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International audience; A small library of molecules combining indolizine and N-alkyl pyridinium was synthesized and evaluated in a multi-target-directed-ligand strategy for Alzheimer's disease (AD) treatment. The new compounds were classified in three series depending on the number of methylene residues linking the two heterocycles (Ind-PyCx with x = 0, 2 or 3). The molecules were synthesized from the corresponding bis-pyridines by two-step formation of the indolizine core including mono-alkylation of pyridine and 1,3-dipolar cycloaddition with an alkylpropiolate. Their activities against AD's key-targets were evaluated in vitro: acetyl- and butyrylcholinesterase (AChE and BChE) inhibition, antioxidant properties and inhibition of amyloid fibril formation. None of the three series showed significant activities against all the targets. The Ind-PyC2 and Ind-PyC3 series are active on eeAChE and hAChE (µM IC50 values). Most of the positively charged molecules from these two series also appeared active against eqBChE, however they lost their activity on hBChE. Comparative molecular modeling of 13 and 15 docked in hAChE and hBChE highlighted the importance of the substituent (p-methoxybenzoyl or methyloxycarbonyl, respectively) located on the indolizine C-3 for the binding. The larger molecule 13 fits more tightly at the active site of the two enzymes than 15 that shows a larger degree of freedom. The Ind-PyC2 and Ind-PyC3 hybrids displayed some antioxidant activity when tested at 750 µg/mL (up to 95% inhibition of DPPH radical scavenging for 10). In both series, most hybrids were also able to interact with amyloid fibers, even if the inhibitory effect was observed at a high 100 µM concentration. The Ind-PyC0 molecules stand out completely due to their spectroscopic properties which prevent their evaluation by Ellman’s and ThT assays. However, these molecules showed interesting features in the presence of preformed fibers. In particular, the strong increase in fluorescence of 3 in the presence of amyloid fibers is very promising for its use as a fibrillation fluorescent reporter dye.

Cellulose nanofibrils (CNF) are renewable bio-based materials with high specific area, which makes them ideal candidates for multiple emerging applications including for instance on-demand drug release. However, in-depth chemical and structural characterization of the CNF surface chemistry is still an open challenge, especially for low weight percentage of functionalization. This currently prevents the development of efficient, cost-effective and reproducible green synthetic routes and thus the widespread development of targeted and responsive drug-delivery CNF carriers. We show in this work how we use dynamic nuclear polarization (DNP) to overcome the sensitivity limitation of conventional solid-state NMR and gain insight into the surface chemistry of drug-functionalized TEMPO-oxidized cellulose nanofibrils. The DNP enhanced-NMR data can report unambiguously on the presence of trace amounts of TEMPO moieties and depolymerized cellulosic units in the starting material, as well as coupling agents on the CNFs surface (used in the heterogeneous reaction). This enables a precise estimation of the drug loading while differentiating adsorption from covalent bonding (∼1 wt% in our case) as opposed to other analytical techniques such as elemental analysis and conductometric titration that can neither detect the presence of coupling agents, nor differentiate unambiguously between adsorption and grafting. The approach, which does not rely on the use of 13C/15N enriched compounds, will be key to further develop efficient surface chemistry routes and has direct implication for the development of drug delivery applications both in terms of safety and dosage., DNP-enhanced solid-state NMR unravels the surface chemistry of functionalized nanocellulose.

Nowadays, drug encapsulation and drug release from cellulose nanofibrils systems are intense research topics, and commercial grades of cellulose nanomaterials are currently available. In this work we present an ester-containing prodrug of metronidazole that is covalently bound to cellulose nanofibrils in aqueous suspension through a two-step immobilization procedure involving green chemistr y principles. The presence of the drug is confirmed by several characterization tools and methods such as Raman spectroscopy, elemental analysis, Dy-namic Nuclear Polarization enhanced NM R . This technique allow s enhancing the sensitivity of NM R by several orders of magnitude. It has been used to study cellulose nanofibrils substrates and it appears as the ultimate tool to confirm the covalent nature of the binding through thiol-yne click chemistry. Moreover, the ester function of the immobilized prodrug can be cleaved by specific enzyme activity thus allowing controlled drug release.

International audience; The light-switch mechanism of the complex [Ru(bpy)2(Br-dpqp)](PF6)2 (1, bpy = 2,2′-bipyridine, Br-dpqp = 12-bromo-14-ethoxydipyrido[3,2-a:2′,3′-c]quinolino[3,2-h]phenazine), i.e., a light-up probe for the selective labeling of G-quadruplexes, is investigated by time-resolved transient absorption and emission spectroscopy. We show that, in contrast to the prototypical light-switch complex [Ru(bpy)2(dppz)](PF6)2 (2, dppz = dipyrido[3,2-a:2′,3′-c]phenazine), a 3ππ* state localized on the π-extended ligand is the state determining the excited-state properties in both protic and aprotic environments. In aprotic environments, emission originates from a bright 3MLCTphen state, which is thermally accessible from the 3ππ* state at ambient temperature. In the presence of water, i.e., in environments resembling in cellulo situations, the thermally accessible 3MLCT state is altered and becomes close in energy to the 3ππ* state, which induces a rapid excited-state deactivation of the 3ππ* state and a comparably weak emission.

A series of RuII complexes exhibiting π-extended, acridine-based ancillary chelating heterocycles display high affinity and selectivity for DNA and RNA quadruplexes. The most promising candidates (3, 4) possess remarkable light-up luminophore properties (up to 330-fold luminescence enhancement upon interaction with quadruplexes), enabling them to discriminate quadruplexes from genomic DNA owing to a photochemical mechanism involving DNA protection against non-radiative decay (DAND), thus deviating from the other complexes of this series of ligands that exhibit an excited-state intramolecular proton transfer (ESIPT) that quenches their luminescence. The in vitro and preliminary in cellulo results shown here confirm the interest of this new family of fluorophores as invaluable molecular tools to detect G-quadruplexes in cells.

Molecular photosensitizers that are able to store multiple reducing equivalents are of great interest in the field of solar fuel production, where most reactions involve multielectronic reduction processes. In order to increase the reducing power of a ruthenium tris-diimine charge-photoaccumulating complex, two structural modifications on its fused dipyridophenazine-pyridoquinolinone ligand were computationally investigated. Addition of an electron-donating oxime group was calculated to substantially decrease the reduction potentials of the complex, thus guiding the synthesis of a pyridoquinolinone-oxime derivative. Its spectroscopic and (spectro)electrochemical characterization experimentally confirmed the DFT predictions, with the first and second reduction processes cathodically shifted by -0.24 and -0.14 V, respectively, compared to the parent complex. Moreover, the ability of this novel artificial photosynthetic system to store two photogenerated electrons at a more reducing potential, via a proton-coupled electron-transfer mechanism, was demonstrated.

Molecular photosensitizers that are able to store multiple reducing equivalents are of great interest in the field of solar fuel production, where most reactions involve multielectronic reduction processes. In order to increase the reducing power of a ruthenium tris-diimine charge-photoaccumulating complex, two structural modifications on its fused dipyridophenazine-pyridoquinolinone ligand were computationally investigated. Addition of an electron-donating oxime group was calculated to substantially decrease the reduction potentials of the complex, thus guiding the synthesis of a pyridoquinolinone-oxime derivative. Its spectroscopic and (spectro)electrochemical characterizations experimentally confirmed the DFT predictions, especially with the first and second reduction processes cathodically-shifted by −0.24 and −0.14 V, respectively, compared to the parent complex. Moreover, the ability of this novel artificial photosynthetic system to store two photogenerated electrons at a more reducing potential, via a proton-coupled electron transfer mechanism, was demonstrated.

International audience

International audience; The severe side effects associated with the use of anthracycline anticancer agents continues to limit their use. Herein we describe the synthesis and preliminary biological evaluation of three enzymatically activatable doxorubicin-oligosaccharide prodrugs. The synthetic protocol allows late stage variation of the carbohydrate and is compatible with the use of disaccharides such as lactose as well as more complex oligosaccharides such as xyloglucan oligomers. The enzymatic release of doxorubicin from the prodrugs by both protease (plasmin) and human carboxylesterases (hCE1 and 2) was demonstrated in vitro and the cytotoxic effect of the prodrugs were assayed on MCF-7 breast cancer cells.

The π-extended ligand of a ruthenium complex stores two photo-generated electrons, mimicking a key step in photosynthesis., Increasing the efficiency of molecular artificial photosynthetic systems is mandatory for the construction of functional devices for solar fuel production. Decoupling the light-induced charge separation steps from the catalytic process is a promising strategy, which can be achieved thanks to the introduction of suitable electron relay units performing charge accumulation. We report here on a novel ruthenium tris-diimine complex able to temporarily store two electrons on a fused dipyridophenazine–pyridoquinolinone π-extended ligand upon visible-light irradiation in the presence of a sacrificial electron donor. Full characterization of this compound and of its singly and doubly reduced derivatives thanks to resonance Raman, EPR and (TD)DFT studies allowed us to localize the two electron-storage sites and to relate charge photoaccumulation with proton-coupled electron transfer processes.

International audience; The pi-extended dipyrido[3,2-a:2',3'-c]phenazine (dppz) ligand of the Ru(II) complex [Ru(bpy)(2)(oxo-dppqp)](PF6)(2) (oxo-dppqp = dipyrido[3,2-a:2',3'-c]pyrido[2?,3?-4,5,6]quinolino[2,3-h]phenazin-15-one, bpy = 2,2'-bipyridine) enables the mononuclear complex for visible-light-driven accumulation of two electrons on a single ligand structure. Although this has been shown before, the excited-state physics underlying this promising feature are exploited in this work. The photophysics of the complex was investigated by excitation-wavelength-dependent resonance Raman and transient absorption spectroscopy in combination with time-dependent density functional theory. The results show that excitation with visible light leads to the population of the two excited-state branches: (i) the population of a short-lived (MLCT)-M-3 state in which the excess electronic density is localized on the pyridoquinolinone moiety of the extended ligand (t = 105 ps) and (ii) the population of a more long-lived (3)pi pi* state (iota = 9 ns). Notably, the long-lived (3)pi pi* state rather than a 3MLCT state is prone to reductive quenching by the sacrificial electron donor and, hence, presents the critical excited-state intermediate in the photochemical charge accumulation experiments

International audience; We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug-biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug-protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug.

The lipase-catalysed reaction of aliphatic amine with ethyl propiolate was investigated using benzylamine as reference amine. The conditions were optimised to favour the 1,2-addition, i.e., formation of N-benzylprop-2-ynamide, versus the 1,4-addition. Immobilised Candida antarctica lipase (CALB) was found to be the most efficient enzyme, and the reactions were performed in solvents, such as tBME, dioxane or toluene. The methods were used to prepare propiolamides from aliphatic amines in good to excellent yields. The reactivity of O- and S-nucleophiles was compared in the same conditions.

Marine microorganisms are of considerable interest as a promising source of enzymes with unsuspected potentials as catalysts for chemical synthesis. We describe here an efficient method for one-pot indolizine synthesis that has been developed using lipase A and lipase B from Candida antarctica as biocatalysts. As showed by HPLC/MS analysis, the yield in indolizines was higher in the presence of the biocatalyst than in absence of enzyme. Lipase A, from Candida antarctica, showed high catalytic activity and selectivity for the cycloaddition reactions. When the reactions were performed under ultrasound irradiation, the Candida antarctica lipase catalyzed reactions yielded pure indolozines, in good yields and in very short time.

International audience; The preparation and characterization of three series of novel ruthenium(ii) complexes are reported, each series differing by the nature of the ancillary ligands (2,2'-bipyridine - bpy, 1,10-phenanthroline - phen or 1,4,5,8-tetraazaphenanthrene - TAP). The third ligand was either the heptacyclic heterocycle dipyrido[3,2-a:2',3'-c]quinolino[3,2-h]phenazine (dpqp) substituted at position 12 by an hydroxyl (oxo), 2,2-dimethoxyethylamine (DMEA) or halogeno (Cl or Br) substituent, or the octacyclic dipyrido[3,2-a:2',3'-c]pyrido[2,3,4-de]quinolino[3,2-h]phenazine (dppqp), prepared by a multi-step "chemistry on the complex" strategy from [RuL2(oxo-dpqp)](PF6)2. The three steps, halogenation, substitution by a dimethoxyethylamino group and cyclization in trifluoroacetic acid, were performed in reasonable to high yields depending on the nature of the ancillary ligands. Isolation and purification processes were facilitated by the ability to switch the solubility of the complex from aqueous to organic solvents, depending on the counter-ion. All new complexes were fully characterized; in particular their absorption properties were compared by UV-vis spectroscopy. Finally, π-stacking properties induced by these extended ligands were studied by 1H NMR studies and quantum chemical calculations.

We report here the electrochemical characterization of eight synthetic DNA intercalators based on the 4H-pyrido[4,3,2- kl ]acridin-4-one structure. We found that the electrochemical behavior of these redox active drugs is strongly influenced by the nature of the solvent. A single two-electron reduction is observed in an aqueous phosphate buffer (PB) whereas two successive one-electron reductions are observed in aprotic solution (acetonitrile). The influence of the molecular structure on the potential values is addressed along with a comparison between the DNA binding constant ( K DNA ) and the cytotoxic activity against HT29 cells (IC 50 ). For typical DNA intercalators, one could expect that toxicity will be roughly proportional to the DNA binding constant. Yet, a structure/activity comparison solely based on the DNA affinity was not conclusive. In contrast, a direct relationship was evidenced for the first time between the decimal logarithm of the in vitro bioactivity and the reduction potential of pyridoacridones recorded in PB at pH 7.0. Moreover, most of the bio/electrochemical relationships previously described for quinone-based drugs were reported with electrochemical characterization in aprotic solvents (typically acetonitrile, dimethylformamide or dimethylsulfoxide). But aqueous solution electrochemistry is definitely the most bio-relevant because the redox mechanism of quinone or iminoquinone reduction directly depends on the protic nature of the solvent.

A small library of heterocycle-fused quinazolin-4-ones was prepared and evaluated as kinase inhibitors. The key step of the two-step process involves the environmental friendly thermolysis of N-ethoxycarbonyl-N'-(hetero) arylguanidines at 130 °C in water. The cyclization is fully regioselective. The most active molecules, 7-(2-hydroxyethylamino)- and 7-(3-hydroxypropylamino)-pyrazolo[4,3-f]quinazolin-9-ones, inhibit DYRK1A and CLK1 at submicromolar concentrations, indicating the potential interest of this new heterocycle in drug design.

A mononuclear Ru(II) complex based on a new heptacyclic ligand (dpqp) has been prepared and characterized by NMR spectroscopy, ES mass spectrometry and electrochemistry. It forms dimers and aggregates of up to seven complex units in CH 3 CN solution observed by ESMS. The monomer has an extremely weak luminescence in water or even in organic solvent probably due to the existence of a low lying π–π ∗ excited state centered on the heptacycle. In spite of the strong interaction of the complex with DNA, its luminescence is not enhanced by the DNA microenvironment.

International audience; Previous works have shown the interest of naturally fluorescent proflavine derivatives to label Abeta deposits in vitro. This study aimed to further characterize the properties of the proflavine 3-acetylamino-6-[3-(propargylamino)propanoyl]aminoacridine (COB231) derivative as a probe. This compound was therefore evaluated on human post-mortem and mice brain slices and in vivo in 18-month-old triple transgenic mice APPswe, PS1M146V and tauP301L (3xTgAD) mice presenting the main characteristics of Alzheimer's disease (AD). COB231 labelled amyloid plaques on brain slices of AD patients, and 3xTgAD mice at 10 and 0.1 μM respectively. However, no labelling of the neurofibrillary tangle-rich areas was observed either at high concentration or in the brain of fronto-temporal dementia patients. The specificity of this mapping was attested in mice using Thioflavin S and IMPY as positive controls of amyloid deposits. After intravenous injection of COB231 in old 3xTgAD mice, fluorescent amyloid plaques were detected in the cortex and hippocampus, demonstrating COB231 blood–brain barrier permeability. We also controlled the cellular localization of COB231 on primary neuronal cultures and showed that COB231 accumulates into the cytoplasm and not into the nucleus. Finally, using a viability assay, we only detected a slight cytotoxic effect of COB231 (< 10%) for the highest concentration (100 μM).

A series of amino- and glycoconjugates of pyrido[4,3,2-kl]acridine and pyrido[4,3,2-kl]acridin-4-one have been prepared. The most active molecules, the amino conjugates 7 and 11, display a cytostatic activity against HT-29 cancer cells at micromolar concentration. This activity correlates well with a strong DNA binding. The molecules, amino or glycoconjugates, bind DNA by intercalation, the amino or glyco substituent being located in one groove. None of the molecules inhibits topoisomerase activity.

The chemical binding of a redox acridone derivative onto a polypyrrole film functionalized by N-hydroxysuccinimide groups provided an electrode capable of anchoring DNA duplex by simple insertion of the grafted acridone intercalator into the dsDNA solution. This electrode was applied for the detection of a ssDNA derived from a West Nile virus sequence. The latter was thus amperometrically detected after its hybridization in solution with a biotinylated complementary oligonucleotide followed by its anchoring and labeling by a glucose oxidase at 1 pg/mL.

In the field of DNA sensing, DNA hybridisation detection is generally performed by fluorescence microscopy. However, fluorescence instrumentation is difficult to miniaturise in order to produce fully integrated DNA chips. In this context, electrochemical detection of DNA hybridisation may avoid this limitation. Therefore, the use of DNA intercalators is particularly attractive due to their selectivity toward DNA double strand enabling DNA labelling without target chemical modification and, for most of them, to their electroactivity. We have synthesized a pyridoacridone derivative dedicated to DNA hybridisation electrochemical-sensing which presents good electrochemical reversibility, electroactivity at mild potentials and specificity toward DNA double strand. The electrochemical behaviour of this molecule has been assessed using cyclic voltammetry (CV). DNA/intercalator interactions were studied by differential pulse voltammetry (DPV) before application to hybridisation detection onto DNA sensors based on polypyrrole modified electrodes.

The synthesis of a novel completely asymmetric mononuclear complex of ruthenium(II) bearing a chiral bis-phenanthroline Troger’s base ligand 1 (TBphen 2 ) is reported. The diastereoisomeric forms of [Ru(phen) 2 TBphen 2 ] 2+ (Δ S /Λ R = rac - 2a and Λ S /Δ R = rac - 2b ) were separated through crystallization. A complete structure elucidation of the diastereoisomers in solution, including chirality assignment, was achieved by 1D and 2D NMR techniques. Photophysical characterization revealed no significant differences in the emission properties of rac - 2a and rac - 2b that closely resemble those of [Ru(phen) 3 ] 2+ .

We describe the synthesis and DNA damaging activities of hybrid molecules in which a purine (adenine) is linked to an intercalating chromophore (acridine) by a polyamino linker. A DNA damaging agent, phenanthroline or para-nitrobenzamide, is tethered to the acridine moiety at various positions. Our goal is to induce upon activation other lesions in close proximity to the abasic site and therefore create cytotoxic multiply damaged sites.

International audience

A series of bis-pyridinium quaternary ammonium salts (bis-PyQAs) with different aryl and heteroaryl moieties were synthesized and their antimicrobial activity investigated. The inhibition effect of the compounds was evaluated against bacteria, molds and yeasts; the activities were expressed as the minimum inhibitory concentrations (MIC). The relationships between the structure descriptors (logP, polarizability, polar surface area (2D), van der Waals area (3D)) and the biological activity of the tested bis-PyQAs are discussed.

The synthesis, and the reactions with nucleophiles, of 4-hydroxymethyl-3-(dimethylamino)- and -3-(methylamino)-acridines are presented. The reactivity of both compounds in methanol and propan-2-ol is studied. The corresponding 4-methoxy- and 4-isopropoxymethyl-3-(alkylamino)acridines are obtained quantitatively. Kinetics data indicate that protonation of the acridine ring nitrogen greatly increases reaction rates, and results are in favour of a very efficient intramolecular acid–base catalysis generating quinone-imine-methide intermediates. Transetherification reactions (i.e., transformation of methyl ethers into isopropyl ethers) are also observed. The reactivity with DNA is studied. Covalent binding to calf-thymus DNA is evidenced by UV–visible analysis of the modified DNA pellets. Ratios of 1 drug bound per 14 base pairs for the 3-methylamino analogue and 1 drug per 16 base pairs for the dimethyl analogue are calculated, and correspond to 50% of the drugs bound to the macromolecule.

The bifunctional Ru(II) complex [Ru(BPY)2POQ-Nmet]2+ (1), in which the metallic unit is tethered by an aliphatic chain to an organic DNA binder, was designed in order to increase the affinity toward nucleic acids. The interaction of 1 with DNA was characterised from luminescence and absorption data and compared with the binding of its monofunctional metallic and organic analogues, [Ru(BPY)2(ac)phen]2+ (2) and Nmet-quinoline (3). The bifunctional complex has a binding affinity one order of magnitude higher than that of each of its separated moieties. Absorption changes induced upon addition of DNA at different pH indicate protonation of the organic sub-unit upon interaction with DNA under neutral conditions. The combination of the luminescence data under steady-state and time-resolved conditions shows that the attachment of the organic unit in 1 induces modifications of the association modes of the metallic unit, owing to the presence of the aliphatic chain which probably hinders the metallic moiety binding. The salt dependence of the binding constants was analysed in order to compare the thermodynamic parameters describing the association with DNA for each complex. This study demonstrates the interest of the derivatisation of a Ru(II) complex with an organic moiety (ia the bifunctional ligand POQ-Nmet) for the development of high affinity DNA probes or photoreactive agents.

3,4-Dihydro-4-methyl-lH-[3,1]oxazinoacridine was prepared in four steps from 3-aminoacridine. DDQ induced opening of the dihydrooxazine ring yielded the 3-methylamino-4-formyl derivative. The same strategy was applied to 11-aminobenzo-[b][1,7]phenanthroline.

2-Amino-6-(1,2,4-triazol-4-yl)purine, prepared from 2,6-diaminopurine, was regioselectively alkylated at position 9. Subsequent alkaline hydrolysis afforded 9-alkylguanines in high yield.

We use molecular modeling calculations to study the structure and the flexibility of abasic (AP sites) and for the design of anticancer drugs targeted against AP sites. For either adenine or cytosine on the opposing strand within the same sequence context, the results are in line with experimental data which show that the two unpaired bases lead to intrahelical forms, but with differences in induced curvature. Results on flexibility, indicate that the two duplexes have the same bending rigidity for cytosine. In previous work a series of polyfunctional molecules, such as ATAc, were designed to selectively recognize and cleave abasic sites in DNA. The nitrobenzamide group which was added to the ATAc molecule to obtain a new molecule, termed ATAc4, can induce a second lesion under irradiation in close proximity to the abasic site. The different conformations of ATAc4 interacting with a DNA oligomer containing a stable analog of the abasic site were compared to the photoinduced cleavage pattern observed experimentally.

Cyclization of 8-bromo-9-alkylaminoethyl-adenine quantitatively affords a substituted imidazo[1,2-e]purine. The corresponding heterodimer, imidazo[1,2-e]purine-acridine, was prepared and its interaction with abasic site containing oligonucleotides was studied.

The synthesis and characterisation of a new bifunctional Ru(II) complex are presented. This compound contains a metallic unit, photoreactive versus the guanines of DNA, and a new bifunctional ligand. An intramolecular luminescence quenching makes this complex an attractive candidate for photoprobing DNA where the intramolecular quenching process is inhibited with restoration of luminescence.

A series of [1,3]oxazino fused acridines has been prepared as precursors of cytotoxic 3-amino-4-hydroxymethylacridine 2. Their cytotoxic activity has been evaluated against HT29 colon carcinoma cell line and was shown to be dependent on the nature of the substituent located on position 2 of the oxazine ring. Additionally, the nitrophenyl derivative 3f is activated by nitroreductase, indicating its potency as prodrug for either gene-directed or antibody-directed enzyme prodrug therapies.

A combination of NMR techniques, including 13C and 1H DEPT, HMQC and HMBC experiments, was used to assign the structure of the compound formed by addition of aniline to 8H-pyrido[2,3,4-mn]acridine. From this NMR study, two structures were possible. This ambiguity was removed by regioselective introduction of one deuterium on the starting compound. © 1997 John Wiley & Sons, Ltd.

[Ru(BPY)2POQ−Nmet]2+ and [Ru(TAP)2POQ−Nmet]2+ (1 and 3) are bifunctional complexes composed of a metallic unit linked by a flexible chain to an organic unit. They have been prepared as photoprobes or photoreagents of DNA. In this work, the spectroscopic properties of these bifunctional complexes in the absence of DNA are compared with those of the monofunctional analogues [Ru(BPY)2Phen]2+, [Ru(BPY)2acPhen]2+, [Ru(TAP)2Phen]2+, and [Ru(TAP)2acPhen]2+ (2 and 4). The electrospray mass spectrometry and absorption data show that the quinoline moiety exists in the protonated and nonprotonated form. Although the bifunctional complex containing 2,2‘-bipyridine (BPY) ligands exhibits photophysical properties similar to those of the monofunctional compounds, the bifunctional complex with 1,4,5,8-tetraazaphenanthrene (TAP) ligands behaves quite differently. It has weaker relative emission quantum yields and shorter luminescence lifetimes than the monofunctional TAP analogue when the quinoline unit is nonprotonated. ...

The presence of a hydroxy or methoxy group in position 2 of acridine directs the electrophilic substitution by formaldehyde in methane sulfonic acid to position 1. This reactivity is applied to the synthesis of pyrido[2,3,4-m,n]acridine.

Tailor-made molecules, DTAc and ATAc, that incorporate a nucleic base (adenine or 2,6-diaminopurine) linked by a diamino chain to an intercalator (9-amino-6-chloro-2-methoxyacridine) selectively recognize and efficiently cleave abasic sites in DNA via a beta-elimination reaction. The three-dimensional structure of the complexes of DTAc and ATAc bound to a DNA undecamer, the 5'd(C1G2C3A4C5X6C7A8C9G10C11)3' x 3'd(G22C21G20T19G18T17G16T15G14C13G12)5' duplex in which the X residue is a stable abasic site [3-hydroxy-2-(hydroxymethyl)tetrahydrofuran], has been studied by combined NMR-energy minimization methods. Analysis of the NMR spectra reveals that DTAc and ATAc interact with a very similar fashion and form two different complexes with DNA, present in a ratio of 70/30 (+/-10). In both complexes, the acridine ring intercalates exclusively between the C3 x G20 and A4 x T19 base pairs, the linker is located in the minor groove, and the base moiety docks in the abasic site. The principal difference between the major and the minor complexes consists of a 180 degrees rotation of the acridine ring around the Acr-C-N bond within the same intercalation site. Molecular modeling studies with few intermolecular ligand-DNA restraints were used to investigate the geometry of the base pair formed between the diaminopurine of DTAc and the T17 ring. The most energetically favored complex has the 2,6-diaminopurine of DTAc base paired with the T17 ring in a Hoogsteen conformation. The models DTAc and ATAc are also discussed as nuclease mimics and cleaving agents at abasic sites.

3-amino-acridine 1 reacts with formaldehyde in acidic medium to give four different compounds depending on the stoechiometry of the reaction: the dihydrooxazine derivative 2 , the tetrahydropyrimidine derivative 3 , the Troger's Base analogue 4 and the acridino[3,4-j]-benzo[b][1,7]phenanthroline 5 . Compounds 3, 4 and 5 could be obtained selectively by using the required amount of formaldehyde. Selective synthesis of 2 was independently realized in a three step sequence. Compounds 2, 3 and 4 in solution in 12 N HCl slowly transformed to give compound 5 as a major product.

A synthetic redox probe structurally related to natural pyridoacridones was designed and electrochemically characterised. These heterocycles behave as DNA intercalators due to their extended planar structure that promotes stacking in between nucleic acid base pairs. Electrochemical characterization by cyclic voltammetry revealed a quasi-reversible electrochemical behaviour occurring at a mild negative potential in aqueous solution. The study of the mechanism showed that the iminoquinone redox moiety acts similarly to quinone involving a two-electron reduction coupled with proton transfer. The easily accessible potential region with respect to aqueous electro-inactive window makes the pyridoacridone ring suitable for the indirect electrochemical detection of chemically unlabelled DNA. Its usefulness as electrochemical hybridization indicator was assessed on immobilised DNA and compared to doxorubicin. The voltamperometric response of the intercalator acts as an indicator of the presence of double-stranded DNA at the electrode surface and allows the selective transduction of immobilised oligonucleotide hybridization at both macro- and microscale electrodes.