Short Scalable Route to Bis-morpholine Spiroacetals and Oxazepane Analogues: Useful 3D-Scaffolds for Compound Library Assembly.

sp-Rich molecular scaffolds incorporating nitrogen heterocycles represent important starting points for assembling compound screening libraries and drug discovery. Herein, we report a four-step synthesis of a conformationally well-defined sp-rich scaffold incorporating two morpholine rings embedded within a spiroacetal framework. The synthesis involves the intermediacy of a 2-chloromethyl-substituted morpholine, accessed from epichlorohydrin and readily available β-aminoalcohols.

Tuning the Electronic Properties of Azophosphines as Ligands and Their Application in Base-Free Transfer Hydrogenation Catalysis.

The design and tuning of new ligands is crucial for unlocking new reactivity at transition metal centers. Azophosphines have recently emerged as a new class of 1,3-P,N ligands in ruthenium piano-stool complexes. This work shows that the azophosphine synthesis can tolerate -aryl substituents with strongly electron-donating and electron-withdrawing -R groups and that the nature of this R group can affect the spectroscopic and structural properties of the azophosphines, as measured by NMR spectroscopy, UV-vis spectroscopy, single-crystal X-ray diffraction, and DFT studies.

A Combined Experimental and Computational Exploration of Heteroleptic cis-PdLL' Coordination Cages through Geometric Complementarity.

Heteroleptic (mixed-ligand) coordination cages are of interest as host systems with more structurally and functionally complex cavities than homoleptic architectures. The design of heteroleptic cages, however, is far from trivial. In this work, we experimentally probed the self-assembly of Pd(II) ions with binary ligand combinations in a combinatorial fashion to search for new cis-PdLL' heteroleptic cages.

Controlling the Helical Pitch of Foldamers through Terminal Functionality: A Solid State Study.

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho-azobenzene/2,6-pyridyldicarboxamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.

Dual, Photo-Responsive and Redox-Active Supramolecular Foldamers.

We report on dual, light-responsive and redox-active foldamers that demonstrate reversible and robust stimuli-induced behaviour. Herein, UV/Vis, H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light- and redox-driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non-irradiative and oxidative/reductive conditions. This proof-of-concept work paves the way towards the creation of novel stimuli-responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli.

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers.

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via β-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates.

Azophosphines: Synthesis, Structure and Coordination Chemistry.

The conceptual replacement of nitrogen with phosphorus in common organic functional groups unlocks new properties and reactivity. The phosphorus-containing analogues of triazenes are underexplored but offer great potential as flexible and small bite-angle ligands. This manuscript explores the synthesis and characterisation of a family of air-stable azophosphine-borane complexes, and their subsequent deprotection to the free azophosphines.

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-]oxazol-6-ium salts.

A polysubstituted 3-aminoimidazo[5,1-]oxazol-6-ium framework has been accessed from a new nitrenoid reagent by a two-step ynamide annulation and imidazolium ring-formation sequence. Metalation with Au(I), Cu(I) and Ir(I) at the C2 position provides an L-shaped NHC ligand scaffold that has been validated in gold-catalysed alkyne hydration and arylative cyclisation reactions.

Diastereoselective Self-Assembly of Low-Symmetry Pd L Nanocages through Coordination-Sphere Engineering.

Metal-organic cages (MOCs) are popular host architectures assembled from ligands and metal ions/nodes. Assembling structurally complex, low-symmetry MOCs with anisotropic cavities can be limited by the formation of statistical isomer libraries. We set out to investigate the use of primary coordination-sphere engineering (CSE) to bias isomer selectivity within homo- and heteroleptic Pd L cages.

Reversible conformational switching of a photo-responsive -azobenzene/2,6-pyridyldicarboxamide heterofoldamer.

We report on a convenient synthetic route to rapidly access a new photo-responsive -azobenzene/2,6-pyridyldicarboxamide heterofoldamer. The adoption of a stable helical conformation has been established for this scaffold in both the solid state and in solution using single crystal X-ray diffraction and circular dichroism (CD) spectroscopy respectively. Reversible control over the stimuli-driven structural re-ordering of the supramolecular scaffold, from a stable helical conformation under non-irradiative conditions, to a less well-ordered state under irradiative conditions, has been identified.

Studies towards the Synthesis of (+)-Dictyoxetane.

The dolabellane-type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)-dictyoxetane is reported. Catalytic asymmetric synthesis of the trans-hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos-Parrish ketone.

Enhancing Dual-State Emission in Maleimide Fluorophores through Fluorocarbon Functionalisation.

Herein, a library of trifluoroethyl substituted aminomaleimide derivatives are reported with small size and enhanced emissions in both solution and solid-state. A diCH CF substituted aminochloromaleimide exhibits the most efficient dual-state emission (Φ >50 % in solution and solid-state), with reduced quenching from protic solvents. This is attributed to the reduction of electron density on the maleimide ring and suppressed π-π stacking in the solid-state.

Glutathione peroxidase mimics based on conformationally-restricted, -like, 4,5-disubstituted fluorene dichalcogenides.

Glutathione peroxidase (GPx) regulates cellular peroxide levels through glutathione oxidation. GPx-mimics based on 4,5-disubstituted fluorene diselenides, their oxides, and ditellurides show catalytic activities consistent with conformational restriction about the dichalcogen bond.

Photo- and Electrochemical Dual-Responsive Iridium Probe for Saccharide Detection.

Dual detection systems are of interest for rapid, accurate data collection in sensing systems and in vitro testing. We introduce an Ir complex with a boronic acid receptor site attached to the 2-phenylpyridine ligand as an ideal probe with photo- and electrochemical signals that is sensitive to monosaccharide binding in aqueous solution. The complex displays orange luminescence at 618 nm, which is reduced by 70 and 40 % upon binding of fructose and glucose, respectively.

Rigidochromism by imide functionalisation of an aminomaleimide fluorophore.

Fluorescent dyes that exhibit high solid state quantum yields and sensitivity to the mechanical properties of their local environment are useful for a wide variety of applications, but are limited in chemical diversity. We report a trityl-functionalised maleimide that displays rigidochromic behaviour, becoming highly fluorescent when immobilised in a solid matrix, while displaying negligible fluorescence in solution. Furthermore, the dye's quantum yield is shown to be sensitive to the nature of the surrounding matrix.

Influence of Terminal Functionality on the Crystal Packing Behaviour and Cytotoxicity of Aromatic Oligoamides.

The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) , -butyloxycarbonyl (Boc) and amine is reported. Single crystal X-ray diffraction analysis of - and a dimethylsulfoxide (DMSO) solvate of (-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH) hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in -. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity.

Direct formation of 4,5-disubstituted carbazoles via regioselective dilithiation.

Carbazoles are widely exploited for their interesting photophysical and electronic properties, however bay (4,5-) functionalization is challenging, and previously inaccessible through carbazole C-H activation. We report a simple methodology which introduces a range of versatile 4,5-functionality, enabling the wider investigation of ring annulation and close proximity effects on carbazole properties.

Förster Resonance Energy Transfer Nanoplatform Based on Recognition-Induced Fusion/Fission of DNA Mixed Micelles for Nucleic Acid Sensing.

The dynamic nature of micellar nanostructures is employed to form a self-assembled Förster resonance energy transfer (FRET) nanoplatform for enhanced sensing of DNA. The platform consists of lipid oligonucleotide FRET probes incorporated into micellar scaffolds, where single recognition events result in fusion and fission of DNA mixed micelles, triggering the fluorescence response of multiple rather than a single FRET pair. In comparison to conventional FRET substrates where a single donor interacts with a single acceptor, the micellar multiplex FRET system showed ∼20- and ∼3-fold enhancements in the limit of detection and FRET efficiency, respectively.

Rotaxanating Metallo-supramolecular Nano-cylinder Helicates to Switch DNA Junction Binding.

A class of rotaxane is created, not by encapsulating a conventional linear thread, but rather by wrapping a large cucurbit[10]uril macrocycle about a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death.

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from and protocols for growing, extracting and derivatising it are reported A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on anti-leukaemic activity and calculated "drug-likeness" properties, and pharmacokinetics studies and hERG liability testing. studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative.

Effect of Regiochemistry and Methylation on the Anticancer Activity of a Ferrocene-Containing Organometallic Nucleoside Analogue.

Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1-(S,R ), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1-(S,R ), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic.

Organometallic nucleoside analogues: effect of the metallocene metal atom on cancer cell line toxicity.

A new chiral organometallic nucleoside analogue containing ruthenocene is reported, in which alkylthymine and alkylhydroxyl groups are attached in adjacent positions on one cyclopentadienyl ring. The synthetic procedures for this metallocene derivative and two control compounds are described, along with their characterisation by cyclic voltammetry and X-ray crystallography. Their biological activities in a human pancreatic cancer cell line (MIA-Pa-Ca-2) were significantly lower than those of three previously reported analogous ferrocene compounds, indicating that the choice of metallocene metal atom (Fe or Ru) plays a pivotal role in determining the anticancer properties of these nucleoside analogues, which in turn suggests a different mode of action from that of a conventional nucleoside analogue.