The Influence of Chirality on the ß-Amino-Acid Naphthalenediimides/G-Quadruplex DNA Interaction.

G-quadruplexes (G4s) have been identified as a potential alternative chemotherapy target. A series of eight ß-amino acid derived naphthalenediimides (NDI) were screened against a series of oncogenic G4 sequences: c-KIT1, h-TELO, and TBA. Three sets of enantiomers were investigated to further our understanding of the effect of point chirality on G4 stabilisation. Enantioselective binding behaviour was observed with both c-KIT1 and h-TELO. Docking studies using GNINA and UV-vis titrations were employed to better understand this selective binding behaviour.

Mueller Matrix Polarimetry on Cyanine Dye J-Aggregates.

Cyanine dyes are known to form H- and J-aggregates in aqueous solutions. Here we show that the cyanine dye, S0271, assembles in water into vortex induced chiral J-aggregates. The chirality of the J-aggregates depends on the directionality of the vortex. This study utilised both conventional benchtop CD spectropolarimeters and Mueller matrix polarimetry. It was found that J-aggregates have real chirality alongside linear dichroism and linear and circular birefringence. We identify the factors that are key to the formation of metastable chiral J-aggregates and propose a mechanism for their assembly.

Triggering G-Quadruplex Conformation Switching with [7]Helicenes.

The dynamic interplay between two types of chiral structures; fully conjugated racemic hetero[7]helicenes and DNA strands prone to fold into G-quadruplex structures is described. Both the [7]helicenes and the G-quadruplex DNA structures exist in more than one conformation in solution. We show that the structures interact with and stabilise each other, mutually amplifying and stabilising certain conformations at increased temperatures. The [7]helicene ligands L1 and L2 stabilise the parallel conformation of k-ras significantly, whereas hybrid (K+ ) and antiparallel (Na+ ) h-telo G-quadruplexes are stabilised upon conformational switching into altered G-quadruplex conformations. Both L1 and L2 induce parallel G-quadruplexes from hybrid structures (K+ ) and L1 induces hybrid G-quadruplexes from antiparallel conformations (Na+ ). Enantioselective binding of one helicene enantiomer is observed for helicene ligand L2, and VTCD melting experiments are used to estimate the racemisation barrier of the helicene.

Mapping the Chiroptical Properties of Local Domains in Thin Films of Chiral Silicon Phthalocyanines by CD Imaging.

The first example of uniformly chiral thin films of silicon phthalocyanines (SiPcs) are reported. The local domains of the films are mapped using circular dichroism (CD) imaging (CDi) technique available at the Diamond B23 beamline. The CDi allowed us to increase the spatial resolution up to 525× when compared with benchtop spectrometers. The results indicate formation on-surface of chiral and stable supramolecular assemblies with homogenous distribution. Chemical functionalization and solvent choice for deposition allow controllable chiroptical properties to be obtained. The method and technique reported in this work could be applied to prepare and characterize a wide variety of chiral thin films.

Importance of Chiral Recognition in Designing Metal-Free Ligands for G-Quadruplex DNA.

Four pairs of amino acid-functionalized naphthalenediimide enantiomers (d- and l-lysine derived NDIs) were screened toward G-quadruplex forming sequences in telomeres (h-TELO) and oncogene promoters: c-KIT1, c-KIT2, k-RAS and BCL-2. This is the first study to address the effect of point chirality toward G-quadruplex DNA stabilization using purely small organic molecules. Enantioselective behavior toward the majority of ligands was observed, particularly in the case of parallel conformations of c-KIT2 and k-RAS. Additionally, Nε-Boc-l-Lys-NDI and Nε-Boc-d-Lys-NDI discriminate between quadruplexes with parallel and hybrid topologies, which has not previously been observed with enantiomeric ligands.

Amino-Acid-Derived Naphthalenediimides as Versatile G-Quadruplex Binders.

The design and synthesis of water soluble, amino-acid-functionalised naphthalenediimides (NDIs) as potential ligands of native G-quadruplexes is reported. The NDIs were tested on a panel of oncogene promoters, on the human telomeric sequence h-telo, and on double-stranded DNA. Out of the ligands tested, NDI 3 (Nϵ -Boc-l-lysine NDI) exhibited a highly discriminating nature by only stabilising the oncogene promoter c-kit2, which is up-regulated up to 80 % in ovarian, gastrointestinal, and breast malignancies.

Chemical Mapping Exposes the Importance of Active Site Interactions in Governing the Temperature Dependence of Enzyme Turnover.

Uncovering the role of global protein dynamics in enzyme turnover is needed to fully understand enzyme catalysis. Recently, we have demonstrated that the heat capacity of catalysis, ΔC P ‡, can reveal links between the protein free energy landscape, global protein dynamics, and enzyme turnover, suggesting that subtle changes in molecular interactions at the active site can affect long-range protein dynamics and link to enzyme temperature activity. Here, we use a model promiscuous enzyme (glucose dehydrogenase from Sulfolobus solfataricus) to chemically map how individual substrate interactions affect the temperature dependence of enzyme activity and the network of motions throughout the protein. Utilizing a combination of kinetics, red edge excitation shift (REES) spectroscopy, and computational simulation, we explore the complex relationship between enzyme-substrate interactions and the global dynamics of the protein. We find that changes in ΔC P ‡ and protein dynamics can be mapped to specific substrate-enzyme interactions. Our study reveals how subtle changes in substrate binding affect global changes in motion and flexibility extending throughout the protein.

Chiral Phthalocyanines through Axial Coordination.

A novel approach to axially induce chirality on silicon phthalocyanines via a microwave-assisted route is reported. CD analysis provides spectroscopic evidence that chirality is transferred onto both Soret and Q-bands of the phthalocyanine core. A chiral naphthalenediimide ligand was found to induce the largest Cotton effect on the macrocycle absorptions.