Minor Groove Mode Research Articles

DNA binding, and apoptosis-inducing activities of a β-ionone-derived ester in human myeloid leukemia cells: multispectral and molecular dynamic simulation analyses

β-Ionone is the end-ring counterpart of β-carotenoids, which are widely found in fruits and vegetables. Recent studies have illustrated the antimetastatic, anti-proliferative, and apoptosis-inducing activities of β-ionone both in vitro and in vivo. We aimed to explore the anti-cancer potency of β-Ionone-derived ester, (E)-4-(2,6,6-trimethylcyclohex-1-enyl) but-3-en-2-ylpyrazine-2-carboxylate (4-TM.P). The cytotoxic effects of the compound on K562 cells were evaluated by MTT assay. The mechanisms of apoptosis induction were investigated by acridine orange/ethidium bromide (AO/EtBr) double staining, cell cycle analysis, and Annexin V/PI staining. Furthermore, the 4-TM.P-DNA interactions have been thoroughly elucidated by various methods, such as ultraviolet–visible spectroscopy, fluorescence assays, viscosity measurements, molecular docking, and dynamic simulation. The MTT cytotoxicity assay revealed that the growth of K562 cells was inhibited by treatment with β-ionone-derived ester, with an IC50 of 25 ± 5.0 µM at 72 h. Morphological studies revealed the occurrence of apoptosis in treated cells, and G0/G1 cell cycle arrest was observed after treatment of the cells with the IC50 value of the compound. Analyses of multi-spectroscopy and viscosity assays revealed that 4-TM.P binds to DNA in the minor groove mode, which was supported by molecular docking studies. The dynamic stability of the complex was also confirmed using molecular dynamic simulation analyses.

Novel Ni(II) Complexes as Minor Groove Binders: Crystal Structures, Biomolecular Interactions, Molecular Docking, and Biological Activities

ABSTRACTA novel ternary Ni(II) complexes, [Ni(5Clsal‐phe)(phen)(H2O)] (1) and [Ni(5Clsal‐phe)(bpy)(H2O)]CH3OH (2), (Schiff base derived from the condensation of L‐phenylalanine and 5‐chlorosalicylaldehyde, phen: 1,10‐phenanthroline, bpy: 2,2′‐bipyridine) has been synthesized. The structure of the complexes was clarified by CHN analysis, FTIR, electronic absorption spectroscopy, ESI‐MS, and X‐ray single crystal diffraction methods. In biological activity studies, the interactions of the complexes with calf thymus DNA (CT‐DNA) were examined using fluorescence spectroscopy. The results show that the complexes could bind to CT‐DNA via a minor groove mode. The interactions of the complexes with bovine serum albumin (BSA) were investigated using electronic absorption and fluorescence spectroscopy techniques, and the BSA quenching mechanism was found. The radical scavenging activity of the complexes was investigated in comparison with hederacolchiside, taxifoline, hederasaponin, arachidonoyl dopamine, and silychristin used as standard. Molecular docking simulations were employed to investigate the interactions between the complexes and biomolecules such as DNA and BSA. The results revealed that the complexes insert into DNA via the minor groove and bind to BSA at subdomains I and IIA. These interactions are facilitated by conventional hydrogen bonds, van der Waals forces, alkyl, and π‐alkyl interactions.

Bromo substituted aroylhydrazones: Synthesis, crystal structures, Hirshfeld surface analysis, 3D energy frameworks, DNA/BSA binding, and antimicrobial activity

Two bromo substituted aroylhydrazones such as 2-benzoylpyridine-4-bromobenzhydrazone (HBpB) and di-2-pyridyl ketone-4-bromobenzhydrazone (HDpB) were synthesized. The synthesized compounds have been characterized physicochemically using CHNS analysis, FT-IR, UV-vis absorption, 1H NMR and high resolution-mass spectra and the structures have been confirmed with single crystal X-ray diffraction technique. HBpB got crystallized in the monoclinic P21/c space group and the HDpB in the triclinic P1¯ space group. The supramolecular interactions present in the crystal system were studied with Hirshfeld surface (HS) analysis. The energy frameworks have been built by using different intermolecular interaction energies in order to study the stability of the molecule and determine the dominant energy type. The average interaction energy values for compounds HBpB and HDpB are found to be -280.4 and -327.2 kJ mol−1, respectively. Further, the nature of frontier orbitals and the stability of the compounds in the gas phase were theoretically analyzed, and the electrostatic potential surface diagram were plotted on optimized geometries. The binding potentials of HBpB and HDpB with DNA and BSA protein were investigated using spectroscopic, electrochemical, and in silico molecular docking methods. The results showed that HBpB has a higher binding affinity with both DNA and BSA compared to HDpB. Both HBpB and HDpB interact with DNA through a minor groove mode, while their binding to BSA involves mainly hydrophobic type. The ADMET analysis of compounds yielded favorable results for their potential use in pharmacological applications. When assessing the antibacterial capabilities of the tested samples, both the compounds showed good antimicrobial activities towards Klebsiella pneumonia, Bacillus Subtilis, Pseudomonas aeruginosa and Escherichia Coli.

Exploration of the Tungsten(VI) complex of hydroxamic acid's RNA binding affinity, histone deacetylase inhibitory activity, and antioxidant activity

Ribonucleic acid (RNA) is a versatile molecule, thus the opportunity to target RNA is abundant. Hence, the current exploration deals with the interaction of a metal complex of hydroxamic acid with t-RNA, along with HDAC8 inhibition activity and antioxidant activity. Binding characteristics of complex 1, Bis(N-phenylbenzohydroxamato)Tungsten(VI), which is represented as [N-PBHA-W(VI)] with Torula yeast RNA (t-RNA) were investigated by using several types of spectroscopic techniques, measurements of viscosity, and computational study through molecular docking. The intrinsic binding constant, Kb was evaluated for complex 1 which shows changes in the shift of absorption spectra, and the intensity of spectra also varies. From fluorescence measurement, the binding constant of complex 1 towards t-RNA is 6.64 ± 0.05 × 105 M−1. Stern-Volmer quenching constant was calculated. Two displacement method sare performed by using the fluorescence spectroscopic technique which discloses a groove mode of binding. The groove mode of binding is also uncovered by viscosity measurement, which was observed by increasing the complex 1 concentration. An electrochemical investigation was carried out by using cyclic voltammetry. A circular dichroism study was also employed, which further suggests a strong binding occurred between the metal complex used and t-RNA. The docked postures of t-RNA with complex 1 expose the strong interactions which suggest a minor groove mode of binding. All the experimental evidence indicates that the interaction of complex 1 with t-RNA is a minor groove mode of binding which complements the molecular docking results. In-silico studies of HDAC8 inhibition activity of complex 1 reveal that the inhibition takes place mainly by hydrophobic interaction. DPPH–radical scavenging method employed for the antioxidant activity.

Synthesis, crystal structure, Hirshfeld surface analysis, DFT, molecular docking and in vitro antitumor studies of (2E)-2-[4-(diethylamino)benzylidene]-N-ethylhydrazinecarbothioamide

The crystal structure and spectral characterization of a new proligand, (2E)-2-[4-(diethylamino)benzylidene]-N-ethylhydrazinecarbothioamide is described. The compound was crystallized in the monoclinic space group P21/c; Z = 8, V = 3192.7(8) Å3 with unit cell parameters a = 26.232(4) Å, b = 7.9196(10) Å, c = 15.369(3) Å,α = 90°, β = 90.217(6)° and γ = 90°. There are two independent molecules in the asymmetric unit. The crystal structure reveals that the compound exists in the thione form and S1 and N2 are at E configuration to each other with respect to N3–C12 bond. Similarly, S2 and N6 are trans to each other with respect to N7–C26 bond in the second molecule of the asymmetric unit. The packing of the molecules in the crystal lattice is stabilized by intermolecular hydrogen bonds, which are quantified with Hirshfeld surface analysis. The synthesized compound was characterized by IR, UV–vis, 1H and 13C NMR spectra. DFT study indicates the molecular chemical stability with a HOMO-LUMO energy gap of 3.79 eV. The molecule is soft with preference for NS coordination mode. The azomethine nitrogen and thione sulfur region are electron rich and can act as a nucleophilic site to bind with the electrophilic regions of DNA or protein receptors. The in silico docking study with 1BNA suggests that the compound can fit comfortably in the curved shape of the DNA target like a minor groove mode of binding. The in vitro cytotoxicity of the compound, which was screened for DLA tumour cells aspirated from the peritoneal cavity of tumor bearing mice, is indicative of its antitumor potential.

Loading of DOX into a tetrahedral DNA nanostructure: the corner does matter.

With the rapid development of nanotechnology, various DNA nanostructures have been synthesized and widely used in drug delivery. However, the underlying mechanisms of drug molecule loading into the DNA nanostructure are still elusive. In this work, we systematically investigate the interactions of a tetrahedral DNA nanostructure (TDN) with the anti-cancer drug doxorubicin (DOX) by combining molecular docking and all-atom molecular dynamics simulations. It is found that there are five possible binding modes in the single TDN–DOX interactions, namely the outside-corner mode, the inside-corner mode, the major-groove mode, the minor-groove mode, and the intercalation mode, where the van der Waals (VDW) interaction and the electrostatic (ELE) interaction dominate in the case of unionized DOX and ionized DOX, respectively. Moreover, with the increase of the DOX number, some of the interaction modes may disappear and the inside-corner mode is the most energy-favorable mode. The present study enhances the molecular understanding of the role of TDN as the drug carrier, which may provide a useful guideline for the future design of DNA nanostructures.

Synthesis, spectroscopic and crystal structure of nickel(II) complex of thiosemicarbazone basedSchiff base: Antimicrobial, anticancer and molecular docking studies

A new thiosemicarbazone based ligand synthesized by the facile condensation reaction of 3-ethoxy salicylaldehyde and 4-phenylthiosemicarbazide. Ni(II) complex prepared by the further reaction of thiosemicarbazoneligand with bis(triphenylphosphine)nickel(II) dichloride and formed complex has the chemical formula of [Ni(PPh3)(L)].1H NMR, FT-IR, UV–Visible and single crystal X-ray diffraction techniques were used to characterize the ligand and Ni(II) complex. The findings indicated that the proposed structural framework of Ni(II) complex is distorted tetrahedral geometry.Antibacterial activities of ligand and Ni(II) complex validated against three different bacteria such as Staphylococci aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa)and Escherichia coli (E. coli) by agar well diffusion method. The results revealed that Ni(II) complex has better antibacterial activities than the ligand. The in vitro cytotoxic activities of the ligand and Ni(II) complex were studied on human breast cancer cell lines (MCF-7) by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.The result showed that ligand and Ni(II) complexes possess significant anticancer ability against the MCF-7 cancer cell lines. Molecular docking of testing compounds with Human Serum Albumin(HSA) and Deoxy ribonucleic acid(DNA) was investigated.The obtained atomic contact energy (ACE)values suggested that Ni(II) complex had a better interacting ability with HSA and DNA molecules than ligand. Based on the molecular docking results, the prepared compounds can interact with DNA through a minor groove mode. The overall results suggested that, the prepared Ni(II) complex would be act as potent anticancer agent with significant targeting efficacy.

Synthesis, DNA-Binding, Anticancer Evaluation, and Molecular Docking Studies of Bishomoleptic and Trisheteroleptic Ru-Diimine Complexes Bearing 2-(2-Pyridyl)-quinoxaline.

Herein, we report the synthesis and characterization of a bishomoleptic and a trisheteroleptic ruthenium (II) polypyridyl complex, namely, [Ru(bpy)2(2, 2′-pq)](PF6)2 (1) and [Ru(bpy) (phen) (2, 2′-pq)](PF6)2 (2), respectively, where bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, and 2, 2′-pq = 2-(2′-pyridyl)-quinoxaline. The complexes were characterized by elemental analysis, TGA, 1H-NMR, FT-IR, UV-Vis, emission spectroscopy, and electrochemistry. Their structures were confirmed by single-crystal X-ray diffraction analysis. Complexes 1 and 2 were crystalized in orthorhombic, Pbca, and monoclinic, P21/n systems, respectively. Various spectroscopic techniques were employed to investigate the interaction of both complexes with calf thymus DNA (CT-DNA). The experimental data were confirmed by molecular docking studies, employing two different DNA sequences. Both complexes, 1 and 2, bind with DNA via a minor groove mode of binding. MTT experiments revealed that both complexes induce apoptosis of MCF-7 (breast cancer) cells in low concentrations. Confocal microscopy indicated that 2 localizes in the nucleus and internalizes more efficiently in MCF-7 than in HEK-293.

Unraveling the binding mechanism of an Oxovanadium(IV) – Curcumin complex on albumin, DNA and DNA gyrase by in vitro and in silico studies and evaluation of its hemocompatibility

An oxovanadium(IV) – curcumin based complex, viz. [VO(cur)(2,2´-bipy)(H2O)] where cur is curcumin and bipy is bipyridine, previously synthesized, has been studied for interaction with albumin and DNA. Fluorescence emission spectroscopy was used to evaluate the interaction of the complex with bovine serum albumin (BSA) and the BSA-binding constant (Kb) was calculated to be 2.56 x 105 M-1, whereas a single great-affinity binding site was revealed. Moreover, the hemocompatibility test demonstrated that the complex presented low hemolytic fraction (mostly below 1%), in all concentrations tested (0-250 μΜ of complex, 5% DMSO) assuring a safe application in interaction with blood. The binding of the complex to DNA was also investigated using absorption, fluorescence, and viscometry methods indicating a binding through a minor groove mode. From competitive studies with ethidium bromide the apparent binding constant value to DNA was estimated to be 4.82 x 106 M-1. Stern-Volmer quenching phenomenon gave a ΚSV constant [1.92 (± 0.05) x 104 M-1] and kq constant [8.33 (± 0.2) x 1011 M-1s-1]. Molecular docking simulations on the crystal structure of BSA, calf thymus DNA, and DNA gyrase, as well as pharmacophore analysis for BSA target, were also employed to study in silico the ability of [VO(cur)(2,2´-bipy)(H2O)] to bind to these target bio-macromolecules and explain the observed in vitro activity.

New insight into the DNA binding studies, In-Vitro anti-cancer activity and molecular modelling of dioxo complexes of Molybdenum(VI) and Tungsten(VI) hydroxamic acids

The present study embodies the detail of interaction of Complex 1, Bis(N-phenyl-o-methoxybenzohydroxamato)Molybdenum(VI): [N-PMBHA-Mo(VI)] and Complex 2, Bis(N-phenylbenzohydroxamato)Tungsten(VI): [N-PBHA-W(VI)] with ct-DNA (Calf thymus-DNA) and its consequences by UV–Visible absorption spectroscopy, fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, viscosity measurements and molecular docking. The intrinsic binding constant, Kb of complexes were determined which follows the order as complex 1 > complex 2 along with variation in shift and intensity for the complexes. Fluorescence spectroscopy applied for the determination of Stern–Volmer quenching constant, binding constant and the number of binding sites which reveals groove mode of binding. Non-radiative energy transfer between donor and acceptor molecule exposed by Förster energy transference theory (FRET) studies. The increase in the relative viscosity of ct-DNA with increasing the concentration of the complex 1 and complex 2 is also revealed. FTIR analysis also revealed that both the complexes interacted positively with bases and phosphates of ct-DNA. The docking studies complemented the experimental results revealing minor groove mode of binding for both the complexes. Finally, the in-vitro cytotoxicity studies indicate that the complexes have excellent anticancer activity against the breast cancer cell line, MCF-7, which could be a constructive guideline to produce new generations of anticancer agents.

Novel Phosphonium Dye TDV1 as a Potential Fluorescent Probe to Monitor DNA Interactions with Lysozyme Amyloid Fibrils

The applicability of the novel cationic phosphonium dye TDV1 to monitor the complexation between DNA and pathologically aggregated proteins, amyloid fibrils, was tested using the optical spectroscopy and molecular docking techniques. TDV1 has been found to be highly emissive in buffer solution and is characterized by one well-defined fluorescence peak attributed to the dye monomers. The association of the dye with the double stranded DNA was followed by the enhancement of monomer fluorescence coupled with a bathochromic shift of the emission maximum. The addition of fibrillar lysozyme (LzF) to TDV1-DNA mixture led to the further enhancement of fluorescence intensity of the monomeric dye form coupled with a hypsochromic shift of the emission maximum and an appearance of a second long-wavelength peak. An assumption has been made that the fluorescence enhancement augmenting with increasing the protein concentration in the TDV1/DNA system is produced by the interaction of the free TDV1 monomers with lysozyme fibrils as well as by the LzF-induced conformational alterations of DNA. The long-wavelength peak emerging in the presence of LzF is presumably a consequence of the J-aggregate formation upon the TDV1 association with lysozyme fibrils. The molecular docking studies showed that TDV1 monomers are incorporated into the fibril grooves associating with 7 β-strands in such a way that the dye long axis is parallel to the fibril axis. The most energetically favorable position of TDV1 is the S60-W62/G54-L56 groove in the lysozyme fibril core. In contrast, the TDV1 dimers seem to associate with the more hydrophilic side of the model β-sheet. Cumulatively, the results from the absorption and fluorescence measurements, together with the molecular docking analysis are consistent with the minor groove mode of the TDV1 binding to dsDNA. The electrostatic interactions seem to play a predominant role in the TDV1 complexation with the double stranded DNA, while the hydrophobic interactions and steric hindrances are supposed to be influential in the association of TDV1 with fibrillar lysozyme.

DNA/Lysozyme-binding affinity study of novel peptides from TAT (47-57) and BRCA1 (782-786) in vitro by spectroscopic analysis.

SISLL-TAT and TAT-SISLL were synthesized by modifying the N- or C-termini of cell-penetrating peptides as transacting activator of transcription TAT (47-57) by attaching BRCA1 (782-786) (SISLL). The novel peptides were synthesized through Fmoc solid-phase synthesis procedures and characterized by LCQ Fleet MS, 1H NMR and 13C NMR. SISLL-TAT and TAT-SISLL displayed forceful antibacterial activities against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Salmonella typhimurium with low hemolysis. SISLL-TAT showed better antibacterial activity than TAT-SISLL, with the minimum inhibitory concentration (MIC) values of 10-33 μg·mL-1. The results of the DNA-binding activities showed that both SISLL-TAT and TAT-SISLL could interact with DNA via the minor groove mode, and the binding constants were 4.97 × 105 L·mol-1 and 4.42 × 105 L·mol-1 at 310 K, respectively. Circular dichroism analysis showed slight transformation of the lysozyme secondary structure caused by SISLL-TAT and TAT-SISLL. We also found that the novel peptides SISLL-TAT and TAT-SISLL targeted bacterial DNA resulting in cell death. This explains the antibacterial mechanism of SISLL-TAT and TAT-SISLL, and is a solid theoretical basis for further designing novel and highly effective antibiotics for clinical application.

Studies of DNA-binding properties of lafutidine as adjuvant anticancer agent to calf thymus DNA using multi-spectroscopic approaches, NMR relaxation data, molecular docking and dynamical simulation

The interactions between lafutidine (LAF) and calf thymus DNA (ctDNA) have been investigated both experimentally and theoretically. UV–vis absorption studies confirmed that LAF binds to ctDNA through non-covalent interactions. Fluorescence quenching and time-resolved fluorescence spectroscopy studies showed that the binding of LAF with ctDNA occurred through static quenching mechanism, resulting in the formation of a LAF–ctDNA complex. The binding constants (K) of the complex were found to be around 103M−1 via NMR relaxation rates and fluorescence data, and the calculated thermodynamic parameters indicated that hydrogen bonds and van der Waals forces played major roles in the binding of LAF to ctDNA. The changes in CD spectra indicated that LAF induced a slight perturbation on the base stacking and helicity of B-DNA. A comparative study of the LAF–ctDNA complex with respect to potassium iodide quenching experiments and competition displacement assays with ethidium bromide, acridine orange, and Hoechst 33258 probes suggested that LAF interacted with ctDNA by minor groove mode. Molecular docking analysis further supported the minor groove binding. Molecular dynamics simulation indicated that LAF depart from the C-G region of DNA, but it can steadily bind with the middle part of DNA composed by A-T base pairs.

Energetics, Thermodynamics, and Molecular Recognition of Piperine with DNA.

Piperine, the bioactive phytochemical from black pepper (Piper nigrum L.), is a nontoxic natural compound exhibiting many physiological and pharmacological properties. They include antioxidant, anti-inflammatory, antimutagenic, antitumor, antiapoptotic, antigenotoxic, antiarthritic, antifungal, antimicrobial, antidepressant, anti-HBV, and gastro-protective activities. It also enhances the bioavailability of phytochemicals and drugs. The molecular mechanism of action of piperine with DNA has not yet been addressed, while its pharmacological activities have been reported. In this work we report for the first time the interaction of piperine molecule with DNA duplex. We have carried out UV-vis absorption and fluorescence spectroscopy to confirm the binding of piperine with calf thymus DNA (ctDNA). The energetics of interaction of piperine with ctDNA was monitored by isothermal titration calorimetry (ITC). Differential scanning calorimetry (DSC) and melting temperature (Tm) analysis were also performed, confirming a minor groove mode of binding of piperine with ctDNA. The binding free energy ΔG values obtained from molecular dynamics simulation studies agree well with ITC values and reveal a sequence dependent minor groove binding exhibiting a specificity toward AT rich sequences.

Dinuclear manganese(II) complexes of hexaazamacrocycles bearing N-benzoylated pendant separated by aromatic spacers: Antibacterial, DNA interaction, cytotoxic and molecular docking studies

Three new homodinuclear manganese(II) complexes of the type [Mn2L1–3(ClO4)(H2O)](ClO4)3 (1–3) have been synthesized via cyclocondensation of terephthalaldehyde with three different benzoylated pendants in the presence of manganese(II) perchlorate and characterized by spectroscopic methods. Cyclic voltammetric investigation of complexes (1–3) depict two quasi-reversible one electron reduction processes in the cathodic potential region (E1pc=–0.73 to–0.83V, E2pc=–1.31 to −1.40V) and two quasi-reversible one electron oxidation processes in the anodic potential region (E1pa=1.03 to 1.10V, E2pa=1.69 to 1.77V). Electronic absorption spectra of the complexes suggested tetrahedral geometry around the central metal ion. The observed low magnetic moment values (μeff, 5.60–5.68 B.M.) of the complexes indicate the presence of an antiferromagnetic spin–exchange interaction between two metal centers, which was also supported by the broad EPR signal. All the compounds were tested for antibacterial activity against Gram (–ve) and Gram (+ve) bacterial strains. The binding studies of complexes with CT-DNA suggested minor-groove mode of interaction. Molecular docking studies were carried out in order to find the binding affinity of complexes with DNA and protein EGFR Kinase. The complexes are stabilized by additional electrostatic and van der Waals interaction with the DNA, and support minor groove mode of binding. The cleavage activity of complexes on pBR322 plasmid DNA displays efficient activity through a mechanistic pathway involving hydroxyl radicals. The cytotoxicity of complexes 2 and 3 have been tested against human liver adenocarcinoma (HepG2) cell line. Nuclear-chromatin cleavage has also been observed with propidium iodide (PI) staining and alkaline single-cell gel electrophoresis (comet assay) techniques.

Phosphate-hydrolysis, antioxidant, DNA binding, and nuclease activities promoted by heteroleptic nickel(II) phenolate complexes

Eight heteroleptic nickel(II) complexes of the type [NiL1–4(co-ligand)] 1–8, where L1–4 = N 1,N 2-bis(5-substituted-2-hydroxybenzylidene)-1,2-ethylene/phenylene diimine and co-ligand = 2,2′-bipyridyl (bpy) or 1,10-phenanthroline (phen), have been synthesized and fully characterized by analytical and spectral methods. The six-coordinated octahedral geometry around the nickel(II) center was inferred from the electronic spectra of the complexes. Cyclic voltammetric studies of the complexes evidenced one-electron irreversible nature of reduction and oxidation process. The observed rate constant (k) values for the hydrolysis of 4-nitrophenylphosphate are in the range of 0.24–2.53 × 10−2 min−1. The obtained room temperature magnetic moment values (2.96–3.31 BM) lies within the range observed for octahedral nickel(II) complexes. Antioxidant studies suggest the considerable radical-scavenging potency of the complexes against DPPH radical. The DNA-binding studies of complexes with calf thymus DNA revealed intercalation with minor-groove mode of binding. The nuclease activity on supercoiled pBR322 DNA revealed the involvement of hydroxyl radical and singlet-oxygen as reactive oxygen species and complexes encourage binding to minor-groove.

Surfactant–copper(II) Schiff base complexes: synthesis, structural investigation, DNA interaction, docking studies, and cytotoxic activity

A series of surfactant–copper(II) Schiff base complexes (1–6) of the general formula, [Cu(sal-R2)2] and [Cu(5-OMe-sal-R2)2], {where, sal = salicylaldehyde, 5-OMe-sal = 5-methoxy- salicylaldehyde, and R2 = dodecylamine (DA), tetradecylamine (TA), or cetylamine (CA)} have been synthesized and characterized by spectroscopic, ESI-MS, and elemental analysis methods. For a special reason, the structure of one of the complexes (2) was resolved by single crystal X-ray diffraction analysis and it indicates the presence of a distorted square-planar geometry in the complex. Analysis of the binding of these complexes with DNA has been carried out adapting UV-visible-, fluorescence-, as well as circular dichroism spectroscopic methods and viscosity experiments. The results indicate that the complexes bind via minor groove mode involving the hydrophobic surfactant chain. Increase in the length of the aliphatic chain of the ligands facilitates the binding. Further, molecular docking calculations have been performed to understand the nature as well as order of binding of these complexes with DNA. This docking analysis also suggested that the complexes interact with DNA through the alkyl chain present in the Schiff base ligands via the minor groove. In addition, the cytotoxic property of the surfactant–copper(II) Schiff base complexes have been studied against a breast cancer cell line. All six complexes reduced the visibility of the cells but complexes 2, 3, 5, and 6 brought about this effect at fairly low concentrations. Analyzed further, but a small percentage of cells succumbed to necrosis. Of these complexes (6) proved to be the most efficient aptotoxic agent.

DNA Binding by 4-Methoxypyrrolic Natural Products. Preference for Intercalation at AT Sites by Tambjamine E and Prodigiosin.

The 4-methoxypyrrolic natural products contain a common 4-methoxy-2,2'-bipyrrole chromophore and exhibit promising anticancer, antimicrobial, and immunosuppressive activities. Herein, the ability of two representative members, tambjamine E (1) and prodigiosin (2), to bind calf thymus DNA (CT-DNA), polyd[G-C](2), and polyd[A-T](2) has been characterized using absorption and fluorescence spectroscopy. Scatchard plots showed that 1 occupies a site size (n) of ca. three base pairs and possesses affinity constants (K) ranging from 1 to 0.1 x 10(5) M(-)(1). Prodigiosin (2) binds DNA by mixed modes, as isobestic points were not evident in titration experiments. The neutral aldehyde precursor 4 was found to possess no measurable DNA binding affinity, indicating that the enamine structure of 1 and the pyrromethene of 2 are essential elements for DNA binding affinity. The enamine of 1 was found to undergo hydrolysis to 4 with a half-life (t(1/2)) of 14.5 h at pH 7.4 and 37.5 degrees C. For the B-ring nitrogen atom of 1, a pK(a) value of 10.06 was also established. From fluorescence spectroscopy it was found that 1, 2, and 4 possess weak emission spectra in water that is increased in nonaqueous solvents. For 1 and 2, DNA binding also increased the emission yield. Energy-transfer measurements suggested an intercalative binding mode, with preference for AT sites. The ability of distamycin to displace 1 and 2 from the helix also suggested that they intercalate from the minor-groove. This specificity differs from other unfused aromatic cations that bind by a minor-groove mode at AT sequences and intercalate at GC sites. Reasons for the specificity displayed by 1 and 2, as well as the implications of our findings to their biological properties are discussed.

Measurement and interpretation of Q 0 and Q 1 band property changes of two cationic metalloporphyrins upon binding with B-DNA: electronic MCD, CD, and optical absorption

Room-temperature Q-band electronic MCD, CD, and optical spectra are reported for the first time for two free and nucleic acid-bound cationic metalloporphyrins. Metalloporphyrins are the high-symmetry ( C 4v or D 4h ) , four-coordinate tetragonal type MP( X) [M=Cu II and Pt II; P( X)= meso-tetrakis( X-N-methylpyridyl)porphine; X=2 or 4], and the nucleic acid is native, B-form calf thymus DNA (CT DNA). For intercalation system PtP(4)/CT DNA, large optical ( λ 0, ϵ max) and MCD ( λ peak, λ trough, A aj , A aj / D aj , and Δ[ θ] M p–t/ ϵ max) band parameter shifts, as well as a single negative (−) induced CD peak for each of Q 0 and Q 1, were observed upon binding of the porphyrin to chiral DNA. The directions and magnitudes of these changes are comparable to those observed for the Soret (B 0) band of this system. Decreases of MCD/optical ratio Δ[ θ] M p–t/ ϵ max(∝ A aj / D aj ) of 30% (Q 0) and 50% (Q 1) upon intercalation indicate substantial reductions of the Q 0[ 1 E u ( a) (0,0),∼1 a 1 u 1 4 e g 1] and Q 1[ 1 E u ( a) (0,1),∼1 a 1 u 1 4 e g 1] excited state angular momenta, 〈 L j 〉. It is of additional interest that intercalation leads to intensity cancellation of one of the four A-term lobes, the (+) lobe of the Q 0 MCD (+) pseudo-A-term, which was also observed previously for intercalation systems PdP(4)/poly(G–C) 2 and /CT DNA. Application of the CD sector method to the constituent x- and y-polarized porphyrin edtms, √ D aj , of the Q 0 (edtms μ 0 x and μ 0 y ) and Q 1 (edtms μ 1 x and μ 1 y ) CD bands leads to the conclusion that PtP(4) is symmetrically intercalated between adjacent GC base pairs, specifically at 5 ′GC3 ′ sites, with each of two adjacent 4- N-methylpyridyl groups extending into each of the major and minor grooves. For outside binder CuP(2), small optical and MCD band parameter shifts and smaller, single positive (+) induced CD peaks are observed for Q 0 and Q 1 upon interaction with CT DNA, similar to what is found for B 0. Little or no change in the MCD/optical ratio, Δ[ θ] M p–t/ ϵ max, informs that external binding has only small effects on the excited state angular momenta, 〈 L j 〉, of these bands. The composite of MCD, CD, and optical spectra are consistent with CuP(2) binding to CT DNA by one or both of two competing external modes, i.e., by an AT-specific, edge-on minor groove mode at 5 ′TA3 ′ sites and/or a face-on major groove mode with high selectivity for 5 ′AT3 ′ or 5 ′CG3 ′ sites. For Q 0 and Q 1 of each of the CuP(2)/CT DNA and PtP(4)/CT DNA systems, we observe that the genuine MCD (+) A-terms of these free MP(X)s retain their (+) sign on becoming pseudo-A-terms upon binding to the low-symmetry, asymmetric DNA sites, and this indicates that the external and intercalative modes result in the 4e g splitting, or ΔLUMO, being less than the |1a 1u–3a 2u| energy separation, or ΔHOMO.

Characterization of Zn(II)·Deglycobleomycin A2 and Interaction with d(CGCTAGCG)2: Direct Evidence for Minor Groove Binding of the Bithiazole Moiety

Deglycobleomycin (dgBLM) binds to and degrades the self-complementary oligonucleotide d(CGCTAGCG)2 in a sequence-selective fashion. To characterize the binding interaction, a 1:1 complex of Zn(II)·dgBLM A2 with the DNA octanucleotide has been examined using two-dimensional NMR experiments and restrained molecular dynamics calculations. Critical elements of the mode of DNA interaction within two structural domains of Zn(II)·dgBLM A2 were fundamentally different than those observed previously for Zn(II)·BLM A2 (Manderville, R. A.; Ellena, J. F.; Hecht, S. M. J. Am. Chem. Soc. 1995, 117, 7891). A minor groove mode of binding by the bithiazole moiety is supported by the present study. Only slight upfield shifting of the bithiazole (Bit) protons Bit H5 and Bit H5‘ is observed, and the sequential intrastrand NOE connectivities are retained upon Zn(II)·dgBLM A2 binding. The orientation of the drug molecule in the complex is based on the finding of 16 intermolecular Zn(II)·dgBLM A2−DNA NOEs. The cationic C-substi...