Synthesis of fluorescent 5-heteroarylpyrimidine-containing oligonucleotides post-synthetic trifluoromethyl conversion.

Post-synthetic conversion of the trifluoromethyl group to a heteroaryl group at the C5 position of the pyrimidine base in DNA oligonucleotides was achieved. Specifically, the oligonucleotides containing 5-trifluoromethylpyrimidine bases were treated with -phenylenediamines and -aminothiophenols as nucleophiles to afford the corresponding 5-(benzimidazol-2-yl)- and 5-(benzothiazol-2-yl)-pyrimidine-modified bases. Furthermore, evaluation of the fluorescence properties of the obtained oligonucleotides revealed that among them the oligonucleotide containing 5-(5-methylbenzimidazol-2-yl)cytosine exhibited the highest fluorescence intensity.

Synthesis of a Hydrophobic Phenanthrene-Containing Universal Support for Solid-Phase Oligonucleotide Synthesis.

Universal solid supports are widely used in solid-phase oligonucleotide (ON) synthesis based on phosphoramidite chemistry. Herein, we describe the synthesis of hydrophobic universal linkers, namely phenanthrene ring-fused 7-oxabicyclo[2.2.

Photoisomerization of "Partially Embedded Dihydropyridazine" with a Helical Structure.

Invited for the cover of this issue are the groups of Kazuteru Usui and Satoru Karasawa at Showa Pharmaceutical University and Yasuhiro Kobori of Kobe University. The image depicts chirality control of helical compounds through cycles of photocleavage and recombination under sunlight with a "Jack and the Beanstalk" motif. Read the full text of the article at 10.

Photoisomerization of "Partially Embedded Dihydropyridazine" with a Helical Structure.

Herein, we report the synthesis of two "partially embedded fused-dihydropyridazine N-aryl aza[5]helicene derivatives" (PDHs) and the demonstration of their intrinsic photo-triggered multi-functional properties based on a Kekulé biradical structure. Introducing bulky electron-withdrawing trifluoromethyl or pentafluoroethyl groups into the aza[5]helicene framework (PDH-CF and -C F ) gives PDH axial chirality based on the helicity of the P and M forms, even at room temperature. Upon photo-irradiation of PDH-CF in a frozen solution, an ESR signal from the triplet biradical with zero-field splitting values, generated by N-N bond dissociation, was observed.

Synthesis of purine derivatives of Me-TaNA and properties of Me-TaNA-modified oligonucleotides.

We previously reported that pyrimidine derivatives of methylated 2'-,4'--methyleneoxy-bridged nucleic acid (Me-TaNA), a unique consecutive three-acetal-containing nucleic acid, are promising building blocks for chemically modified oligonucleotides. Herein, purine derivatives of Me-TaNA (Me-TaNA-A and -G) were synthesized and introduced into oligonucleotides. During the synthesis, we found stereoselective introduction of a substituent on the 4' carbons by using 2',3'-carbonate compounds as substrates.

Expansion of Phosphoramidite Chemistry in Solid-Phase Oligonucleotide Synthesis: Rapid 3'-Dephosphorylation and Strand Cleavage.

In solid-phase oligonucleotide synthesis, a solid support modified with a universal linker is frequently used to prepare oligonucleotides bearing non-natural- or non-nucleosides at the 3'-end. Generally, harsh basic conditions such as hot aqueous ammonia or methylamine are required to release oligonucleotides by 3'-dephosphorylation via the formation of cyclic phosphate with the universal linker. To achieve 3'-dephosphorylation under milder conditions, we used -alkyl phosphoramidites instead of the commonly used -cyanoethyl phosphoramidites at the 3'-end of oligonucleotides.

Generation of 4'-Carbon Radicals via 1,5-Hydrogen Atom Transfer for the Synthesis of Bridged Nucleosides.

The rapid and facile generation of 4'-carbon radicals from oxime imidates of nucleosides via 1,5-hydrogen atom transfer induced by iminyl radicals was developed. The cyclization of 4'-carbon radicals with olefins, followed by the hydrolysis of imidate residues, provided various 2'-,4'-- and 3'-,4'--bridged nucleosides. This operationally simple approach can be applied to the few-step syntheses of 6'-methyl-2'-,4'--ethylene-bridged 5-methyluridine (6'-Me-ENA-T) and -constrained ethyl-bridged 5-methyluridine (-cEt-T).

Synthesis and Properties of Oligonucleotides Containing 2'-,4'--Methyleneoxy-Bridged Pyrimidine Derivatives.

In this study, 2'-,4'--methyleneoxy-bridged nucleic acid, a unique consecutive three-acetal-containing nucleic acid (TaNA), was designed. Pyrimidine derivatives of methylated TaNA (Me-TaNA) were also synthesized and introduced into oligonucleotides via solid-phase synthesis. The Me-TaNA-modified oligonucleotides exhibited higher stabilities when forming duplexes with single-stranded RNA or triplexes with double-stranded DNA, relative to the natural oligonucleotides and modified oligonucleotides containing another 2',4'-bridged 5-methyluridine, such as 2',4'-BNA/LNA and 2',4'-ENA.

Artificial Host Molecules to Covalently Capture 8-Nitro-cGMP in Neutral Aqueous Solutions and in Cells.

New 1,3-diazaphenoxazine derivatives (nitroG-Grasp-Guanidine, NGG) have been developed to covalently capture 8-nitro-cGMP in neutral aqueous solutions, which furnish a thiol reactive group to displace the 8-nitro group and a guanidine unit for interaction with the cyclic phosphate. The thiol group was introduced to the 1,3-diazaphenoxazine skeleton through a 2-aminobenzylthiol group (NGG-H) and its 4-methyl (NGG-Me) and 6-methyl (NGG-Me) substituted derivatives. The covalent adducts were formed between the NGG derivatives and 8-nitro-cGMP in neutral aqueous solutions.

Characterization of Push-Pull-Type Benzo[X]quinoline Derivatives (X = or ): Environmentally Responsive Fluorescent Dyes with Multiple Functions.

Benzo[X]quinoline (X = or : ) derivatives bearing bis-trifluoromethyl and amine groups have been designed as push-pull-type fluorescent dyes. Through the synthesis of derivatives from 2,7-diaminonaphthalene, linear-type () and angular-type () structural isomers were obtained. X-ray structures of single crystals from six given derivatives revealed that the and series adopt planar- and bowl-shaped structures.

Push-Pull Bisnaphthyridylamine Supramolecular Nanoparticles: Polarity-Induced Aggregation and Crystallization-Induced Emission Enhancement and Fluorescence Resonance Energy Transfer.

Emissive push-pull-type bisnaphthyridylamine derivatives (BNA-X: X=Me, Et, Bzl, Ph, BuBr, and BuTEMPO) aggregate in aqueous methanol. Furthermore, a two-step emission and aggregation process is controllable by varying the methanol-to-water ratio. At 2:3 MeOH/H O, crystallization-induced emission enhancement (CIEE) occurs via formation of an emissive crystal phase, whereas, at 1:9 MeOH/H O, aggregation-induced emission enhancement (AIEE) occurs, induced by emissive supramolecular nanoparticles (NPs).

A fully synthetic 6-aza-artemisinin bearing an amphiphilic chain generates aggregates and exhibits anti-cancer activities.

Installation of a nitrogen at the C6 position of artemisinin facilitates the addition of a functional unit on the cyclohexane moiety (C-ring). In this study, conjugation of an amphiphilic chain, composed of sequentially connected hydrophilic oligoethylene glycol, hydrophobic alkyl chain, urea, and 4,4'-disubstituted biphenyl linker, imparted self-assembling properties. The fully synthetic mid-molecular weight 6-aza-artemisinin 6 bearing the amphiphilic moiety formed aggregates (approx.

Characterization and Water-Proton Longitudinal Relaxivities of Liposome-Type Radical Nanoparticles Prepared via a Supramolecular Approach.

For the construction of metal-free magnetic resonance imaging (MRI) contrast agents, radical-based nanoparticles () are promising materials because they allow the water-proton longitudinal relaxivity () to be enhanced not only by paramagnetic resonance effects but also by prolonging the rotational correlation times (τ). However, the τ effect is limited because the radical units are often located within the central hydrophobic core of oil-in-water (o/w) emulsions, resulting in a lack of water molecules surrounding the radical units. In this study, to construct supramolecular that have high values, we designed a liposome-type in which the radical units are located at positions with sufficient surrounding water molecules.

Effects of Substituents on the Properties of Metal-Free MRI Contrast Agents.

Materials possessing electron spin can shorten the relaxation times in magnetic resonance imaging (MRI). For example, gadolinium (Gd) complexes with seven f-orbital electrons are widely used as contrast agents in clinical applications. However, Gd has severe potential side effects, and thus metal-free alternatives are needed.

Photophysical Properties of Emissive Pyrido[3,2-c]carbazole Derivatives and Apoptosis Induction: Development towards Theranostic Agents in Response to Light Stimulus.

Pyridocarbazole moieties are present in many natural products, such as olivacine and ellipticine, and their derivatives are well-known anticancer agents. To develop functional therapeutic and diagnostic compounds, three emissive pyrido[3,2-c]carbazole derivatives, PC-X, containing secondary or tertiary amine groups, were synthesized from an aminoquinoline derivative using a palladium complex as the catalyst. X-ray diffraction analyses revealed that PC-X showed highly planar structures between the pyridine ring and the carbazole framework, exhibiting high fluorescence intensities along with solvatochromic behavior.

Fluorescence Properties and Exciplex Formation of Emissive Naphthyridine Derivatives: Application as Sensors for Amines.

Water-soluble donor-acceptor-type fluorophore 15Nap-Cl having two trifluoromethyl groups and a Cl group on a 1,5-aminonaphthyridine framework was prepared. Fluorophore 15Nap-Cl showed strong solvatochromic fluorescence, and, as the solvent polarity increased, a bathochromic shift was observed accompanied by an increase in the fluorescence quantum yield. In addition, in the presence of amines such as ethylamine, diethylamine, and aniline, further considerable bathochromic shifts in the fluorescence were observed.

Development of Turn-On Probes for Acids Triggered by Aromaticity Enhancement Using Tricyclic Amidine Derivatives.

Two fluorophores consisting of tricyclic amidine derivatives (DHIm and DHPy) were prepared as selective turn-on probes for acids, which were triggered by an aromaticity enhancement. Both amidine derivatives were expanded rings prepared by condensed reactions between the corresponding dibromoalkanes and an aminonaphthyridine analogue. In X-ray analyses, DHIm, in which the dihydroimidazole ring was condensed into aminonaphthyridine, showed high planarity, compared to DHPy, with condensed dihydropyrimidine.

Fluorescence Tumor-Imaging Using a Thermo-Responsive Molecule with an Emissive Aminoquinoline Derivative.

We synthesized (2,4-trifluoromethyl-7--bis(2,5,8,11-tetraoxatridecane-13-yl)-aminoquinoline) TFMAQ-diEg4, an emissive aminoquinoline derivative that incorporated two tetraethyleneglycol chains into an amino group. TFMAQ-diEg4 showed fluorescence and thermo-responsive properties accompanied by a lower critical solution temperature (LCST), due to the introduction of the oligoethylene glycol chain. This thermo-responsive LCST behavior occurred at the border of a cloud point.

Luminescent europium sensors for specific detection of 8-oxo-dGTP by time-gated fluorescence.

The 9-hydroxy-1,3-diazaphenoxazine-2-one unit was conjugated with the Eu-cyclen complex through a linker. This diazaphenoxazine group was expected as an antenna unit for the excitation of europium ion, and a selective recognition site for 8-oxo-dGTP base. Among the synthesized three derivatives, the highest fluorescence emission was obtained by the complex constructed of an ethylene linker and the cyclen unit with three N,N-dimethylacetamide groups.

Synthetic receptor molecules for selective fluorescence detection of 8-oxo-dGTP in aqueous media.

A series of 9-hydroxy-1,3-diazaphenoxazine-2-one derivatives were synthesized as fluorescent receptor molecules for 8-oxo-dGTP, which attach the cyclen-zinc complex at the 3-N position as the binding site for the triphosphate and the (2-aryloxycarbonylamino)ethyl group at the 9-O position as the hydrogen bonding site for 8-oxoguanine. Among these molecules, the receptor molecule 5a-Zn constructed of the ethyl linker at 3-N and the (2-benzyloxycarbonyl amino)ethyl group at 9-O displayed the best recognition ability for 8-oxoguanosine triphosphate (8-oxo-dGTP) in aqueous media. The receptor 5a-Zn was also shown to selectively detect 8-oxo-dGTP in a cell lysate solution.

New NitroG-Grasp Molecules with Enhanced Capture Reactivity for 8-Nitroguanosine in the Aqueous Media.

8-Nitroguanosine is formed by the nitration of guanosine, and has been conventionally classified as a genotoxic material. Recently, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has become of great interest due to its biological role as an intracellular signaling molecule. In an attempt to develop recognition molecules for 8-nitroguanosine, we have determined a 1,3-diazaphenoxazine nucleoside derivative (nitroG-grasp) bearing a thiol group with a urea linker, which efficiently displaces the nitro group through the formation of multiple hydrogen-bonded complexes with 8-nitroguanosine.

Development of new 1,3-diazaphenoxazine derivatives (thioG-grasp) to covalently capture 8-thioguanosine.

The derivatives of 8-thioguanosine are thought to be included in the signal transduction system related to 8-nitroguanosine. In this study, we attempted to develop new 1,3-diazaphenoxazine (G-clamp) derivatives to covalently capture 8-thioguanosine (thioG-grasp). It was expected that the chlorine atom at the end of the linker would be displaced by the nucleophilic attack by the sulfur atom of 8-thioguanosine via multiple hydrogen-bonded complexes.

Efficient covalent capture of 8-nitroguanosine via a multiple hydrogen-bonded complex.

A novel 1,3-diazaphenoxazine nucleoside derivative (nitroG-Grasp) bearing a thiol group with a urea linker forms multiple hydrogen-bonded complexes with 8-nitroguanosine and efficiently displaces the nitro group; thus, it is the first molecule that can covalently capture 8-nitroguanosine.

Novel Benzofurans with (99m)Tc Complexes as Probes for Imaging Cerebral β-Amyloid Plaques.

Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an animal model of AD, (99m)Tc-BAT-BF clearly labeled β-amyloid plaques.