Chiroptical Second-Harmonic Tyndall Scattering from Silicon Nanohelices.

Chirality is omnipresent in the living world. As biomimetic nanotechnology and self-assembly advance, they too need chirality. Accordingly, there is a pressing need to develop general methods to characterize chiral building blocks at the nanoscale in liquids such as water─the medium of life. Here, we demonstrate the chiroptical second-harmonic Tyndall scattering effect. The effect was observed in Si nanohelices, an example of a high-refractive-index dielectric nanomaterial. For three wavelengths of illumination, we observe a clear difference in the second-harmonic scattered light that depends on the chirality of the nanohelices and the handedness of circularly polarized light. Importantly, we provide a theoretical analysis that explains the origin of the effect and its direction dependence, resulting from different specific contributions of "electric dipole-magnetic dipole" and "electric dipole-electric quadrupole" coupling tensors. Using numerical simulations, we narrow down the number of such terms to 8 in forward scattering and to a single one in right-angled scattering. For chiral scatterers such as high-refractive-index dielectric nanoparticles, our findings expand the Tyndall scattering regime to nonlinear optics. Moreover, our theory can be broadened and adapted to further classes where such scattering has already been observed or is yet to be observed.

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.

Borazatruxenes as precursors for hybrid C-BN 2D molecular networks.

Synthesizing atomically thin, crystalline two-dimensional (2D) molecular materials which combine carbon with other elements is an emerging field requiring both custom-designed molecular precursors and their ability to organize into networks (hydrogen-bonded or covalent). Hybrid carbon-boron nitride (C-BN) networks face the additional challenge of needing hydrolytically-stable BN-containing molecular precursors. Here, we show that borazatruxenes (truxene-like molecules with a borazine core) and their halogenated derivatives are highly stable precursors suitable for on-surface assembly. Using scanning tunneling microscopy (STM) and density functional theory (DFT) simulations we demonstrate hierarchical H-bonded assembly based on chiral homodimers of tribromo-borazatruxenes (3Br-borazatruxenes) as building blocks for both 1D chains and 2D networks. A low-symmetry, H-bonded chiral 2D lattice forms on Au(111) from the C3-symmetric 3Br-borazatruxenes, leading to large enantiomorphic domains that are molecularly homochiral. Such homochiral segregation is a necessary condition if chiral C-BN covalent networks are to be obtained via subsequent on-surface reactions. We show via DFT that up to two Na atoms can be trapped within the small pores of this dense lattice, while further Na atoms can adsorb on preferred network sites; this leads to hybrid Na-molecular network electronic bands with anisotropic dispersion and significant (up to hundreds of meV) bandwidths, as well as significant doping, that can engender anisotropic transport through the network. Finally, electronic structure comparisons (combining both experiment and computation) between borazatruxene, its tri-brominated derivative and truxene show that the borazine core controls the band gap increase, while also inducing C-B pz-pz electron delocalization that facilitates a continuous electron path across the molecule. Furthermore, as shown by DFT, the borazine core drives inter-layer B-N polar interactions that promote adsorption of BN containing molecules in a staggered configuration, a mechanism to be exploited in layer-by-layer supra-molecular assembly of novel hybrid C-BN materials.

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.

Single- and double-helices of α,α'-dibenzylaminotripyrrin: solution and solid state studies.

The dimeric association of α,α'-di(benzylamino)tripyrrin in chloroform was found to be 40 times less effective than that of previously reported α,α'-dianilinotripyrrin, which, however, led us to observe the co-crystal structure of single and double helix forms. Attachment of chiral phenylethylamines on the same tripyrrin platform was also performed to induce helical chirality.

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.

Subphthalocyanine-Stoppered [2]Rotaxanes: Synthesis and Size/Energy Threshold of Slippage.

Subphthalocyanine (SubPc)-stoppered [2]rotaxanes were synthesized for the first time. The rotaxane bearing unsubstituted SubPc as a stopper exhibited an equilibrium of slipping-on and slipping-off, whereas a perfluorinated SubPc stopper completely blocked slippage of the ring due to its slightly larger size. Kinetic studies revealed the Gibbs free energy of activation for the slipping-on and slipping-off processes. The optical properties of the rotaxanes, including photoinduced electron transfer, were also revealed.

Discovery of an all-donor aromatic [2]catenane.

We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single component libraries. The building block is a benzo[1,2-b:4,5-b']dithiophene derivative, a π-donor molecule, with cysteine appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the first known DCC-disulphide-based interlocked molecule to be fluorescent.

Borazatruxenes.

We report the synthesis and characterization of a series of arene-borazine hybrids called borazatruxenes. These molecules are BN-isosteres of truxene whereby the central benzene core has been replaced by a borazine ring. The straightforward three step synthesis, stability and their chiroptical and electronic properties recommend them as new scaffolds for BN-carbon hybrid materials. Computational studies at DFT level, closely matching the experimental data, provided insights in the electronic structure of these molecules.

Dynamic Generation of G-Quadruplex DNA Ligands by Target-Guided Combinatorial Chemistry on a Magnetic Nanoplatform.

Dynamic combinatorial chemistry (DCC) has emerged as a promising strategy for template-driven selection of high-affinity ligands for biological targets from equilibrating combinatorial libraries. However, only a few examples using disulfide-exchange-based DCC are reported for nucleic acid targets. Herein, we have demonstrated that gold-coated magnetic nanoparticle-conjugated DNA targets can be used as templates for dynamic selection of ligands from an imine-based combinatorial library. The implementation of DCC using DNA nanotemplates enables efficient identification of the lead compounds, from the dynamic combinatorial library via magnetic decantation. It further allows quick separation of DNA nanotemplates for reuse in DCC reactions. The identified lead compound exhibits significant quadruplex versus duplex DNA selectivity and suppresses promoter activity of c-MYC gene that contains G-quadruplex DNA forming sequence in the upstream promoter region. Further cellular experiments indicated that the lead compound is able to permeate into cell nuclei and trigger a DNA damage response in cancer cells.

Excitation-Energy-Dependent Molecular Beacon Detects Early Stage Neurotoxic Aß Aggregates in the Presence of Cortical Neurons.

There is now crucial medical importance placed on understanding the role of early stage, subvisible protein aggregation, particularly in neurodegenerative disease. While there are strategies for detecting such aggregates in vitro, there is no approach at present that can detect these toxic species associated with cells and specific subcellular compartments. We have exploited excitation-energy-dependent fluorescence edge-shift of recombinant protein labeled with a molecular beacon, to provide a sensitive read out for the presence of subvisible protein aggregates. To demonstrate the potential utility of the approach, we examine the major peptide associated with the initiation of Alzheimer's disease, amyloid ß-protein (Aß) at a patho-physiologically relevant concentration in mouse cortical neurons. Using our approach, we find preliminary evidence that subvisible Aß aggregates are detected at specific subcellular regions and that neurons drive the formation of specific Aß aggregate conformations. These findings therefore demonstrate the potential of a novel fluorescence-based approach for detecting and imaging protein aggregates in a cellular context, which can be used to sensitively probe the association of early stage toxic protein aggregates within subcellular compartments.

High-Yielding Synthesis of Chiral Donor-Acceptor Catenanes.

We report the synthesis of [2]catenanes (Hopf links) in water utilizing disulfides and aromatic donor-acceptor interactions. The electron-rich dialkoxynaphthalene (DN) building blocks interact with electron-deficient naphthalenediimide (NDI) moieties connected by a polyamine chain. We study the effect of the polyamine linkers on the behavior of the library. The polyamine's length and the number of nitrogen atoms in the chain affect the library distribution, leading in some cases to the assembly of catenanes in up to 93% yield.

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.

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.

Aromatic donor-acceptor interactions in non-polar environments.

We have evaluated the strength of aromatic donor-acceptor interactions between dialkyl naphthalenediimide and dialkoxynaphthalene in non-polar environments. (1)H NMR, UV-vis spectroscopy and isothermal titration calorimetry were used to characterise this interaction. We concluded that the strength of donor-acceptor interactions in heptane is sufficient to drive supramolecular assemblies in this and other aliphatic solvents.

A fluorescent Arg-Gly-Asp (RGD) peptide-naphthalenediimide (NDI) conjugate for imaging integrin α(v)ß(3) in vitro.

We have developed a fluorescent peptide conjugate (TrpNDIRGDfK) based on the coupling of cyclo(RGDfK) to a new tryptophan-tagged amino acid naphthalenediimide (TrpNDI). Confocal fluorescence microscopy coupled with fluorescence lifetime imaging (FLIM) mapping, single and two-photon fluorescence excitation, lifetime components and corresponding decay profiles were used as parameters able to investigate qualitatively the cellular behavior regarding the molecular environment and biolocalisation of TrpNDI and TrpNDI-RGDfK in cancer cells.

Molecular motion of donor-acceptor catenanes in water.

In this article, we use (1)H NMR spectroscopy to study the spontaneous molecular motion of donor-acceptor [2]catenanes in water. Our data supports the hypothesis that conformational motion dominantly occurs through a pirouetting mechanism, which involves less exposure of hydrophobic surfaces than in a rotation mechanism. Motion is controlled by the size of the catenane rings and the arrangement of the electron-deficient and electron-rich aromatic units.

Direct core functionalisation of naphthalenediimides by iridium catalysed C-H borylation.

We report the first boron-substituted naphthalenediimides (NDIs), prepared by iridium catalysed C-H activation. When the NDI substrates bear N-benzyl substituents, the naphthyl NDI core is borylated in preference, suggestive of a directed borylation mechanism. Borylated NDIs are substrates for Suzuki-Miyaura couplings and borylation of an NDI bearing two inequivalent N-substituents has also been demonstrated.

Homochiral and meso figure eight knots and a Solomon link.

A homochiral naphthalenediimide-based building block forms in water a disulfide library of macrocycles containing topological isomers. We attempted to identify each of these isomers, and explored the mechanisms leading to their formation. The two most abundant species of the library were assigned as a topologically chiral Solomon link (60% of the library, as measured by high-performance liquid chromatography (HPLC)) and a topologically achiral figure eight knot (18% by HPLC), competing products with formally different geometries but remarkably similar 4-fold symmetries. In contrast, a racemic mixture of building blocks gives the near-quantitative formation of another new and more stable structure, assigned as a meso figure eight knot. Taken together, these results seem to uncover a correlation between the point chirality of the building block used and the topological chirality of the major structure formed. These and the earlier discovery of a trefoil knot also suggest that the number of rigid components in the building block may translate into corresponding knot symmetry and could set the basis of a new strategy for constructing complex topologies.