Oxovanadium phenanthroimidazole derivatives: synthesis,DNA binding and antitumor activities

Four unsymmetrical oxovanadium phenanthroimidazole complexes, [VO(hntdtsc)(NPIP)] (1), [VO(hntdtsc)(CPIP)] (2), [VO(hntdtsc)(MEPIP)] (3) and [VO(hntdtsc)(HPIP)] (4) (hntdtsc = 2-hydroxy-1-naphthaldehyde thiosemicarbazone, NPIP = 2-(4-nitrophenyl)-imidazo[4,5-f]1,10-phenanthroline, CPIP = 2-(4-chlorphenyl)-imidazo[4,5-f]1,10-phenanthroline), MEPIP = 2-(4-methylphenyl)-imidazo[4,5-f]1,10-phenanthroline), HPIP = 2-(4-hydroxylphenyl)-imidazo[4,5-f] 1,10-phenanthroline), have been synthesized and characterized. Their DNA binding and antitumor activities were determined by biochemical methods. All four oxovanadium complexes can bind with CT-DNA by an intercalation model and can also cleave supercoiled plasmid DNA in the presence of H₂O₂. The antitumor properties and mechanism of the complexes have been analyzed by MTT assay, cell cycle analysis, apoptosis assay and Western blot analysis. The results showed that the free ligands and their corresponding complexes all possess antiproliferative activities with very low IC₅₀ values against Hela, BIU-87 and SPC-A-1 cell lines. Complex 1, which has a strongly electron-withdrawing nitro group, exhibited the best antiproliferative activities. Complex 1 caused G₀/G₁ phase arrest of the cell cycle and induced apoptosis in Hela cells. Additionally, complex 1 attenuated the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2).This indicates that inhibition of the ERK1/2 signaling pathway may contribute to the antitumor effects of these complexes.     

Voltammetric and spectroscopic studies on binding of antitumor Morin, Morin-Cu complex and Morin-beta-cyclodextrin with DNA

A systematic comparative study of the binding of antitumor Morin and its complexes with DNA has been investigated in the Britton-Robison (BR) buffer solutions using voltammetric and spectroscopic methods. The results show that Morin molecule, acting as an intercalator, is inserted into the cavity of the beta-cyclodextrin (beta-CD) as well as into the base stacking domain of the DNA double helix. The interaction of Morin-Cu complex or the inclusion complex of Morin-beta-CD with ds-DNA causes hypochromism in the absorption spectra, along with pronounced changes in the electrochemical behavior of the Morin complexes. An isobestic point and a new spectrum band appeared indicating the formation of the new system of Morin-Cu-DNA at lambda(m)=391 nm and Morin-beta-CD-DNA at lambda(m)=375 nm. The intercalation of Morin-Cu and Morin-beta-CD complexes with DNA produces an electrochemically inactive supramolecular complex. The binding constants were calculated from the increase of the solubility, the strong hypochromism, and the decrease in peak current of Morin and its complexes upon the addition of the host molecules. Calculation of the thermodynamic parameters of the interaction of the inclusion complex of Morin-beta-CD with DNA, including Gibbs free energy change, Helmholz free energy and entropy change shows that the complexation is a spontaneous process of association.     

Photoaddition of thienocoumarin derivatives to DNA: stoichiometry and kinetics of binding

Photoreaction of the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II) to DNA was studied. The quantitative evaluation of the photobound molecules was performed by means of inductively coupled plasma atomic emission spectrometry (ICP-AES), exploiting the presence of the sulphur atom inside the tricyclic chromophore. The concurrent estimation of the phosphorus atom, present exclusively in the macromolecule, allowed possible intercalation sites to be identified and their involvement in the photoaddition reaction to be determined. The development of a kinetic model made it possible to discriminate and evaluate the single kinetic events that constitute the overall photoaddition process of I and II to DNA.     

Synthesis, spectroscopic characterization and comparative DNA binding studies of Schiff base complexes derived from L-leucine and glyoxal

The mononuclear Schiff base complexes of the type, [ML(CH₃OH)₂] [M = Co(II), Ni(II), Cu(II) and Zn(II)] have been synthesized by template condensation of l-leucine and glyoxal. The complexes have been characterized on the basis of the results of the elemental analysis, molar conductance, magnetic susceptibility measurements and spectroscopic studies viz, FT-IR, Mass, ¹H NMR and ¹³C NMR spectra. The UV–vis and magnetic moment data revealed an octahedral geometry around Co(II), Ni(II) ion with distortion around Cu(II) ion complex confirmed by EPR data. The conductivity data show a non-electrolytic nature of the complexes. Absorption and fluorescence spectroscopic studies support that all the complexes exhibit a significant binding to calf thymus DNA.     

DNA binding and antitumor activities of zinc(II) complexes with some S-alkenyl derivatives of thiosalicylic acid

Transition Metal Chemistry - Two zinc(II) complexes with S-alkenyl derivatives of thiosalicylic acid as ligands have been synthesized and characterized by microanalysis, IR, 1H and 13C NMR...     

Comparative binding of antitumor drugs to DNA containing the telomere repeat sequence

Telomeres are the ends of the linear chromosomes of eukaryotes and consist of tandem GT-rich repeats in telomere sequence i.e. 500-3000 repeats of 5'-TTAGGG-3' in human somatic cells, which are shortened gradually with age. The G-rich overhang of telomere sequence can adopt different intramolecular fold-backs and tetra-stranded DNA structures, in vitro, which inhibit telomerase activity. In this report, DNA binding agents to telomere sequence were studied novel therapeutic possibility to destabilize telomeric DNA sequences. Oligonucleotides containing the guanine repeats in human telomere sequence were synthesized and used for screening potential antitumor drugs. Telomeric DNA sequence was characterized using spectral measurements and CD spectroscopy. CD spectrum indicated that the double-stranded telomeric DNA is in a right-handed conformation. Polyacrylamide gel electrophoresis was performed for binding behaviors of antitumor compounds with telomeric DNA sequence. Drugs interacted with DNA sequence caused changes in the electrophoretic mobility and band intensity of the gels. Depending on the binding mode of the anticancer drugs, telomeric DNA sequence was differently recognized and the efficiency of cleavage of DNA varies in the bleomycin-treated samples under different conditions. DNA cleavage occurred at about 1% by the increments of 1 micromM bleomycin-Fe(III). These results imply that the stability of human telomere sequence is important in conjunction with the cancer treatment and aging process.     

Solution processable indoloquinoxaline derivatives containing bulky polyaromatic hydrocarbons: synthesis, optical spectra, and electroluminescence

New hybrid materials featuring the dipolar fragment 6H-indolo[2,3-b]quinoxaline attached to the bulkier polyaromatic hydrocarbons such as fluoranthene, triphenylene, or polyphenylated benzene have been synthesized by a two-step procedure involving Sonogashira and Diels-Alder reactions. They were characterized by absorption, emission, electrochemical, thermal, and theoretical investigations. The electronic properties of the compounds were dominated by the 6H-indolo[2,3-b]quinoxaline chromophore, and the incorporation of polyaromatic hydrocarbons reduces the chances of nonradiative deactivation processes associated with the excited state and improves the emission properties. The compounds displayed cyan emission with moderate quantum efficiency when excited at the absorption maximum. All of the compounds exhibited an irreversible reduction process corresponding to the addition of electron at the quinoxaline segment. They showed moderate thermal stability and glass transition temperature greater than 100 °C. The presence of rigid 6H-indolo[2,3-b]quinoxaline and bulkier polyaromatic hydrocarbon segments enhances the thermal stability and glass transition temperature significantly. Finally, the dyes were successfully applied as an electron-transporting and emitting layer in multilayered organic light-emitting diodes comprising a N,N'-bis(l-naphthyl)-N,N'-diphenyl-1,1'-biphenyl-4,4'-diamine hole-transporting layer. The cyan emitting devices were characterized by moderate device performance parameters.     

The binding properties of photosensitizer methylene blue to herring sperm DNA: a spectroscopic study

Methylene blue (MB) is a phenothiazinium photosensitizer with promising applications in the photodynamic therapy (PDT) for anticancer treatment. The binding properties of MB to herring sperm DNA have been investigated by the measurements of absorption spectra, quenching experiments and the elucidation of the photobleaching processes. Remarkable hypochromic and bathochromic effects of MB in the presence of increasing amounts of DNA have been observed in the absorption spectra. The quenching of MB by the DNA bases obeys the Stern-Volmer equation and ferrocyanide quenching of MB in the absence and presence of DNA is also measured as extended experiments. Results from the above spectral measurements are all consistent with the intercalative binding mode of MB to DNA with the Kb value of 1.89 x 10(4) M(-1). The photobleaching processes of MB and its DNA complex have also been studies, which indicate that the photobleaching of MB and its DNA complex proceeds with different mechanisms and the reactive oxygen species are responsible for the self-sensitized photooxidation of MB.     

Gold dithiocarbamate derivatives as potential antineoplastic agents: design, spectroscopic properties, and in vitro antitumor activity

At present, cisplatin (cis-diamminodichloroplatinum(II)) is one of the most largely employed anticancer drugs as it is effective in the treatment of 70-90% of testicular and, in combination with other drugs, of ovarian, small cell lung, bladder, brain, and breast tumors. Anyway, despite its high effectiveness, it exhibits some clinical problems related to its use in the curative therapy, such as a severe normal tissue toxicity (in particular, nephrotoxicity) and the frequent occurrence of initial and acquired resistance to the treatment. To obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin, we report here on some gold(I) and gold(III) complexes with dithiocarbamate ligands (DMDT = N,N-dimethyldithiocarbamate; DMDTM = S-methyl-N,N-dimethyldithiocarbamate; ESDT = ethylsarcosinedithiocarbamate), which have been synthesized, purified, and characterized by means of elemental analyses, conductivity measurements, mono- and bidimensional NMR, FT-IR, and UV-vis spectroscopy, and thermal analyses. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. All the synthesized gold complexes have been tested for their in vitro cytotoxic activity. Remarkably, most of them, in particular gold(III) derivatives of N,N-dimethyldithiocarbamate and ethylsarcosinedithiocarbamate, have been proved to be much more cytotoxic in vitro than cisplatin, with IC50 values about 1- to 4-fold lower than that of the reference drug, even toward human tumor cell lines intrinsically resistant to cisplatin itself. Moreover, they appeared to be much more cytotoxic also on the cisplatin-resistant cell lines, with activity levels comparable to those on the corresponding cisplatin-sensitive cell lines, ruling out the occurrence of cross-resistance phenomena and supporting the hypothesis of a different antitumor activity mechanism of action.     

Study of DNA interactions with cyclic chalcone derivatives by spectroscopic techniques

A series of chalcone derivatives (1-4) were studied. The interaction between these ligands and calf thymus DNA was studied with UV-vis spectrophotometry, fluorescence and circular dichroism spectroscopy. The binding constants K were estimated at 0.5-4.6×10(5) M(-1). All these measurements indicated that the compounds behave as effective DNA-intercalating agents. Electrophoretic separation proved that ligands inhibited topoisomerase I at a concentration of 60 μM.     

Receptor binding affinity based comparative QSAR study of testosterone derivatives

The quantitative structure activity relationship models of 22 testosterone derivatives have been made with the help of topological and quantum chemical parameters. The molecular modeling and geometry optimization have been carried out with CAChe Pro software. The calculations of topological and quantum chemical parameters have been done by MOPAC 2007. The statistical parameters are calculated by STATISTICA and SSP software. The study indicates that the topological parameters better predict the receptor binding affinity of testosterone derivatives, whereas quantum chemical parameters better predict androgenic potency of testosterone derivatives as indicated by correlation coefficient, standard error, standard error of estimation, p value, t value, and degree of freedom of the quantitative structure activity relationship (QSAR) models. The predicted activity values obtained by these QSAR models are close to observed activity. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

Water-soluble amino derivatives of free-base dppz--syntheses and DNA binding studies

The syntheses of two water soluble dipyrido-[3,2-a:2',3'-c]-phenazine analogues containing one or two appended amino/amide chains are reported. Steady state optical studies on the two new compounds reveal high-energy dppz-based luminescence in water and non-aqueous solvents. Optical titrations with duplex DNA show that the luminescence is quenched on the addition of DNA. Binding curves constructed from absorption and emission changes indicate that, while one of the compounds display negligible binding properties, the other binds DNA with relatively high affinity (>10(5) M(-1)). Isothermal calorimetry experiments, designed to investigate the higher binding compound in more detail, reveals that its interaction with CT-DNA is actually biphasic with one tight (>10(5) M(-1)) and one weaker binding site (~10(5) M(-1)). In both cases binding is entropically driven. Further calorimetry studies involving the interaction of the new compound with a variety of polynucleotides were carried out. To aid comparisons, similar experiments involving a previously reported bipyridyldiylium derivative of dppz were also carried out. These studies reveal that the bipyridyldiylium derivative binds all these sequences monophasically with relatively low affinities (~10(4) M(-1)). However, while the amino/amide chain appended derivative binds to Poly(dA).poly(dT) monophasically with relatively low affinities, it binds all the other polynucleotide studied biphasically, with affinities ranging from <10(6) M(-1) to >10(8) M(-1). The ITC data reveals that for both compounds thermodynamic signatures for binding are dependent on the sequence being bound. In both cases, the data for Poly(dA).poly(dT) is particularly anomalous. An analysis of the data shows that binding is selective, with affinities at flexible sequences being several orders of magnitude higher than those at more rigid sequences.     

DNA binding and antitumor activities of platinum(IV) and zinc(II) complexes with some S-alkyl derivatives of thiosalicylic acid

A series of complexes of platinum(IV) (C1–C5) and zinc(II) (C6–C10) with S-alkyl derivatives of thiosalicylic acid were prepared and characterized. The interactions of the complexes with calf thymus DNA were analyzed by absorption (UV–Vis) and emission spectral studies (ethidium bromide displacement studies). The cytotoxic activities of complexes C1–C10 were determined against mouse B cell lymphocytic leukemia cells (BCL1), human B-prolymphocytic leukemia (JVM-13), mouse mammary carcinoma cells (4T1), and human mammary carcinoma cells (MDA-MB-468) and compared to the activities of the free ligand precursors and cisplatin. The cytotoxicities of the platinum(IV) and zinc(II) complexes toward mouse tumor cell lines were higher compared with their effects on human tumor cell lines. The zinc(II) complex C9 showed the highest antitumor activity toward the tested human cell lines, while the platinum(IV) complex C4 exhibited the highest antitumor activity toward mouse BCL1 and 4T1 cells. Both C4 and C9 have ligands derived from S-propyl thiosalicylic acid.     

Synthesis and antitumor activity of DNA binding cationic porphyrin-platinum(II) complexes

A new series of DNA binding 5,10,15-tri(N-methyl-4-pyridiniumyl)porphyrin (TrisMPyP)-platinum(II) conjugates was synthesized, in which different spacer ligands were used for appropriate coordination to platinum(II) complexes. Compound 9b exhibited in vivo antitumor activity (T/C%, 294) superior to cisplatin (T/C%, 184) against the leukemia L1210 cell line.     

Polyoxometalate binding to human serum albumin: a thermodynamic and spectroscopic approach

The molecular recognition of polyoxometalates by human serum albumin is studied using two different polyoxometalates (POMs) at pH 7.5. The results are compared with those obtained at pH 3.5 and 9.0. At pH 7.5, both POMs strongly interact with the protein with different binding behaviors. The Keggin shaped POM, [H(2)W(12)O(40)](6-) (H2W12), specifically binds the protein, forming a complex with a 1:1 stoichiometry with Ka = 2.9 x 10(6) M(-1). The binding constant decreased dramatically with the increase of the ionic strength, thus indicating a mostly electrostatic binding process. Isothermal titration calorimetry (ITC) experiments show that the binding is an enthalpically driven exothermic process. For the wheel shaped POM [NaP(5)W(30)O(110)](14-) (P5W30), there are up to five binding sites on the protein. Increasing the ionic strength changes the binding behavior significantly, leading to a simple exothermic process, with several binding sites. Competitive binding experiments indicate that the two POMs share one common binding site. In addition, they show the existence of another important binding site for P5W30. The two POMs exhibit different binding dependences on the pH. The combination of the experimental results with the knowledge of the surface map of the protein in its N-B conformation transition domain leads to the proposal for the probable binding site of POMs. The present work reveals a protein conformation change upon P5W30 binding, a new feature not explicitly documented in previous studies.     

Determination of acetamiprid partial-intercalative binding to DNA by use of spectroscopic, chemometrics, and molecular docking techniques

Acetamiprid (ACT) is an insecticide widely used for controlling a variety of insect pests. The binding mode associated with calf thymus DNA (ctDNA) upon interaction with ACT was determined using spectroscopic, chemometrics, and molecular docking techniques to clarify the interaction mechanism at the molecular level. Fluorescence titration suggested that the fluorescence quenching of ACT by ctDNA is a static procedure. The binding constants between ACT and ctDNA at different temperatures were calculated to be of the order 10³?10⁴ L mol^?1. The positive values of enthalpy and entropy change suggested that the binding process is primarily driven by hydrophobic interactions. Multivariate curve resolution?alternating least squares (MCR?ALS), a chemometrics approach, was used to resolve the expanded UV–visible spectral data matrix. The concentration profiles and the spectra for the three reaction components (ACT, ctDNA, and ACT?ctDNA complex) of the system, which formed a highly overlapping composite response, were then successfully obtained and used to evaluate the progress of ACT interacting with ctDNA. The results of the single-stranded ctDNA and iodide quenching experiments, ctDNA-melting investigations, and viscosity measurements indicated that ACT binds to ctDNA by means of a partial intercalation. Molecular docking studies showed that the specific binding site is mainly located between the ACT and G–C base pairs of ctDNA. This docking prediction was confirmed by use of Fourier-transform infrared (FT-IR) spectral analysis. Results from circular dichroism (CD) spectroscopy revealed that ACT induced a conformational change from the B–ctDNA form to the A–ctDNA form.

Synthesis,DNA binding and topoisomerase inhibition of mononaphthalimide homospermidine derivatives

Two novel mononaphthalimide homospermidine derivatives （2a, 2b） with three or four methylene unit as linkages were synthesized and evaluated for cytotoxicity against human leukemia K562, murine melanoma B 16 and Chinese hamster ovary CHO cell lines. The presence of homospermidine motif could greatly elevate the potency of 1,8-naphthalimide. Conjugate 2b with longer spacer exhibited higher in vitro cytotoxicity than 2a. The DNA binding experiments indicated that conjugates 2b could bind to herring sperm DNA. The topoisomerase Ⅱ poison trials revealed that 2b could inhibit the activity of top. Ⅱ.     

Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors

(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH homologs. The binding of these compounds to the CB(1) and CB(2) cannabinoid receptors are compared. Surprisingly, contrary to the compounds in the (-) series, which do not bind to the receptors, most of the derivatives in the (+) series bind to the CB(1) receptor in the low nanomole range. Some of these compounds also bind weakly to the CB(2) receptor.     

Optical evodiamine derivatives:Asymmetric synthesis and antitumor activity

Evodiamine and its derivatives have an asymmetric center at the C13 b position.Herein,isomers of evodiamine derivatives 2 and 3 were obtained by straightforward asymmetric total synthesis.Their inhibitory activities toward topoisomerases I and II and their cytotoxicities in cancer cell lines were evaluated.All the four isomers exhibited good to excellent antitumor potency and the(S)-isomers were generally more active than the(R)-isomers.The binding modes of(S)-2 with topoisomerases I and II were also clarified by molecular docking.     

DNA sequence dependent monomer-dimer binding modulation of asymmetric benzimidazole derivatives

A number of studies indicate that DNA sequences such as AATT and TTAA have significantly different physical and interaction properties. To probe these interaction differences in detail and determine the influence of charge, we have synthesized three bisbenzimidazole derivatives, a diamidine, DB185, and monoamidines, DB183 and DB210, that are related to the well-known minor groove agent, Hoechst 33258. Footprinting studies with several natural and designed DNA fragments indicate that the synthetic compounds bind at AT sequences in the minor groove and interact more weakly at sites with TpA steps relative to sites without such steps. Circular dichroism spectroscopy also indicates that the compounds bind in the DNA minor groove. Surprisingly, Tm studies as a function of ratio indicate that the monoamidines bind to TTAA sequences as dimers, whereas the diamidine binds as a monomer. Biosensor-surface plasmon resonance (SPR) studies allowed us to quantitate the interaction differences in more detail. SPR results clearly show that the monoamidine compounds bind to the TTAA sequence in a cooperative 2:1 complex but bind as monomers to AATT. The dication binds to both sequences in monomer complexes but the binding to AATT is significantly stronger than binding to TTAA. Molecular dynamics simulations indicate that the AATT sequence has a narrow time-average minor groove width that is a very good receptor site for the bisbenzimidazole compounds. The groove in TTAA sequences is wider and the width must be reduced to form a favorable monomer complex. The monocations thus form cooperative dimers that stack in an antiparallel orientation and closely fit the structure of the TTAA minor groove. The amidine groups in the dimer are oriented in the 5' direction of the strand to which they are closest. Charge repulsion in the dication apparently keeps it from forming the dimer. It instead reduces the TTAA groove width, in an induced fit process, sufficiently to form a minor groove complex. The dimer-binding mode of DB183 and DB210 is a new DNA recognition motif and offers novel design concepts for selective targeting of DNA sequences with a wider minor groove, including those with TpA steps.