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This study aims to deepen the knowledge of the current state of rational G4‐ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well‐known G4‐ligands. This resulted in novel synthetic methods and G4‐ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4‐ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4‐binding and ‐selectivity, b) molecular pre‐organization is of key importance in the development of strong novel binders, c) an electron‐deficient aromatic core is essential to engage in strong arene‐arene interactions with the G4‐surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4‐binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

The transformation of glycals into 2,3‐unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR‐based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen‐containing C‐aryl glycosides and C‐alkyl glycosides under superacid and flow conditions, respectively. [ABSTRACT FROM AUTHOR]

The transformation of glycals into 2,3‐unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR‐based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen‐containing C‐aryl glycosides and C‐alkyl glycosides under superacid and flow conditions, respectively. [ABSTRACT FROM AUTHOR]

The fluorinated piperidine iminosugars 2a-4a and their N -octyl and N -decyl derivatives 2b,c-4b,c were synthesized from d -mannose/ d -xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2 / 3 , either 2 C 5 or 5 C 2 , was assigned based on the 1 H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N -alkylated fluorinated d - manno -iminosugars 3b/4b were found to be better immunosuppressive agents (IC 50  = 5–6  μ M) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β -glucosidase (IC 50  = 4–8  μ M). The N -alkyl-iminosugars 4b-c were found to be moderate inhibitors of α -glucosidase (yeast) and α -galactosidase (coffee beans), respectively. [ABSTRACT FROM AUTHOR]

Phosphoramidite building blocks of CF3-modified N4(6-amino-2-pyridinyl)deoxycytidines were synthesized, incorporated into triplex-forming 2'-deoxyoligonucleotide strands and the applicability of the probes to recognize nucleobase content in the pyrimidine-rich strand of double-helical DNA targets was evaluated. As expected, the obtained 19F NMR resonances were sensitive to the base content and unique 19F NMR spectral fingerprints could be obtained. [ABSTRACT FROM AUTHOR]

A new class of 3′-deoxy-3 β ′-fluoro-3 α ′- C -hydroxymethyl-pyrimidine 1a-c and purine 1d nucleosides were synthesized using modified Corey-Link reaction with 3-oxo- d -glucofuranose derivative to get C-3 quaternary carbon with 3 β′ -fluoro-3 α′ - C -hydroxymethyl groups, in the sugar frame work. Conformational preferences of fluorinated nucleosides were studied by the DFT calculations. Anti-proliferative activity of nucleosides 1a-d was tested against MDA-MB-231, L-132, HeLa and neural cell lines and found to be moderate active. [ABSTRACT FROM AUTHOR]

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window. [Display omitted] • Low molecular weight G-quadruplex DNA-ligands with high affinity and selectivity. • Aliphatic amine side chains increase binding through arene-arene interactions. • Strong binding is linked to low electrostatic potential and low desolvation penalty. • Organoid co-culture model of pancreatic cancer reveals promising therapeutic window. [ABSTRACT FROM AUTHOR]

A concise synthesis of four C-3 fluoro/chloro- d -xylono-δ-lactams 3/4 has been reported. The methodology involves Corey–Link approach with suitably protected 3-oxo- d -gluco-furanose to introduce F/Cl as well as ester/amide functionalities at C-3 of glucose. In next steps, 5,6- O -isopropylidene group was converted to the 5-azido xylosugars that on opening of 1,2-acetonide group, and intramolecular Schmidt–Boyer reaction with TFA/H 2 O, in one pot, afforded lactams 3/4 . Conformational aspect of δ-lactams was studied by the 1 H NMR spectroscopy. The halogenated δ-lactams 3/4 showed no inhibition against different glycosidase enzymes. [ABSTRACT FROM AUTHOR]

Syntheses of fluorinated sugar amino acid derived α,γ-cyclic tetra- and hexapeptides are reported. The IR, NMR, ESI-MS, CD, and molecular modeling studies of cyclic tetra- and hexapeptides showed C2 and C3 symmetric flat oval- and triangular-ring shaped β-strand conformations, respectively, which appear to self-assemble into nanotubes. The α,γ-cyclic hexapeptide (EC50 = 2.14 μM) is found to be a more efficient ion transporter than α,γ-cyclic tetrapeptide (EC50 = 14.75 μM). The anion selectivity and recognition of α,γ-cyclic hexapeptide with NO3- ion is investigated. [ABSTRACT FROM AUTHOR]

Acyclic αγα-tripeptides derived from fluorinated-furanoid sugar amino acid frameworks act as reverse-turn inducers with a U-shaped conformation, whereas the corresponding nonfluorinated αγα-tripeptides show random peptide conformations. The NMR studies showed the presence of bifurcated weak intramolecular hydrogen bonding (F···HN) and N+···Fδ- charge-dipole attraction compel the amide carbonyl groups to orient antiperiplanar to the C-F bond, thus, demonstrating the role of the fluorine substituent in stabilizing the U-shaped conformation. The NOESY data indicate that the U-shaped tripeptides self-assembly formation is stabilized by the intermolecular hydrogen bonding between C=O···HN with antiparallel orientation. This fact is supported by ESI-MS data, which showed mass peaks up to the pentameric self-assembly, even in the gas phase. The morphological analysis by FE-SEM, on solid samples, showed arrangement of fibers into nanorods. The antiparallel self-assembled pore of the fluorinated tripeptides illustrates the selective ion-transport activity. The experimental findings were supported by DFT studies. [ABSTRACT FROM AUTHOR]