Guanine Units Research Articles

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death.

Energy transfer to ground state triplet molecular oxygen results in the generation of singlet molecular oxygen (1O2), which has potent oxidizing ability. Irradiation of light, notably ultraviolet A, to a photosensitizing molecule results in the generation of 1O2, which is thought to play a role in causing skin damage and aging. It should also be noted that 1O2 is a dominant tumoricidal component that is generated during the photodynamic therapy (PDT). While type II photodynamic action generates not only 1O2 but also other reactive species, endoperoxides release pure 1O2 upon mild exposure to heat and, hence, are considered to be beneficial compounds for research purposes. Concerning target molecules, 1O2 preferentially reacts with unsaturated fatty acids to produce lipid peroxidation. Enzymes that contain a reactive cysteine group at the catalytic center are vulnerable to 1O2 exposure. Guanine base in nucleic acids is also susceptible to oxidative modification, and cells carrying DNA with oxidized guanine units may experience mutations. Since 1O2 is produced in various physiological reactions in addition to photodynamic reactions, overcoming technical challenges related to its detection and methods used for its generation would allow its potential functions in biological systems to be better understood.

Adaptive Chirality of an Achiral Cage: Chirality Transfer, Induction, and Circularly Polarized Luminescence through Aqueous Host–Guest Complexation

Chirality transfer, induction, and circularly polarized luminescence (CPL) using supramolecular hosts, such as macrocycles and cages, have been explored for wide-ranging applications in chiral reco...

Synthesis and aggregation properties of boron-dipyrromethene dyes conjugated with guanine units

Two boron-dipyrromethene dyes bearing a conjugated guanine unit (G-BODIPYs) 1 and 2 were synthesized and fully characterized. The self-assembly properties of these dyes were investigated by X-ray crystallography, [Formula: see text]H NMR and UV-vis spectroscopy. As revealed by X-ray crystal structure studies, G-BODIPY 1 self-assembled into ribbon-like structures due to the intermolecular hydrogen bonding and [Formula: see text]–[Formula: see text] stacking interaction. Concentration-dependent [Formula: see text]H NMR experiments confirmed the formation of hydrogen bonds of the guanine units in solution for both dye 1 and 2. In the presence of K[Formula: see text], the characteristic signals for the formation of cyclic G-quadruplex structures were observed in the [Formula: see text]H NMR study. Aggregation of G-BODIPY dyes was further monitored by UV-vis absorption spectroscopy by varying the solvent polarity and temperature. H-type aggregates of dye 1, which was characterized by a new hypsochromically shifted absorption band with [Formula: see text] 461 nm, was obtained. In the presence of K[Formula: see text], the enhancement of stability was observed for the H-aggregates of dye 1.

Acetyl-protected cytosine and guanine containing acrylics as supramolecular adhesives

ABSTRACTHydrogen bonding among nucleobase pairs serves as an efficient noncovalent interaction for designing supramolecular polymers with desired properties for pressure sensitive adhesives. Michael addition yielded acetyl-protected cytosine/guanine containing acrylic monomers with flexible spacers between the hydrogen bonding units and the acrylic backbone. Free radical polymerization of nucleobase-containing monomers afforded acetyl-protected cytosine/guanine homopolymers and random copolymers with n-butyl acrylate. Nucleobase incorporation significantly affected thermal, thermomechanical, rheological, morphological properties, and adhesive performance of polyacrylates. Guanine/cytosine-containing copolymers each exhibited a single glass transition (Tg) that increased with increasing nucleobase content. Self-association of acetyl cytosine and acetyl guanine units converted low Tg polyacrylates to physically crosslinked networks with mechanical integrity. Solution casting acetyl guanine-containing copolymers with 8 mol% or higher guanine content yielded free-standing films with microphase-separated morphologies. Acetyl cytosine-containing copolymers with 15 mol% or more cytosine formed free-standing films with less microphase-separation compared to the guanine copolymers. 1H NMR titration experiments established a 1:1 binding stoichiometry between acetyl cytosine and acetyl guanine monomers in CDCl3, similar to guanine-cytosine association. However, the acetyl protecting group hindered the formation of triple hydrogen bonding, resulting in double hydrogen bonding between acetyl cytosine and acetyl guanine with an intermediate binding strength comparable to their self-associations. Acetyl guanine-containing copolymers with 3 mol% acetyl guanine exhibited higher peel strength on stainless steel and higher extended service frequency range compared to cytosine-containing copolymers and various pressure sensitive adhesive controls.

Catalysis of a 1,3-dipolar reaction by distorted DNA incorporating a heterobimetallic platinum(ii) and copper(ii) complex.

A novel catalytic system based on covalently modified DNA is described. This catalyst promotes 1,3-dipolar reactions between azomethine ylides and maleimides. The catalytic system is based on the distortion of the double helix of DNA by means of the formation of Pt(ii) adducts with guanine units. This distortion, similar to that generated in the interaction of DNA with platinum chemotherapeutic drugs, generates active sites that can accommodate N-metallated azomethine ylides. The proposed reaction mechanism, based on QM(DFT)/MM calculations, is compatible with thermally allowed concerted (but asynchronous) [π4s + π2s] mechanisms leading to the exclusive formation of racemic endo-cycloadducts.

Luminescent Helical Nanofiber Self-Assembled from a Cholesterol-Based Metalloamphiphile and Its Application in DNA Conformation Recognition

Compared to pure organic amphiphiles, metalloamphiphiles display distinctive features, including luminescence, magnetism and catalytic properties. However, the self-organization of metalloamphiphiles is commonly driven by solvophobic effects. Alkyl chains and oligomeric ethylene glycol moieties are thus the most frequently used aggregation units to drive the self-assembly of metalloamphiphiles. We expect novel metallo-supramolecular structures with exciting functions to be created if additional noncovalent interaction modes are incorporated. In this work, a new type of metalloamphiphile, consisting of a Tb(III) complex head and a cholesteryl unit (TbL3+(I)), was designed and synthesized. TbL3+(I) spontaneously self-assembles into helical nanofibers (d = 6 nm) in water. This synthetic multivalent nanoscale binding array displays powerful capability for the recognition of DNA conformations through a turn-on luminescence sensing mechanism. ssDNA-kit1 triggered a 26-fold increase in the luminescence intensity of TbL3+(I). Its corresponding G-quadruplex structure (G-quadruplex-kit1), however, induced a 6.6-fold enhancement under the same conditions. Consequently, TbL3+(I) nanofibers can monitor DNA folding. In contrast, neither ssDNA-kit1 nor G-quadruplex-kit1 markedly promoted the luminescence of molecularly dispersed TbL3+(II), illustrating that the multivalent electrostatic interactions between the phosphate groups on the backbone of DNA and TbL3+(I) self-assembled into nanofibers could greatly improve the efficiency of the energy transfer between the guanine units and the organized TbL3+(I). The TbL3+(I) nanofibers could bind and distinguish not only the kit1-ssDNA/G-quadruplex but also the conformations of other G-rich DNA, such as spb1, htelo, and intermolec-htelo. The self-assembly of luminescent metalloamphiphiles thus provides a general and convenient strategy for the efficient recognition and conversion of molecular information.

Organostannoxane-supported nucleobase arrays: synthesis and supramolecular structures of polymeric and molecular organotin complexes containing guanine, uracil and 2-aminopurine

The reaction of L1H {L1H = 3-(N9-guaninyl)propionic acid} with Me3SnCl or (n-Bu3Sn)2O afforded the 1D coordination polymers, [Me3Sn(L1)]n (1) and [n-Bu3Sn(L1)]n (2) respectively. A reaction between L2H {L2H = 3-(N7-guaninyl)propionic acid} with Me3SnCl also afforded a 1D coordination polymer, [Me3Sn(L2)]n (3). A similar reaction between L3H [uracil-6-carboxylic acid] with (Ph3Sn)2O in a 2 : 1 ratio afforded a dimer [(n-Bu3SnL3)2·H2O] (4). A mononuclear compound [Me3Sn(L4)·H2O] (5) was obtained in a 1 : 1 reaction of 3-{N9-(2-aminopurinyl)}propanoic acid (L4H) with Me3SnCl. Complexes 1–5 show rich supramolecular structures in the solid state as a result of several intermolecular interactions. Thus, in the one-dimensional coordination polymer 3, triple hydrogen bonding (GG), between inter-chain guanine units has been observed. Similarly a homo orotatequartet has been observed in 4 as a result of intermolecular interactions.

Layered molybdenum selenide stacking flower-like nanostructure coupled with guanine-rich DNA sequence for ultrasensitive ochratoxin A aptasensor application

Sensitive detection of ochratoxin A (OTA) plays an important role in the field of food safety control. In this study, we are reporting for the first time an electrochemical biosensor which employs the integration of MoSe2 nanoflowers, Au nanoparticles (AuNPs), aptamer and the guanine-rich complementary DNA sequence for the sensitive detection of OTA. MoSe2 nanoflowers are prepared by a simple hydrothermal method and used as a promising sensing platform based on its large surface area. The methylene blue is used as a tracer and a guanine-rich complementary DNA sequence is designed to bind with the unbound OTA aptamer for signal amplification. The aptamer is immobilized on the AuNPs/MoSe2 modified electrode surface through Au–S interaction. Since OTA can competitively bind with the aptamer due to their high affinity, the presence of OTA will induce the decrease of guanine-rich DNA on the electrode surface, in turn reduces the signal of methylene blue which can specifically adsorb to the guanine units of DNA. The proposed assay shows a good linear relationship within the range of 0.0001–1nM with a detection limit of 0.08pM for OTA. The developed biosensor has been applied to determine OTA concentration in wine samples.

The Use of a Peptidic Scaffold for the Formation of Stable Guanine Tetrads: Control of a H‐bonded Pattern in Water

With a little help from a scaffold: The pre-organization of guanine units onto a peptidic scaffold allows a remarkable stabilization of the G-quartet motif (see graphic). Indeed, the quartet motif was found to be stable even in water without addition of salts. The present study shows the first formation of a single synthetic G-tetrad under these aqueous conditions.

Acronycine Derivatives: A Promising Series of Anti-Cancer Agents

The pyranoacridone acronycine (1) exhibits antitumor properties against a large panel of solid tumor models, but its moderate potency and low water solubility severely hampered the subsequent clinical trials. Development of synthetic analogues followed the isolation from several Sarcomelicope species of acronycine epoxide (17), which led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine derivatives exhibited antitumor properties, with a broadened spectrum of activity and an increased potency. The demonstration that acronycine interacted with DNA led to the development of benzo[a], [b], and [c]acronycine analogs. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters were active in human orthotopic models of cancers xenografted in nude mice. The activity of these compounds, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (49), developed in phase I clinical trials under the code S23906-1, was correlated with their ability to give covalent adducts with DNA, involving reaction between the N-2 amino group of guanines in the minor groove and the ester group at the benzylic position of the drug. The influence of the kinetics of DNA alkylation on the cytotoxic and antitumor properties showed a strong correlation between antiproliferative activity and DNA alkylation kinetics, with the most cytotoxic compounds, appearing as the slowest DNA alkylators. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also displayed potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

G‐Quadruplex DNA Structures and Organic Chemistry: More Than One Connection

AbstractG‐Quadruplexes represent a group of unusual DNA secondary structures, based on Hoogsteen G–G paired hydrophobic planar rings consisting of four guanine units. Many studies have shown that G‐quadruplex structures appear to be involved in several important biological processes, such as DNA replication, gene expression and recombination, as well as cell transformation. For these reasons, in the last few years G‐quadruplexes have become the main research interest of many eminent scientists in different fields: from molecular to cellular biologists, from physicians to chemists. In this respect, organic chemists can play fundamental roles in many different areas. First of all, research into specific G‐quadruplex ligands as potential drugs, in particular as telomerase inhibitors and thus potential anticancer drugs, has attracted strong attention. The rational design of and the various synthetic approaches toward these kinds of ligands represent two specific fields of interest for organic chemists. The molecules capable of stabilizing G‐quadruplexes covered in this review are each characterized by an aromatic core that favours stacking interactions with the G‐tetrads and, in most cases, by basic side chains that interact with DNA grooves. First generations and new classes of synthetic G‐quadruplex ligands, as well as natural compounds, are presented. Moreover, because the specificities of the interactions between the studied ligands and different DNA structures (both duplex and quadruplex) are without doubt a main concern, determining the different biological effects of these compounds, several chemists are involved in developing approaches to explore this important subject. The last part of this review is devoted to a brief introduction of new fields of application of G‐quadruplex structures with open synthetic challenges: quadruplex‐forming modified oligonucleotides and nanostructures based on the G‐quadruplex.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Antitumor Psoropermum Xanthones and Sarcomelicope Acridones: Privileged Structures Implied in DNA Alkylation

Fused isopropylfuran and dimethylpyran units are privileged structures present in numerous bioactive natural products exemplified, in the field of anticancer drugs, by the furanoxanthone psorospermin and the pyranoacridone acronycine. Psorospermin binds to the N-7 position of the guanine units in the presence of topoisomerase II. In contrast, acronycine derivatives such as cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine alkylate the 2-amino group of DNA guanine residues in the minor groove. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also display very potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

Synthesis, Cytotoxic Activity, and Mechanism of Action of Furo[2,3-c]acridin-6-one and Benzo[b]furo[3,2-h]acridin-6-one Analogues of Psorospermin and Acronycine

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.

Ru(II) complexes and light: molecular tools for biomolecules

AbstractRuthenium(II) (Ru(II)) complexes are the focus of numerous research works with various applications mainly due to their attractive photophysical and photochemical properties. In biological research areas, in particular, they are developed as efficient photoprobes or photosensors of biological molecules. More interestingly specific Ru(II) complexes bearing π‐deficient ligands such as TAP = 1,4,5,8‐tetraazaphenanthrene, bpz = 2,2′‐bipyrazyl or HAT = 1,4,5,8,9,12‐hexaazatriphenylene exhibit interesting photoreactivity with biomolecules (DNA, polypeptides). The photoreactions are initiated by a photo‐electron transfer from the biomolecule to the excited metal complex. A back electron transfer (BET) succeeds this primary process. However in competition with this BET, a DNA photocleavage and/or formation of adducts of the complex with guanine units of DNA or with tryptophan (Trp) residues of polypeptides can take place. In this review we highlight the studies of these photo‐adducts carried out by our laboratories, and connected to some applications. Copyright © 2008 John Wiley & Sons, Ltd.

In vivo detection of DNA adducts induced by cisplatin using capillary HPLC–ICP-MS and their correlation with genotoxic damage in Drosophila melanogaster

The antitumoral effect of cisplatin [cis-diamminodichloroplatinum(II)] in mammals is related to its binding to DNA components. However, there is a lack of specific chemical methods to selectively detect those adducts formed in vivo at low concentrations. In this work, a new sensitive and selective method of determining cisplatin-DNA adducts based on the use of element-selective mass spectrometry is proposed, and the method is then applied to detect cisplatin adducts induced in vivo in somatic cells of Drosophila melanogaster. The bioanalytical strategy proposed here allows the determination of the most important DNA adduct formed between adjacent guanine units of the same DNA strand with cisplatin, and it is based on the coupling of capillary liquid chromatography (cap-LC) to inductively coupled plasma mass spectrometry (ICP-MS). This set-up allows the simultaneous monitoring of the Pt (from the drug) and P (from the DNA components) present in these adducts, once they have been cleaved by enzymatic hydrolysis of the DNA samples. Using this instrumental set-up, the adducts of cisplatin formed in vivo when D. melanogaster flies are exposed to different cisplatin concentrations can be detected and their concentration determined. The results obtained show a direct correlation between the concentration of cisplatin adducts, the induced genotoxic damage (measured as DNA strand breaks using the Comet assay) and the cisplatin concentration. [figure: see text] The work illustrates the complementary use of bioanalytical and biological information to study cisplatin interactions with DNA is vivo at biologically relevant concentrations of the drug.

Amplified Oligonucleotide Sensing in Microliter Volumes Containing Copper Ions by Solution Streaming

We present a simple, cost-effective design for amplifying oligodeoxynucleotide (ODN) sensing, in microliter ODN volumes containing copper ions, by solution streaming (bubbling). The inert gas streaming (bubbling) at a constant pressure of 0.04 bar drives the motion of a 30-microL ODN droplet containing a three-electrode circuit (inverted drop microcell), and in the presence of copper ions offers an approximately 50-times improvement in the detection of ODN samples. The detection of ODNs at the carbon paste electrode is based on the enhancement of the oxidation peaks of purine bases (adenine and guanine) by the anodic stripping of the electrochemically accumulated complex of Cu(I) with purine base residues of acid hydrolyzed ODN samples (Cu(I)-ahODN complex). We used the proposed method for (i) the determination of the percentage content of adenine and guanine units within analyzed ODN samples at subnanomolar concentrations (related to monomer content) and (ii) the detection of the (TTC)n triplet expansion using magnetic DNA hybridization with reporter probes containing guanine units (the TTC trinucleotide repeat expansion is associated with serious hereditary diseases, including Friedreich ataxia).

Photoadducts of Metallic Compounds with Nucleic Acids — Role Played by the Photoelectron Transfer Process and by the TAP and HAT Ligands in the RuII Complexes

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photoadducts of Metallic Compounds with Nucleic Acids − Role Played by the Photoelectron Transfer Process and by the TAP and HAT Ligands in the RuII Complexes

AbstractThe properties that are characteristic of TAP (1,4,5,8‐tetraazaphenanthrene) and HAT (1,4,5,8,9,12‐hexaazatriphenylene) RuII complexes under illumination are highlighted and compared with those of other metallic complexes. In particular, the photo‐oxidizing power of their 3MLCT states leads to a quenching of luminescence accompanied by a photoreaction when they are in presence of nucleic acids. The proton‐coupled photoinduced electron transfer with the guanine nucleobases produces metallic adducts on DNA guanine units. The mechanism of formation, structure, and possible applications of these photoadducts are discussed and compared with other DNA metallic adducts currently in the literature. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Mesoscopic-scale sheet-like assembly: critical role of inter-tape hydrogen bonds in the organogel formation and gel–liquid crystal transition of an alkylsilylated deoxyguanosine–dodecane system

2′-Deoxy-3′,5′-bis-O-(octyldiisopropylsilyl)guanosine (1) showed a good gelation ability for non-polar solvents like alkanes. Atomic force micrography of the organogel showed the formation of mesoscopic-scale sheet-like assemblies, whose width and height were 50–300 and 2.5 nm, respectively. From the IR spectral analysis and crystallographic data of reference compounds, the gel was shown to have a structural hierarchy with different levels of hydrogen bonds, i.e., a one-dimensional tape motif with double hydrogen bonds between guanine units and a mesoscopic-scale sheet-like assembly with hydrogen bonds between adjacent tape motifs. Formation of the sheet structure was shown to be essential for the gelation process. On heating, the concentrated 1–dodecane (37–63 wt%) gel showed gel (G)–lamellar liquid crystal (L)–isotropic fluid (I) phase, and the G–L transition was ascribed to the cleavage of the inter-tape hydrogen bonds.

Rates of Aziridinium Alkylation of Polynucleotides and Ribonucleic Acid

The exceptionally high rate of alkylation of guanine units in double helix DNA (k g /kw1 = 150,000) (P rice , C. C., G aucher , G. M., K oneru , P., S hibakawa , R., S owa , J. R., and Y amaguchi , M. (1968) Biochim. Biophys. Acta 166, 327) has now been observed for tRNA (k g /kw = 97,000), rRNA (k g /kw = 93,000), and a 1:1 mixture of polyguanylic and polycytidylic acid (k g /kw = 80,000). The unreactivity of adenine units in double helix DNA (1) has also been found in a 1:1 mixture of polyadenylic and polyuridylic acids. Poly(A), poly(C), and poly(G) all show markedly greater base reactivity than their monomers, ascribed partly to enhanced reactivity from stacking of the bases in the polymers. Poly(G), poly(C), tRNA, and rRNA showed sharp rate changes after 5 to 10% reaction, interpreted as due to “denaturation” or degradation resulting from alkylation of the bases and/or the phosphate groups. Very high initial reactivities (kp/kw ≃ 106) for the phosphate groups, in poly(A), (A)n·(U)n, tRNA, and rRNA, are ascribed to electrostatic effects, neutralized as alkylation proceeds.