Nicolas Saettel | Université de Caen Normandie (original) (raw)
Papers by Nicolas Saettel
Collection Symposium Series, 2015
![Research paper thumbnail of ChemInform Abstract: Ab initio Studies of [1,5]-H Shifts: Pentadiene and Beyond](https://attachments.academia-assets.com/42997243/thumbnails/1.jpg)
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ChemInform, 2004
ABSTRACT For Abstract see ChemInform Abstract in Full Text.
Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.
A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has... more A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for Gquadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (ΔT 1/2 up to 30 • C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA.
Tetrahedron Letters, 2005
Palladium-versus Copper-Catalyzed N-Arylation Towards an Efficient Access to Polysubstituted Dibe... more Palladium-versus Copper-Catalyzed N-Arylation Towards an Efficient Access to Polysubstituted Dibenzophenanthrolines and Carbazoles. -Brominated arenes (I) and (IV) can be efficiently coupled with o-amino acids (II) to give poly-substituted products (III) and (V) when Pd-catalysts are used. Diiodoarene (VIII) in the presence of a Cu-catalyst system gives a mono-substitution reaction allowing the preparation of unsymmetrically disubstituted diacid (XI). The products are immediate precursors of the dibenzophenanthroline skeleton. -(JACQUELIN, C.; SAETTEL, N.; HOUNSOU, C.; TEULADE-FICHOU*, M.-P.; Tetrahedron Lett. 46 (2005) 15, 2589-2592; Chim. Interact. Mol., CNRS, Coll. Fr., F-75005 Paris, Fr.; Eng.) -Mais 32-089
Tetrahedron, 2006
The electron transfer catalyzed cycloreversion of cyclobutane pyrimidine dimers is the key step i... more The electron transfer catalyzed cycloreversion of cyclobutane pyrimidine dimers is the key step in repair of light-induced DNA lesions catalyzed by the enzyme CPD photolyase. The formation of the CPD radical anion was found to be strongly solvent dependent due to a specific hydrogen bond that stabilizes the valence bound state over the dipole bound state of the additional electron. The effect of solvation on the vertical and adiabatic electron affinity of uracil and uracil dimers as well as on the mechanism of the cycloreversion of the uracil dimer radical anion is explored for three model systems that include explicit solvent molecules at the B3LYP/6-311++G**/B3LYP/6-31+G* level of theory. The second solvation shell is described using the implicit C-PCM solvation model. These calculations indicate an effectively barrierless mechanism. These results are in agreement with the available experimental data for the reaction energies and isotope effects. It is also shown that a single hydrogen bond donor is a sufficient minimal model for the first solvation shell by adequately describing the stabilization of the valence bound state of the radical anion through hydrogen bonding. The relationship of these model systems with the enzymatic reaction catalyzed by DNA photolyase is also discussed.
Journal of the American Chemical Society, 2002
The electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied... more The electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied by a combination of experimental and theoretical methods. The (13)C kinetic isotope effects were determined at natural abundance by NMR methodology. B3LYP/6-31G* calculations allow for the first time a quantitatively accurate description of the different possible pathways and provide the basis for an analysis of the experimentally observed isotope effects. The computational results, in conjunction with experimental observations, show that the reaction has a stepwise mechanism that is initiated by attack of the diene into the 3-position of the indole. Numerical simulation of the experimentally observed isotope effects shows that the first step is rate-determining and that the electron exchange in the reactant contributes partially to the overall isotope effect. The combination of electronic structure theory, experimental isotope effects, and numerical simulation thus allows a detailed analysis of a complex reaction mechanism.
![Research paper thumbnail of DFT Study of the [2 + 2] Cycloreversion of Uracil Dimer Anion Radical: Waters Matter](https://attachments.academia-assets.com/42997254/thumbnails/1.jpg)
](Journal of the American Chemical Society, 2001
UV irradiation induces a [2 + 2] cycloaddition between adjacent thymine bases in DNA to form cycl... more UV irradiation induces a [2 + 2] cycloaddition between adjacent thymine bases in DNA to form cyclobutane-like cis,synthymine dimer T〈〉T as the major product ( ). This lesion is the principal cause for skin cancer as it blocks cell replication and transcription. The enzyme DNA photolyase is capable of reversing this process using visible light. The accepted pathway is a photoinduced electron transfer from a cofactor FADH 2 to T〈〉T via a light-harvesting. 1 Less known is the mechanism of the splitting of the thymine dimer radical anion. The cycloreversion of thymine or uracil dimer has been studied computationally in an attempt to reproduce the thermodynamics of the reaction, as well as getting insight into the mechanism. 2 However, these studies were performed in the gas phase, and their applicability to reactions in solution or the enzyme is not clear. This is particularly true in light of experimental 3-5 and computational 6 studies of the electron attachment to uracil. These studies indicate a dipole-bound state with an electron affinity (EA) of 1.24 kcal/ mol, whereas the valence-bound state is not stable. 7 This behavior should be even more pronounced in the case of the uracil dimer as the stabilization of the dipole-bound state increases with the dipole moment. The valence-bound state of pyrimidines can be stabilized by hydrogen bonding with water 8-10 or between base pairs. 11 It can therefore be expected that the gas-phase calculations will not give an adequate representation of the reaction. We have therefore investigated the electron affinity of uracil and the cycloreversion of the uracil dimer U〈〉U, which is also a substrate for DNA photolyase. 12 Three water molecules are introduced to mimic the specific interactions in aqueous solution and in the enzyme DNA photolyase, where Trp 384 is hydrogen-bonded to the C4 carbonyl of the U〈〉U substrate. Table 1 summarizes our results obtained at the B3LYP/6-31+G* level of theory using the Gaussian98 14 series of programs. On the basis of the gas-phase calculations of electron affinities, these results demonstrate how incorporation of hydrogen-bonded water molecules stabilizes the uracil anion valence state and provide a reasonable model for the study of the subsequent reaction. UHF or MP2/6-31G* calculations give a negative EA of about -28 kcal/mol; 2d introduction of one bridging H 2 O across the C4 carbonyl groups of U〈〉U increases the EA to +28 kcal/ mol. Three water molecules do not change the adiabatic EA significantly but give a positive vertical EA. We thus decided to investigate the mechanism of hydrogen-bonded uracil dimer anion radical splitting.
Journal of the American Chemical Society, 2013
We report on the design and synthesis of two-photon fluorescent triphenylamines bearing two or th... more We report on the design and synthesis of two-photon fluorescent triphenylamines bearing two or three vinyl branches terminated by a N-methyl benzimidazolium moiety. The new compounds (TP-2Bzim, TP-3Bzim) are light-up fluorescent DNA probes with a long wavelength emission (>580 nm). Compared to their pyridinium models, the TP-Bzim dyes exhibit a remarkable improvement of both their DNA affinity and fluorescence quantum yield, especially for the two-branch derivative (TP-2Bzim: ΦF = 0.54, Ka = 10(7) M(-1)), resulting in a large fluorescence emission turn-on ratio of up to 140. Concomitantly, the two-photon absorption cross-section of TP-2Bzim is dramatically enhanced upon DNA binding (δ = 1080 vs 110 GM for the free form). This effect of the DNA matrix on the nonlinear absorption is uncovered for the first time. This is attributed to a tight fit of the molecule inside the minor groove of AT-rich DNA which induces geometrical rearrangements in the dye ground state as supported by circular dichroism and molecular modeling data. Consequently, TP-2bzim displays an exceptional two-photon molecular brightness (δ×ΦF = 583 GM), a value unrivalled for a small biofluorophore. These properties enable to image nuclear DNA in fixed cells at submicromolar concentration ([TP-2Bzim] = 100 nM) and to visualize ultrabright foci of centromeric AT-rich chromatin. Finally TP-2Bzim exhibits a high photostability, is live-cell permeant, and does not require RNase treatment. This outstanding combination of optical and biological properties makes TP-2Bzim a bioprobe surpassing the best DNA stainers and paves the way for studying further nonlinear optical processes in DNA.
Journal of Porphyrins and Phthalocyanines, 2010
ABSTRACT We report the synthesis of a series of zinc porphyrins conjugated with pyrimidine deriva... more ABSTRACT We report the synthesis of a series of zinc porphyrins conjugated with pyrimidine derivatives. V shaped porphyrin dimer with a pyrimidine central core exhibits a planar geometry according to DFT computational studies, presents an internal charge transfer upon excitation proved by typical solvatochromic behavior and moderate two-photon absorption properties. Such porphyrin conjugates can afford valuable advantages in applications of TPA materials such as in photodynamic therapy and imaging of biological entities.
The Journal of Organic Chemistry, 2004
A low-molecular-weight biomimetic affinity ligand selective for binding elastase has been designe... more A low-molecular-weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X-ray crystallographic structure of the enzyme-inhibitor complex. Limited solid-phase combinatorial chemistry was used to synthesize 12 variants of the lead ligand using the triazine moiety as the scaffold for assembly. The ligand library was screened for its ability to bind elastase and trypsin, and two ligands were studied further. Ligand C4/6 [2-alanyl-alanyl-4-tryptamino-6-(alpha-lysyl)-s-triazine] was found to bind porcine pancreatic elastase, but not trypsin, with a dissociation constant of 6 x 10(-5) M and a binding capacity of 21 mg elastase per ml gel. The adsorbent was used to purify elastase from a crude extract of porcine pancreas. Immobilized ligand C4/5 6 [2-alanyl-alanyl-4-tyramino-6-(alpha-lysyl)-s-triazine] was similarly chosen for optimal binding of elastase from cod and used to purify the enzyme from a crude extract of cod pyloric caeca. Ligand C4/6 was subsequently synthesized in solution and its structure verified by 1H-NMR.
The Journal of Organic Chemistry, 2000
... The transition state, a Hückel (4n + 2) π-electron array, has the C s symmetry and a suprafac... more ... The transition state, a Hückel (4n + 2) π-electron array, has the C s symmetry and a suprafacial topology predicted by Woodward and Hoffmann. 33 An IRC connects this transition state to the local minimum s-cis pentadiene. ... Woodward, RB; Hoffmann, R. Angew. Chem., Int. Ed. ...
![Research paper thumbnail of Sterically Crowded Bicyclo[1.1.0]butane Radical Cations](https://attachments.academia-assets.com/42997605/thumbnails/1.jpg)
](The Journal of Organic Chemistry, 2003
The variability of carbon-carbon single bonds by steric and electronic effects is probed by DFT c... more The variability of carbon-carbon single bonds by steric and electronic effects is probed by DFT calculations of sterically crowded bicyclo[1.1.0]butanes and their radical cations. The interplay of sterics and electronics on the gradual weakening and breaking of bonds was studied by investigating bridgehead substitution in 1,3-di-tert-butylbicyclo[1.1.0]butane and 2,2′,4,4′-tetramethyl-1,3-di-tert-butylbicyclo[1.1.0]butane and geminal substitution in 2,2′-di-tertbutylbicyclo[1.1.0]butane and 2,2′,4,4′-tetra-tert-butylbicyclo-[1.1.0]butane. Bridgehead substitution leads to a lengthening of the central bond, whereas bisubstitution on the geminal carbon leads to a shortening of this bond due to a Thorpe-Ingold effect. Although the character of the central bond can be modulated by substitution and electron transfer over a range of 0.35 Å, the state forbidden ring planarization does not occur. Sterically crowded bicyclo[1.1.0]butane radical cations are therefore promising candidates for the investigation of extremely long carbon-carbon single bonds. Supporting Information Available: Energies, zero point energies, and Cartesian coordinates of all structures reported. This material is available free of charge via the Internet at http://pubs.acs.org. JO0267549 (20) Richtsmeier, S. C.; Gassman, P. G.; Dixon, D. A. J. Org. Chem. 1985, 50, 311.
Journal of Materials Chemistry, 2005
ABSTRACT A novel threefold symmetry planar system based on a π-conjugated triazatrinaphthylene co... more ABSTRACT A novel threefold symmetry planar system based on a π-conjugated triazatrinaphthylene core has been synthesized and deposited on atomically flat surfaces of highly oriented pyrolytic graphite (HOPG). Scanning tunnelling microscopy (STM) of 2,8,14-trimethyl-5,11,17-triazatrinaphthylene (denoted TrisK by analogy with the Triskele Celtic symbol) deposited at the n-tetradecane/HOPG interface reveals the spontaneous formation of self-assembled monolayers with a hexagonal close-packed arrangement extending over several tens of nanometers. Surprisingly, sub-molecular STM resolution reveals an extremely bright contrast spot on one of the three symmetrical branches of the triangular-shaped molecule TrisK. This non-equivalent adsorption site can be interpreted as originating from a local specific molecule–HOPG interaction. Besides, ab-initio calculations show that a purely molecular contribution may also be involved.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2008
5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst s... more 5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT(4) receptor-ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT(4) antagonist pharmacophore was established.
Chemistry - A European Journal, 2010
A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by o... more A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by one- or two-step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thymine residue (TX), as well as to the fully paired control (TA), was investigated by thermal denaturation and fluorescent-intercalator-displacement experiments. The bisnaphthalene derivatives, in particular, the 2,7-disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocycles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch-binding affinity and selectivity of the macrocyclic bisintercalators.
Biochimie, 2011
Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl ca... more Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl carbazole-based light-up probes initially designed for two-photon absorption. The vinylic derivatives (Cbz-2Py, Cbz-3Py) display strong fluorescence enhancement when bound to various duplex- and quadruplex-forming oligonucleotides whereas the oxazole derivative is not fluorescent in DNA. Determination of affinity constants by fluorimetric titrations evidenced that Cbz-2Py has a clear preference for AT-rich duplex structures. Circular Dichroism (CD) measurements confirmed the sequence-dependent binding of this compound and suggest insertion in the minor groove as shown by a strong induced CD (ICD) signal and further supported by molecular modeling. Altogether the data indicate that duplex vs quadruplex selectivity of the dyes is strongly dependent on the sequence of the duplex. Finally, the dyes exhibit high two-photon absorption cross-sections (up to 540GM in glycerol) and allow a fine and bright staining of nuclear DNA with low background fluorescence as shown by one and two-photon confocal microscopy imaging of fixed cells.
Collection Symposium Series, 2015
ChemInform, 2004
ABSTRACT For Abstract see ChemInform Abstract in Full Text.
Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.
A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has... more A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for Gquadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (ΔT 1/2 up to 30 • C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA.
Tetrahedron Letters, 2005
Palladium-versus Copper-Catalyzed N-Arylation Towards an Efficient Access to Polysubstituted Dibe... more Palladium-versus Copper-Catalyzed N-Arylation Towards an Efficient Access to Polysubstituted Dibenzophenanthrolines and Carbazoles. -Brominated arenes (I) and (IV) can be efficiently coupled with o-amino acids (II) to give poly-substituted products (III) and (V) when Pd-catalysts are used. Diiodoarene (VIII) in the presence of a Cu-catalyst system gives a mono-substitution reaction allowing the preparation of unsymmetrically disubstituted diacid (XI). The products are immediate precursors of the dibenzophenanthroline skeleton. -(JACQUELIN, C.; SAETTEL, N.; HOUNSOU, C.; TEULADE-FICHOU*, M.-P.; Tetrahedron Lett. 46 (2005) 15, 2589-2592; Chim. Interact. Mol., CNRS, Coll. Fr., F-75005 Paris, Fr.; Eng.) -Mais 32-089
Tetrahedron, 2006
The electron transfer catalyzed cycloreversion of cyclobutane pyrimidine dimers is the key step i... more The electron transfer catalyzed cycloreversion of cyclobutane pyrimidine dimers is the key step in repair of light-induced DNA lesions catalyzed by the enzyme CPD photolyase. The formation of the CPD radical anion was found to be strongly solvent dependent due to a specific hydrogen bond that stabilizes the valence bound state over the dipole bound state of the additional electron. The effect of solvation on the vertical and adiabatic electron affinity of uracil and uracil dimers as well as on the mechanism of the cycloreversion of the uracil dimer radical anion is explored for three model systems that include explicit solvent molecules at the B3LYP/6-311++G**/B3LYP/6-31+G* level of theory. The second solvation shell is described using the implicit C-PCM solvation model. These calculations indicate an effectively barrierless mechanism. These results are in agreement with the available experimental data for the reaction energies and isotope effects. It is also shown that a single hydrogen bond donor is a sufficient minimal model for the first solvation shell by adequately describing the stabilization of the valence bound state of the radical anion through hydrogen bonding. The relationship of these model systems with the enzymatic reaction catalyzed by DNA photolyase is also discussed.
Journal of the American Chemical Society, 2002
The electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied... more The electron-transfer-catalyzed Diels-Alder reaction of indole and 1,3-cyclohexadiene was studied by a combination of experimental and theoretical methods. The (13)C kinetic isotope effects were determined at natural abundance by NMR methodology. B3LYP/6-31G* calculations allow for the first time a quantitatively accurate description of the different possible pathways and provide the basis for an analysis of the experimentally observed isotope effects. The computational results, in conjunction with experimental observations, show that the reaction has a stepwise mechanism that is initiated by attack of the diene into the 3-position of the indole. Numerical simulation of the experimentally observed isotope effects shows that the first step is rate-determining and that the electron exchange in the reactant contributes partially to the overall isotope effect. The combination of electronic structure theory, experimental isotope effects, and numerical simulation thus allows a detailed analysis of a complex reaction mechanism.
Journal of the American Chemical Society, 2001
UV irradiation induces a [2 + 2] cycloaddition between adjacent thymine bases in DNA to form cycl... more UV irradiation induces a [2 + 2] cycloaddition between adjacent thymine bases in DNA to form cyclobutane-like cis,synthymine dimer T〈〉T as the major product ( ). This lesion is the principal cause for skin cancer as it blocks cell replication and transcription. The enzyme DNA photolyase is capable of reversing this process using visible light. The accepted pathway is a photoinduced electron transfer from a cofactor FADH 2 to T〈〉T via a light-harvesting. 1 Less known is the mechanism of the splitting of the thymine dimer radical anion. The cycloreversion of thymine or uracil dimer has been studied computationally in an attempt to reproduce the thermodynamics of the reaction, as well as getting insight into the mechanism. 2 However, these studies were performed in the gas phase, and their applicability to reactions in solution or the enzyme is not clear. This is particularly true in light of experimental 3-5 and computational 6 studies of the electron attachment to uracil. These studies indicate a dipole-bound state with an electron affinity (EA) of 1.24 kcal/ mol, whereas the valence-bound state is not stable. 7 This behavior should be even more pronounced in the case of the uracil dimer as the stabilization of the dipole-bound state increases with the dipole moment. The valence-bound state of pyrimidines can be stabilized by hydrogen bonding with water 8-10 or between base pairs. 11 It can therefore be expected that the gas-phase calculations will not give an adequate representation of the reaction. We have therefore investigated the electron affinity of uracil and the cycloreversion of the uracil dimer U〈〉U, which is also a substrate for DNA photolyase. 12 Three water molecules are introduced to mimic the specific interactions in aqueous solution and in the enzyme DNA photolyase, where Trp 384 is hydrogen-bonded to the C4 carbonyl of the U〈〉U substrate. Table 1 summarizes our results obtained at the B3LYP/6-31+G* level of theory using the Gaussian98 14 series of programs. On the basis of the gas-phase calculations of electron affinities, these results demonstrate how incorporation of hydrogen-bonded water molecules stabilizes the uracil anion valence state and provide a reasonable model for the study of the subsequent reaction. UHF or MP2/6-31G* calculations give a negative EA of about -28 kcal/mol; 2d introduction of one bridging H 2 O across the C4 carbonyl groups of U〈〉U increases the EA to +28 kcal/ mol. Three water molecules do not change the adiabatic EA significantly but give a positive vertical EA. We thus decided to investigate the mechanism of hydrogen-bonded uracil dimer anion radical splitting.
Journal of the American Chemical Society, 2013
We report on the design and synthesis of two-photon fluorescent triphenylamines bearing two or th... more We report on the design and synthesis of two-photon fluorescent triphenylamines bearing two or three vinyl branches terminated by a N-methyl benzimidazolium moiety. The new compounds (TP-2Bzim, TP-3Bzim) are light-up fluorescent DNA probes with a long wavelength emission (>580 nm). Compared to their pyridinium models, the TP-Bzim dyes exhibit a remarkable improvement of both their DNA affinity and fluorescence quantum yield, especially for the two-branch derivative (TP-2Bzim: ΦF = 0.54, Ka = 10(7) M(-1)), resulting in a large fluorescence emission turn-on ratio of up to 140. Concomitantly, the two-photon absorption cross-section of TP-2Bzim is dramatically enhanced upon DNA binding (δ = 1080 vs 110 GM for the free form). This effect of the DNA matrix on the nonlinear absorption is uncovered for the first time. This is attributed to a tight fit of the molecule inside the minor groove of AT-rich DNA which induces geometrical rearrangements in the dye ground state as supported by circular dichroism and molecular modeling data. Consequently, TP-2bzim displays an exceptional two-photon molecular brightness (δ×ΦF = 583 GM), a value unrivalled for a small biofluorophore. These properties enable to image nuclear DNA in fixed cells at submicromolar concentration ([TP-2Bzim] = 100 nM) and to visualize ultrabright foci of centromeric AT-rich chromatin. Finally TP-2Bzim exhibits a high photostability, is live-cell permeant, and does not require RNase treatment. This outstanding combination of optical and biological properties makes TP-2Bzim a bioprobe surpassing the best DNA stainers and paves the way for studying further nonlinear optical processes in DNA.
Journal of Porphyrins and Phthalocyanines, 2010
ABSTRACT We report the synthesis of a series of zinc porphyrins conjugated with pyrimidine deriva... more ABSTRACT We report the synthesis of a series of zinc porphyrins conjugated with pyrimidine derivatives. V shaped porphyrin dimer with a pyrimidine central core exhibits a planar geometry according to DFT computational studies, presents an internal charge transfer upon excitation proved by typical solvatochromic behavior and moderate two-photon absorption properties. Such porphyrin conjugates can afford valuable advantages in applications of TPA materials such as in photodynamic therapy and imaging of biological entities.
The Journal of Organic Chemistry, 2004
A low-molecular-weight biomimetic affinity ligand selective for binding elastase has been designe... more A low-molecular-weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X-ray crystallographic structure of the enzyme-inhibitor complex. Limited solid-phase combinatorial chemistry was used to synthesize 12 variants of the lead ligand using the triazine moiety as the scaffold for assembly. The ligand library was screened for its ability to bind elastase and trypsin, and two ligands were studied further. Ligand C4/6 [2-alanyl-alanyl-4-tryptamino-6-(alpha-lysyl)-s-triazine] was found to bind porcine pancreatic elastase, but not trypsin, with a dissociation constant of 6 x 10(-5) M and a binding capacity of 21 mg elastase per ml gel. The adsorbent was used to purify elastase from a crude extract of porcine pancreas. Immobilized ligand C4/5 6 [2-alanyl-alanyl-4-tyramino-6-(alpha-lysyl)-s-triazine] was similarly chosen for optimal binding of elastase from cod and used to purify the enzyme from a crude extract of cod pyloric caeca. Ligand C4/6 was subsequently synthesized in solution and its structure verified by 1H-NMR.
The Journal of Organic Chemistry, 2000
... The transition state, a Hückel (4n + 2) π-electron array, has the C s symmetry and a suprafac... more ... The transition state, a Hückel (4n + 2) π-electron array, has the C s symmetry and a suprafacial topology predicted by Woodward and Hoffmann. 33 An IRC connects this transition state to the local minimum s-cis pentadiene. ... Woodward, RB; Hoffmann, R. Angew. Chem., Int. Ed. ...
The Journal of Organic Chemistry, 2003
The variability of carbon-carbon single bonds by steric and electronic effects is probed by DFT c... more The variability of carbon-carbon single bonds by steric and electronic effects is probed by DFT calculations of sterically crowded bicyclo[1.1.0]butanes and their radical cations. The interplay of sterics and electronics on the gradual weakening and breaking of bonds was studied by investigating bridgehead substitution in 1,3-di-tert-butylbicyclo[1.1.0]butane and 2,2′,4,4′-tetramethyl-1,3-di-tert-butylbicyclo[1.1.0]butane and geminal substitution in 2,2′-di-tertbutylbicyclo[1.1.0]butane and 2,2′,4,4′-tetra-tert-butylbicyclo-[1.1.0]butane. Bridgehead substitution leads to a lengthening of the central bond, whereas bisubstitution on the geminal carbon leads to a shortening of this bond due to a Thorpe-Ingold effect. Although the character of the central bond can be modulated by substitution and electron transfer over a range of 0.35 Å, the state forbidden ring planarization does not occur. Sterically crowded bicyclo[1.1.0]butane radical cations are therefore promising candidates for the investigation of extremely long carbon-carbon single bonds. Supporting Information Available: Energies, zero point energies, and Cartesian coordinates of all structures reported. This material is available free of charge via the Internet at http://pubs.acs.org. JO0267549 (20) Richtsmeier, S. C.; Gassman, P. G.; Dixon, D. A. J. Org. Chem. 1985, 50, 311.
Journal of Materials Chemistry, 2005
ABSTRACT A novel threefold symmetry planar system based on a π-conjugated triazatrinaphthylene co... more ABSTRACT A novel threefold symmetry planar system based on a π-conjugated triazatrinaphthylene core has been synthesized and deposited on atomically flat surfaces of highly oriented pyrolytic graphite (HOPG). Scanning tunnelling microscopy (STM) of 2,8,14-trimethyl-5,11,17-triazatrinaphthylene (denoted TrisK by analogy with the Triskele Celtic symbol) deposited at the n-tetradecane/HOPG interface reveals the spontaneous formation of self-assembled monolayers with a hexagonal close-packed arrangement extending over several tens of nanometers. Surprisingly, sub-molecular STM resolution reveals an extremely bright contrast spot on one of the three symmetrical branches of the triangular-shaped molecule TrisK. This non-equivalent adsorption site can be interpreted as originating from a local specific molecule–HOPG interaction. Besides, ab-initio calculations show that a purely molecular contribution may also be involved.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2008
5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst s... more 5-Hydroxytryptamine subtype-4 (5-HT(4)) receptors have stimulated considerable interest amongst scientists and clinicians owing to their importance in neurophysiology and potential as therapeutic targets. A comparative analysis of hierarchical methods applied to data from one thousand 5-HT(4) receptor-ligand binding interactions was carried out. The chemical structures were described as chemical and pharmacophore fingerprints. The definitions of indices, related to the quality of the hierarchies in being able to distinguish between active and inactive compounds, revealed two interesting hierarchies with the Unity (1 active cluster) and pharmacophore fingerprints (4 active clusters). The results of this study also showed the importance of correct choice of metrics as well as the effectiveness of a new alternative of the Ward clustering algorithm named Energy (Minimum E-Distance method). In parallel, the relationship between these classifications and a previously defined 3D 5-HT(4) antagonist pharmacophore was established.
Chemistry - A European Journal, 2010
A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by o... more A collection of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was prepared by one- or two-step condensation of aromatic dialdehydes with aliphatic diamines; notably, the heterodimeric scaffolds were synthesized for the first time. The binding of these macrocycles to DNA duplexes containing a mispaired thymine residue (TX), as well as to the fully paired control (TA), was investigated by thermal denaturation and fluorescent-intercalator-displacement experiments. The bisnaphthalene derivatives, in particular, the 2,7-disubstituted ones, have the highest selectivity for the TX mismatches, as these macrocycles show no apparent binding to the fully paired DNA. By contrast, other macrocyclic ligands, as well as seven conventional DNA binders, show lesser or no selectivity for the mismatch sites. The study demonstrates that the topology of the ligands plays a crucial role in determining the mismatch-binding affinity and selectivity of the macrocyclic bisintercalators.
Biochimie, 2011
Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl ca... more Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl carbazole-based light-up probes initially designed for two-photon absorption. The vinylic derivatives (Cbz-2Py, Cbz-3Py) display strong fluorescence enhancement when bound to various duplex- and quadruplex-forming oligonucleotides whereas the oxazole derivative is not fluorescent in DNA. Determination of affinity constants by fluorimetric titrations evidenced that Cbz-2Py has a clear preference for AT-rich duplex structures. Circular Dichroism (CD) measurements confirmed the sequence-dependent binding of this compound and suggest insertion in the minor groove as shown by a strong induced CD (ICD) signal and further supported by molecular modeling. Altogether the data indicate that duplex vs quadruplex selectivity of the dyes is strongly dependent on the sequence of the duplex. Finally, the dyes exhibit high two-photon absorption cross-sections (up to 540GM in glycerol) and allow a fine and bright staining of nuclear DNA with low background fluorescence as shown by one and two-photon confocal microscopy imaging of fixed cells.