 carcinoma cell lines, high cytotoxicity was clearly recorded with BIGPPd complex with IC50% are established to be (5, 6.25 and 7.14 µg/mL) respectively. Furthermore, antioxidant activity was examined, and the complexes exhibited high reactivity with trapping free radicals. The BIGPPd exhibited significant free radical scavenging activity with an IC50 value of 20.15 μg/ml. The interaction of metal chelates with DNA was detected by gel electrophoreses, viscosity and spectral studies. Spectrophotometric titration and viscosity studies expose that each of tested complex is an avid binder to DNA. The intrinsic binding constants were calculated for all the tested compounds could bind to Ct-DNA generally through replacement, intercalative mode & minor groove binding of interactions with the sequence: BIGPVO (6.05×104) > BIGPCu > BIGPPd> BIGPAg >BIG (1.16×103). This may be due to enhanced hydrophobic & electrostatic interaction of aromatic rings. Finally, such complexes may be considered as a promising bioactive agent.

Influence of diimine bidentate ligand in the nitrosyl and nitro terpyridine ruthenium complex on the HSA/DNA interaction and antiviral activity

Nitric oxide (NO) acts in different physiological processes, such as blood pressure control, antiparasitic activities, neurotransmission, and antitumor action. Among the exogenous NO donors, ruthenium nitrosyl/nitro complexes are potential candidates for prodrugs, due to their physicochemical properties, such as thermal and physiological pH stability. In this work, we proposed the synthesis and physical characterization of the new nitro terpyridine ruthenium (II) complexes of the type [RuII(L)(NO2)(tpy)]PF6 where tpy = 2,2':6′,2″-terpyridine; L = 3,4-diaminobenzoic acid (bdq) or o-phenylenediamine (bd) and evaluation of influence of diimine bidentate ligand NH.NHq-R (R = H or COOH) in the HSA/DNA interaction as well as antiviral activity. The interactions between HSA and new nitro complexes [RuII(L)(NO2)(tpy)]+ were evaluated. The Ka values for the HSA–[RuII(bdq)(NO2)(tpy)]+ is 10 times bigger than HSA–[RuII(bd)(NO2)(tpy)]+. The sites of interaction between HSA and the complexes via synchronous fluorescence suppression indicate that the [RuII(bdq)(NO2)(tpy)]+ is found close to the Trp-241 residue, while the [RuII(bd)(NO2)(tpy)]+ complex is close to Tyr residues. The interaction with fish sperm fs-DNA using direct spectrophotometric titration (Kb) and ethidium bromide replacement (KSV and Kapp) showed weak interaction in the system fs-DNA-[RuII(bdq)(NO)(tpy)]+. Furthermore, fs-DNA–[RuII(bd)(NO2)(tpy)]+ and fs-DNA–[RuII(bd)(NO)(tpy)]3+ system showed higher intercalation constant. Circular dichroism spectra for fs-DNA–[RuII(bd)(NO2)(tpy)]+ and fs-DNA–[RuII(bd)(NO)(tpy)]3+, suggest semi-intercalative accompanied by major groove binding interaction modes. The [RuII(bd)(NO2)(tpy)]+ and [RuII(bd)(NO)(tpy)]3+ inhibit replication of Zika and Chikungunya viruses based in the nitric oxide release under S-nitrosylation reaction with cysteine viral.

Effect of Silver-Graphene Oxide-Cobalt Oxide Nanocomposite on Cytotoxic Levels in MRC-5 and HepG2 Cell Lines and Molecular Docking Studies

The cytotoxic properties of cobalt oxide (Co3O4) nanoparticles (NPs), in addition to graphene oxide (GO)-Co3O4 and silver (Ag)-GO-Co3O4 nanocomposites (NCs), were evaluated against both human healthy lung fibroblast (MRC-5) and hepatocellular carcinoma (HepG2) cell lines utilizing the XTT assay. The investigation revealed that synthesized Co3O4 NPs and NCs (GO-Co3O4 and Ag-GO-Co3O4) elicited significant cytotoxic responses in MRC-5 and HepG2 cell lines in a concentration-dependent manner. Through molecular docking analyses, it was observed that all fabricated nanomaterials exhibited DNA recognition via minor groove binding, with molecular affinities ranging from − 4.82 to -11.66 kcal/mol. Furthermore, the docking outcomes illustrated that the angular conformations of GO-Co3O4 and Ag-GO-Co3O4 conferred ‘shape-selective’ characteristics as DNA minor groove binders, leading to heightened cytotoxicity, particularly in the HepG2 cell line compared to the normal MRC-5 cell line.

Free energy calculations reveal the interaction and stability of ligands in the vicinity of B-DNA dodecamer

The double stranded Deoxyribonucleic acid (DNA) is stated as one of the idyllic targets for cancer and other various diseases. The in-depth investigation of DNA-drug interaction plays a crucial role for the recognition of drug mechanism action as well as in advance scheming of more proficient drugs with minor aftermath. Imidazoles and molecules possessing them are well known for their antimicrobial action and also possess different therapeutic properties. With the intention to improve a computational protocol towards the development of novel improvised antimicrobial agent, di-cationic molecules. Primarily, four diarylfuran derivatives having varied substituted groups have been proposed, analysed and compared for antimicrobial potential by studying their binding strength and steady complex formation with DNA. Molecular docking analysis was used to forecast the binding mode involved for DNA-drug complex and molecular dynamics was employed for studying the kinetics of interaction. The docking investigation revealed AT rich region binding for all the proposed ligands which is the preferred location for DNA minor groove binders establishing Mol-1 and Mol-3 as lead molecules. The stability of drug-DNA complexes was inferred from an analysis of the data from Molecular dynamics (MD) analysis, which showed that ligands remained coupled to the preferred binding locations of DNA without experiencing any significant changes in the minor groove.

Interaction with CT-DNA and in vitro cytotoxicity of two new copper(II)-based potential drugs derived from octanoic hydrazide ligands

Two copper(II) complexes [Cu(Hpmoh)(NO3)(NCS)] (1) and [Cu(peoh)(N3)]2 (2) were designed and synthesized by reaction of Cu(NO3)2·3H2O with hydrazone Schiff base ligands,abbreviated with Hpmoh and Hpeoh. Hpmoh and Hpeoh were prepared by condensation reaction of octanoic hydrazide with pyridine-2-carboxyaldehyde and 2-acetylpyridine, respectively. Complexes 1 and 2 were characterized using different analytical techniques such as FT-IR, UV–Vis, IR, EPR and single X-ray diffraction (XRD) analyses as well as computational methods (DFT). The XRD of 1 and 2 shows a mononuclear or a dinuclear structure with the copper(II) centre adopting a slightly distorted square pyramidal geometry. In water-containing solution and in DMSO, 1 and 2 undergo a partial transformation with formation of [Cu(Hpmoh)(NO3)(NCS)] (1) and [Cu(Hpmoh)(NO3)(H2O/DMSO)] (1a) in one system and [Cu(peoh)(N3)] (2a) in the other one, as supported by DFT calculations. Docking simulations confirmed that the intercalation is the preferred binding mode with DNA for 1, 1a and 2a, but suggested that the minor groove binding is also possible. A significant fluorescence quenching of the DNA–ethidium bromide conjugate was observed upon the addition of complexes 1 and 2 with a quenching constant around 104 M−1 s−1. Finally, both 1 and 2 were examined for anti-cancer activity using MDA-MB-231 (human breast adenocarcinoma) and A375 (malignant melanoma) cell lines through in vitro MTT assay which suggest comparable cancer cell killing efficacy, with the higher effectiveness of 2 due to the dissociation into two [Cu(peoh)(N3)] units.

A disaggregation-driven BODPIY-based probe for ratiometric detection of G4 DNA

In conventional systems, fluorescent probes with planar structures usually experience the phenomenon of aggregation-induced quenching (ACQ) that limits their practical applications in bio-medical sensing. To confront such problem, an attractive way is to develop a disaggregation-induced emission (DIE) sensing strategy, where the quenched fluorescence is recovered via a disaggregation process. Currently most of the fluorescent probes designed based on DIE mechanism are signal off-on type with the fluorescent intensity changed at a single wavelength. On the other hand, ratiometric fluorescent probes have the advantage of having two distinct emission wavelengths, effectively avoiding environmental interference. The DIE probes with a ratiometric fluorescence response still poorly established. Herein, we report a BODIPY-based probe BODPA, where a 2,2′-dipicolylamine group was introduced to the meso-position of BODIPY core, for the selective ratiometric detection of G-quadruplex (G4) DNA. This probe in buffer solution formed aggregates with weak fluorescence at 508 nm. In the presence of G4 DNA, bright fluorescence was emitted at 518 nm through DIE mechanism. Taking advantage of the ratiometric manner, probe BODPA exhibited selectivity for G4 DNA over duplex DNA. The binding details between probe BODPA and G4 DNA were assessed by spectroscopic and molecular modeling methods, which suggested the ability of this probe could coordinate with G4 structure via end stacking and partial groove binding mode.

Abstract 5805: A novel platform of diversified payloads to drive ADC innovation

Abstract First generation of antibody drug conjugates (ADCs) for anticancer therapy has been described more than two decades ago with gemtuzumab-ozogamicin receiving the first approval in 2000. Over the last 4 years, 8 new ADCs got FDA approval essentially due to the innovation on the linker improving the disposition in patients and the manufacturability together with the technical advantages in the engineering of biologics and the introduction of new cytotoxic payloads such as deruxtecan. In the future, next generation ADCs will be developed exploring payloads beyond the currently used cytotoxins to improve safety, efficacy and durability of responses and therefore the short- and long-term therapeutic benefit to patients. Nerviano Medical Sciences (NMS) generated a portfolio of novel and diversified payload linkers leveraging on its proprietary chemical collection that includes cytotoxic and targeted payloads. A rigorous screening funnel has been applied considering diversification in terms of MoAs, pharmacokinetic properties, mechanism of resistance and combinability with other therapies to identify the optimal match with specific tumor types and targets, generating a new class of ADCs with improved selectivity and efficacy for hard-to-treat cancers even in chemoresistant settings. NMS ADC platform incorporates 1) our patent protected payload linker NMS-P945, a duocarmycin like DNA minor groove binder and alkylating agent inducing DNA damage, acting in chemoresistant cells with bystander effect and immunogenic cell death properties and generating ADCs highly efficacious in mouse xenograft models and safe when administered in NHP, 2) novel anthracyclines (PNU-682 derivatives) with an improved stability and safety profile and 3) targeted molecules with different mechanism of action including payloads active in synthetic lethality contexts. Payload linkers with different functionalization generated from each payload have been evaluated for chemical stability, sensitivity to lysosomal protease cleavage, and conjugability to monoclonal antibodies. The ADCs, generated with proof-of-concept antibodies (e.g. Trastuzumab), were characterized in terms of Drug to Antibody Ratio (DAR), aggregation level, plasma stability, antigen binding and differential antiproliferative activity in target positive vs target negative tumor cells. The best products resulting from the screening funnel have been subjected to a multidimensional analysis taking into consideration payload properties, tumor features and antigen expression in selected populations with the aim of identifying tumor types particularly sensitive to the payload. Our multidimensional approach coupling new payload linker with innovative MoA to careful selection of patients will allow to reach unprecedented efficacy and safety profile. Citation Format: Paolo Orsini, Matteo Salsa, Simona Rizzi, Ulisse Cucchi, Daniela Faiardi, Alessia Burocchi, Antonella Ciavolella, Rosita Lupi, Fabio Gasparri, Barbara Valsasina. A novel platform of diversified payloads to drive ADC innovation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5805.

Synthesis and DNA Interactions Study of Novel Fluorinated Pyridinium Platinum (IV) Complexes with Tumor Targeting Activity

AbstractPicoplatin can effectively circumvent cisplatin‐induced resistance through the “steric hindrance effect” of its structure, but there are still problems such as toxicity and side effects, so the search for safer, more efficient platinum analogs is crucial. Here we report three fluorinated pyridine‐containing Pt(IV) complexes employing biotin as an axial ligand to provide targeting functionality. Lipid solubility studies showed that all the synthesized complexes possessed improved lipid‐water partition coefficients, which are beneficial for transmembrane transport of drugs. The DNA binding activity of the compounds was studied using UV titration, fluorescence titration, and PicoGreen staining, demonstrating the presence of potential intercalation and electrostatic interaction binding modes. It probably attributable to planar π‐π interactions provided by the aromatic pyridine ligands. Meanwhile, molecular docking studies showed that the introduction of axial biotin molecules allowed the complexes to effectively target cancer cells, which was simultaneously confirmed by the results of cellular uptake studies. And another docking result showed that the Pt(IV) complexes binds to DNA by minor groove binding. The synthesized complexes exhibited similar cytotoxicity to cisplatin in five cell lines (SW480, HCT116, HepG2, A549 and LO2), with complex 3 being superior to the parent drug, picoplatin.

An Efficient Probe-Based Quantitative PCR Assay Targeting Human-Specific DNA in ST6GALNAC3 for the Quantification of Human Cells in Preclinical Animal Models.

Precise quantification of human cells in preclinical animal models by a sensitive and specific approach is warranted. The probe-based quantitative PCR (qPCR) assay as a sensitive and swift approach is suitable for the quantification of human cells by targeting human-specific DNA sequences. In this study, we developed an efficient qPCR assay targeting human-specific DNA in ST6GALNAC3 (termed ST6GAL-qPCR) for the quantification of human cells in preclinical animal models. ST6GAL-qPCR probe was synthesized with FAM and non-fluorescent quencher-minor groove binder conjugated to the 5' and 3' end of the probe, respectively. Genomic DNA from human, rhesus monkeys, cynomolgus monkeys, New Zealand White rabbits, SD rats, C57BL/6, and BALB/c mice were utilized for analyzing the specificity and sensitivity of the ST6GAL-qPCR assay. The ST6GAL-qPCR assay targeted human-specific DNA was cloned to pUCM-T vector and released by EcoR I/Hind III digestion for generating a calibration curve. Cell mixing experiment was performed to validate the ST6GAL-qPCR assay by analysis of 0.1%, 0.01%, and 0.001% of human leukocytes mixed with murine thymocytes. The ST6GAL-qPCR assay detected human DNA rather than DNA from the tested animal species. The amplification efficiency of the ST6GAL-qPCR assay was 93% and the linearity of calibration curve was R2 = 0.999. The ST6GAL-qPCR assay detected as low as 5 copies of human-specific DNA and is efficient to specially amplify as low as 30-pg human DNA in the presence of 1μg of DNA from the tested species, respectively. The ST6GAL-qPCR assay was able to quantify as low as 0.01% of human leukocytes within murine thymocytes. This ST6GAL-qPCR assay can be used as an efficient approach for the quantification of human cells in preclinical animal models.

The Therapeutic Potential in Cancer of Terpyridine-Based Metal Complexes Featuring Group 11 Elements.

Terpyridine-based complexes with group 11 metals emerge as potent metallodrugs in cancer therapy. This comprehensive review focuses on the current landscape of anticancer examples, particularly highlighting the mechanisms of action. While Cu(II) complexes, featuring diverse ancillary ligands, dominate the field, exploration of silver and gold species remains limited. These complexes exhibit significant cytotoxicity against various cancer cell lines with a commendable selectivity for non-tumorigenic cells. DNA interactions, employing intercalation and groove binding, are pivotal and finely tuned through terpyridine ligand functionalization. In addition, copper complexes showcase nuclease activity, triggering apoptosis through ROS generation. Despite silver's high affinity for nitrogen donor atoms, its exploration is relatively sparse, with indications of acting as intercalating agents causing DNA hydrolytic cleavage. Gold(III) compounds, overshadowing gold(I) due to stability concerns, not only intercalate but also induce apoptosis and disrupt the mitochondrial membrane. Further investigations are needed to fully understand the mechanism of action of these compounds, highlighting the necessity of exploring additional biological targets for these promising metallodrugs.

Probing the interaction of an antiviral drug 8-methoxy-3-nitro-2-(4-methoxyphenyl)-2H-chromene (MNC) with DNA by experimental and computational approach

Deoxyribonucleic acid (DNA) is a major target in research pertaining to antiviral and anticancer therapies since it is the principal genetic material that controls vital biological functions. The complex relationship between calf thymus DNA (ct-DNA) and 8-Methoxy-3-nitro-2-(4-methoxyphenyl)-2H-chromene (MNC), an anticancer drug derivative of 2-aryl-3-nitro-2H-chromenes, is explored in this work. Using various spectroscopic methods such as fluorescence, circular dichroism (CD), UV–visible, isothermal titration calorimetry (ITC) experiment, and molecular docking calculations, this study elucidates the binding characteristics and affinity between MNC and ct-DNA. Through predominant groove binding and moderate intercalation, MNC demonstrates a complicated binding pattern with DNA at the minor groove, as shown by the UV–Vis spectra and emission-based dye displacement investigations. DNA undergoes a little conformational change that MNC induces, as shown by CD spectroscopy. The thermodynamics parameters such as the binding constant, binding enthalpy, and binding free energy of DNA-MNC interaction, as calculated by the ITC experiment, were approximately ∼ 104 M−1, −26 kcal mol−1, and 6 kcal/mol, respectively. The binding process is enthalpy driven implying a stabilizing contact of MNC with DNA and the entropic penalty (−TΔS = +20.1 kcal mol−1) points to a reduction in the degree of freedom of movement. The molecular docking investigation also estimates the similar interaction energy and binding locations of MNC with DNA. Interestingly, MNC attaches to the surface of the DNA via electrostatic interactions; a stronger attachment through van der Waals and hydrophobic contacts within the minor groove follows this. These studies are anticipated to provide researchers with important direction for designing new drug molecules for further biomolecular investigations.

Copper(II) complexes incorporated with 2,2-bipyridyl and 2,2′-(((1E,1′E)-1,4-phenylene-bis(methanylylidene))bis(azanylylidene)) diphenol derivatives: In-vitro interaction with DNA/BSA, DFT, molecular docking and cytotoxicity

Certain metal complexes have created their own benchmark in the category of cytotoxic drugs. Down the line, copper metal complexes are found among the most prominent biologically active agents of high reputation. Considering breast cancer as one of the epicenters in malignant tumors, a series of three new derivatives of copper(II) CuL1, CuL2 and CuL3 have been synthesized and characterized associated with newly developed ligands 2,2′-(((1E,1′E)-1,4-phenylene-bis(methanylylidene))bis(azanylylidene)) diphenol supported by 2,2-bipyridine. All the complexes appeared in tetracoordination with tetrahedral geometry. The complexes were made to bind with ct-DNA through groove binding as established by molecular docking and computational DFT studies carried out for the determination of the HOMO and LUMO interactions and ESP mapping. Further, confirmation of BSA binding with complexes was confirmed by UV and fluorescence spectral studies. All these copper complexes were subjected for DPPH assay to determine the antioxidant properties, cytotoxicity towards the breast adenocarcinoma was retrieved by MTT assay, dual staining and cell cycle analysis against MCF7 cell line. Eventually, new copper derivative CuL2 (IC50 = 30.20 μg/mL) was found to exhibit the highest anticancer activity as compared to CuL1 (IC50 = 41.07 μg/mL) and CuL3 (IC50 = 42.01 μg/mL).

A Nanoscale Trans-Platinum(II)-Based Supramolecular Coordination Self-Assembly with a Distinct Anticancer Mechanism.

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl2(pyridine)(NH3)] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.

Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine Lymphoma.

Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process. DNA binding studies of these selected derivatives by ultraviolet-visible (UV-vis), fluorescence spectroscopy, intercalating dye (EtBr, acridine orange)-DNA competitive assay, and minor groove binding dye Hoechst 33342-DNA competitive assay suggested that the synthesized novel molecules intercalated between the two strands of DNA due to its naphthalimide moiety and its counterpart artesunate binds with the minor groove of DNA. Napthalimide-artesunate conjugates inhibit the growth of lymphoma and induce apoptosis, including ready incorporation and reduction in cell viability. The remodeled drug has a significant tumoricidal effect against solid DL tumors developed in BALB/c mice in a dose-dependent manner. The novel drug appears to inhibit metastasis and increase the survival of the treated animals compared with untreated littermates.