Agata Głuszyńska

Enantioselective modification of the Pomeranz–Fritsch–Bobbitt synthesis of tetrahydroisoquinoline alkaloids synthesis of (−)-salsolidine and (−)-carnegine

Abstract (−)-Salsolidine 7 and (−)-carnegine 8 were prepared in 46 and 36% e.e. , respectively, by enantioselective addition of methyllithium to the Pomeranz–Fritsch imine 13 in the presence of ligands 9 – 12 , followed by acid-catalyzed cyclization and hydrogenolysis.

Transformation of (+)-thiomicamine into a new ligand for the enantioselective addition of methyllithium to prochiral imines

Abstract A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8–10 tested. The non-racemic secondary amines 11–13 were prepared in 60–90% chemical yield with the enantioselectivity ranging from 2 to 41%. 6,7-Dimethoxy-3,4-dihydroisoquinoline 8 was transformed into (+)-salsolidine 11 with an e.e. of 41%.

Interaction of metallacrown complexes with G-quadruplex DNA.

Interactions of the G-quadruplex (GQ) DNA with two pentacoordinate lanthanide (III) metallacrown (MC) complexes containing phenylalanine hydroxamic acid (pheHA) and copper(II) ions of the formula Eu 15-[MCCu,pheHA]-5 (1) and Tb 15-[MCCu,pheHA]-5 (2) were investigated. Binding of both metallacrowns to human telomeric G-quadruplex DNA was followed using CD spectroscopy, DNA melting profiles, and fluorescent intercalator displacement (FID) assay. A new G-quadruplex binding assay based of quenching of Tb(III)-GQ luminescence was proposed and evaluated. All performed tests confirmed interactions of MCs with studied GQ structure. Binding affinities of MCs were appreciable (KMC ~2-5×10(5)M(-1)). Higher concentration of MCs (the ratio of GQ:MC above 2.5) caused destabilization of tetraplex structure of GQ as evidenced by CD spectroscopy, melting temperatures, and Tb(III)-GQ luminescence quenching results.

Synthesis and spectroscopic characterisation of (E)-2-(2-(9-(4-(1H-1,2,4-triazol-1-yl)butyl)-9H-carbazol-3-yl)vinyl)-3-ethylbenzo[d]thiazol-3-ium, a new ligand and potential DNA intercalator

Three new compounds based on carbazole planar skeleton were synthesised. Among them there is a new ligand and a potential DNA intercalator which contains a benzothiazolium moiety connected to the carbazole ring by a vinyl bridge. The absorption and emission spectral properties of this new ligand have been studied by spectroscopic methods.

Carbazole ligands as c-myc G-quadruplex binders

The interactions of c-myc G-quadruplex with three carbazole derivatives were investigated by UV-Vis spectrophotometry, fluorescence, CD spectroscopy, and molecular modeling. The results showed that a combination of carbazole scaffold functionalized with ethyl, triazole and imidazole groups resulted in stabilization of the intramolecular G-quadruplex formed by the DNA sequence derived from the NHE III1 region of c-myc oncogene (Pu22). Binding to the G-quadruplex Pu22 resulted in the significant increase in fluorescence intensity of complexed ligands 1-3. All ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex with comparable affinity, which agrees with binding model of end-stacking on terminal G-tetrads.

Conjugation of hemin to G-quadruplex forming oligonucleotide using click chemistry

Peroxidase-mimicking DNAzyme is one of the systems that recently gained a great interest. It has been successfully applied for designing numerous bioassays. The success of this system is connected to its advantages over a protein enzyme, horseradish peroxidase. Promising strategy for further improvement of performance of DNAzyme with peroxidase-like activity was proposed recently. It was based on the covalent attachment of hemin moiety to the G-quadruplex scaffold. We report here the first attempt of conjugating hemin to the G-quadruplex DNA using click chemistry approach. We modified hemin molecule through attachment of an azide-terminated linker to the porphyrin carboxylic group. Two click chemistry approaches were examined to conjugate the azide-modified hemin to a G-quadruplex oligonucleotide: copper-catalyzed and Cu-free cycloaddition reactions. Using Cu-free click reaction, we successfully synthesized G-quadruplex-hemin conjugate that exhibited promising peroxidase activity.

Dataset on characterization of hemin-azide derivative and DNA oligonucleotide-hemin conjugate

In this article newly synthesized azide derivative of hemin and DNA-hemin conjugate are characterized. Hemin-azide was purified using HPLC and characterized using elemental analysis, IR and NMR. The DNA-hemin conjugate was obtained via click chemistry [1] and click reaction was carried out using traditional Cu-catalyzed and Cu-free approaches. The final product was successfully obtained using Cu-free cycloaddition. The identity of product was confirmed using Maldi TOF spectrometry. Obtained hemin-DNA conjugate exhibited peroxidase-like activity.

Carbazole Derivatives’ Binding to c-KIT G-Quadruplex DNA

The binding affinities of three carbazole derivatives to the intramolecular G-quadruplex (GQ) DNA formed by the sequence 5′-AGGGAGGGCGCTGGGAGGAGGG-3′, derived from the c-KIT 1 oncogene region, were investigated. All carbazole cationic ligands that differed in the substituents on the nitrogen atom were able to stabilize G-quadruplex, as demonstrated using UV-Vis, fluorescence and CD spectroscopic techniques as well as molecular modeling. The spectrophotometric titration results showed spectral features characteristic of these ligands-bathochromic shifts and initial hypochromicity followed by hyperchromicity at higher GQ concentrations. All free carbazole ligands exhibited modest fluorescent properties, but after binding to the DNA the fluorescence intensity increased significantly. The binding affinities of carbazole ligands to the c-KIT 1 DNA were comparable showing values in the order of 105 M−1. Molecular modeling highlights the differences in interactions between each particular ligand and studied G-quadruplex, which potentially influenced binding strength. Obtained results relevant that all three investigated ligands have stabilization properties on studied G-quadruplex.