Liquid Crystal Dimers and the Twist-Bend Phases: Non-Symmetric Dimers Consisting of Mesogenic Units of Differing Lengths.

The syntheses and characterisation of the 4-[{[4-({n-[4-(4-cyanophenyl)phenyl]-n-yl}oxy)phenyl]-methylidene}amino]phenyl-4-alkoxybenzoates (CBnOIBeOm) are reported with n=8 and 10 and m=1-10. The two series display fascinating liquid crystal polymorphism. All twenty reported homologues display an enantiotropic nematic (N) phase at high temperature. When the length of the spacer (n) is greater than that of the terminal chain (m), the twist-bend nematic (NTB) phase is observed at temperatures below the N phase. As the length of the terminal chain is increased and extends beyond the length of the spacer up to three smectic phases are observed on cooling the N phase. One of these smectic phases has been assigned as the rare twist-bend smectic C subphase, the SmCTB-α phase. In all the smectic phases, a monolayer packing arrangement is seen, and this is attributed to the anti-parallel associations of the like mesogenic units.

Ferroelectric Nematic-Isotropic Liquid Critical End Point.

A critical end point above which an isotropic phase continuously evolves into a polar (ferroelectric) nematic phase with an increasing electric field is found in a ferroelectric nematic liquid crystalline material. The critical end point is approximately 30 K above the zero-field transition temperature from the isotropic to nematic phase and at an electric field of the order of 10 V/µm. Such systems are interesting from the application point of view because a strong birefringence can be induced in a broad temperature range in an optically isotropic phase.

Molecular Shape, Electronic Factors, and the Ferroelectric Nematic Phase: Investigating the Impact of Structural Modifications.

The synthesis and characterisation of two series of low molar mass mesogens, the (4-nitrophenyl) 2-alkoxy-4-(4-methoxybenzoyl)oxybenzoates (NT3.m) and the (3-fluoro-4-nitrophenyl) 2-alkoxy-4-(4-methoxybenzoyl)oxybenzoates (NT3F.m), are reported in order to investigate the effect of changing the position of a lateral alkoxy chain from the methoxy-substituted terminal ring to the central phenyl ring in these two series of materials based on RM734. All members of the NT3.m series exhibited a conventional nematic phase, N, which preceded the ferroelectric nematic phase, NF , whereas all the members of the NT3F.m series exhibited direct NF -I transitions except for NT3F.1 which also exhibited an N phase. These materials cannot be described as wedge-shaped, yet their values of the ferroelectric nematic-nematic transition temperature, T N F N ${{_{{\rm N}{_{{\rm F}}}{\rm N}}}}$ , exceed those of the corresponding materials with the lateral alkoxy chain located on the methoxy-substituted terminal ring. In part, this may be attributed to the effect that changing the position of the lateral alkoxy chain has on the electronic properties of these materials, specifically on the electron density associated with the methoxy-substituted terminal aromatic ring. The value of TNI decreased with the addition of a fluorine atom ortho to the nitro group in NT3F.1, however, the opposite behaviour was found when the transition temperatures of the NF phase were compared which are higher for the NT3F.m series. This may reflect a change in the polarity and polarizability of the NT3F.m series compared to the NT3.m series. Therefore, it is suggested that, rather than simply promoting a tapered shape, the role of the lateral chain in inhibiting anti-parallel associations and its effect on the electronic properties of the molecules are the key factors in driving the formation of the NF phase.

Using Lateral Substitution to Control Conformational Preference and Phase Behaviour of Benzanilide-based Liquid Crystal Dimers.

The inclusion of secondary and tertiary benzanilide-based mesogenic groups into liquid crystal dimers is reported as a means to develop new materials. Furthermore, substitution at the nitrogen atom is shown to introduce an additional synthetic 'handle' to modify the molecular structure of the tertiary materials. The design of these materials has proved challenging due to the strong preferences of 3° benzanilides for the E amide conformation. In this work, lateral substitution is used to modify the conformational preferences of the amide linkage and promote liquid crystallinity for a series of N-methyl benzanilide dimers. As the proportion of the E conformer decreases, the nematic-isotropic transition temperatures increase, and enantiotropic nematic behaviour is observed. We also report the synthesis and characterisation of the analogous 2° benzanilide-based materials, which show nematic and twist-bend nematic behaviour. This approach highlights the effects that seemingly small structural modifications, such as the inclusion and position of a methyl group, can have on molecular shape and hence, liquid crystalline behaviour.

Intrinsically Chiral Twist-Bend Nematogens: Interplay of Molecular and Structural Chirality in the NTB Phase.

Non-symmetric lactate-based chiral liquid crystal dimers containing an odd-membered spacer are shown to exhibit a chiral twist-bend nematic phase which is stable on cooling to room temperature. A comparison of racemic and optically pure materials reveals that the pitch length in the N*TB phase is not influenced by molecular chirality, whereas the nematic-twist-bend nematic transition temperature is increased.

Intrinsically Chiral Twist-Bend Nematogens: Interplay of Molecular and Structural Chirality in the NTB Phase.

The front cover artwork is provided by Dr Rebecca Walker of the Liquid Crystals Group at the University of Aberdeen. The image is a cartoon depiction of the formation of the heliconical chiral twist-bend nematic phase (N*TB ) from its constituent bent molecules. The presence of a single enantiomer of the chiral, lactate-based liquid crystal dimers biases the formation of helices with only one handedness, unlike in the conventional NTB phase, observed for achiral molecules, for which the left- and right-handed helices are doubly degenerate. Read the full text of the Research Article at 10.1002/cphc.202200807.

Exploring the Anti-Hypoxaemia Effect of Hydromethylthionine: A Prospective Study of Phase 3 Clinical Trial Participants.

Methylthioninium chloride (MTC) is a standard treatment for methaemoglobinaemia. A preparation of reduced MTC has been reported to increase blood oxygen saturation (SpO2) and lower respiratory rates in patients with severe COVID-19. We have developed a stable form of reduced methylthionine (hydromethylthionine-mesylate, HMTM) having a benign safety profile in two Phase 3 trials in Alzheimer's disease. The aim of this prospective study was to determine the effects of oral HMTM on SpO2 and methaemoglobin (metHb) levels in a cohort of patients with mild hypoxaemia not due to COVID-19. Eighteen participants randomised to a single dose of 4, 75, 100 or 125 mg doses of HMTM had SpO2 levels below 94% at baseline. Patients were routinely monitored by pulse oximetry after 4 h, and after 2 and 6 weeks of twice daily dosing. Significant ~3% increases in SpO2 occurred within 4 h and were sustained over 2 and 6 weeks with no dose differences. There were small dose-dependent increases (0.060-0.162%) in metHb levels over 2 to 6 weeks. Minimum-energy computational chemistry revealed that HMT can bind within 2.10 Å of heme iron by donating a pair of electrons from the central nitrogen of HMT to d orbitals of heme iron, but with lower affinity than oxygen. In conclusion, HMTM can increase SpO2 without reducing metHb by acting as a strong displaceable field ligand for heme iron. We hypothesise that this facilitates a transition from the low oxygen affinity T-state of heme to the higher affinity R-state. HMTM has potential as an adjunctive treatment for hypoxaemia.

New patterns of twist-bend liquid crystal phase behaviour: the synthesis and characterisation of the 1-(4-cyanobiphenyl-4'-yl)-10-(4-alkylaniline-benzylidene-4'-oxy)decanes (CB10O·m).

The synthesis and characterisation of the 1-(4-cyanobiphenyl-4'-yl)-10-(4-alkylanilinebenzylidene-4'-oxy)decanes (CB10O·m) are reported. This series shows a rich liquid crystal polymorphism including twist-bend nematic and smectic phases. All the homologues reported exhibit an enantiotropic conventional nematic phase. For the homologues with m ≤ 10, the local packing in the nematic phases and the layer spacing in the smectic phases indicates an intercalated arrangement of the molecules. An intercalated smectic CA phase is observed if m/11 ≈ 0.5. Either side of this condition, the twist-bend nematic phase is observed, a novel pattern of behaviour for a series on increasing a terminal chain length. For longer chain lengths, m = 12, 14, 16 and 18, two twist-bend smectic C (SmCTB) phases are observed, and the packing of the molecules is now of a bilayer-type. The higher temperature variant is termed SmCTB-SH in which SH (single helix) refers to the presence of a short, distorted clock-type helix. In the lower temperature SmCTB-DH phase, an additional longer helix is superimposed on the short one, and DH denotes double helix.

Distinct differences in the nanoscale behaviors of the twist-bend liquid crystal phase of a flexible linear trimer and homologous dimer.

We synthesized the liquid crystal dimer and trimer members of a series of flexible linear oligomers and characterized their microscopic and nanoscopic properties using resonant soft X-ray scattering and a number of other experimental techniques. On the microscopic scale, the twist-bend phases of the dimer and trimer appear essentially identical. However, while the liquid crystal dimer exhibits a temperature-dependent variation of its twist-bend helical pitch varying from 100 to 170 Å on heating, the trimer exhibits an essentially temperature-independent pitch of 66 Å, significantly shorter than those reported for other twist-bend forming materials in the literature. We attribute this to a specific combination of intrinsic conformational bend of the trimer molecules and a sterically favorable intercalation of the trimers over a commensurate fraction (two-thirds) of the molecular length. We develop a geometric model of the twist-bend phase for these materials with the molecules arranging into helical chain structures, and we fully determine their respective geometric parameters.

Multiple Polar and Non-polar Nematic Phases.

Liquid-crystal materials exhibiting up to three nematic phases are reported. Dielectric response measurements show that while the lower temperature nematic phase has ferroelectric order and the highest temperature nematic phase is apolar, the intermediate phase has local antiferroelectric order. The modification of the molecular structure by increasing the number of lateral fluorine substituents leads to one of the materials showing a direct isotropic-ferronematic phase transition.

Understanding the remarkable difference in liquid crystal behaviour between secondary and tertiary amides: the synthesis and characterisation of new benzanilide-based liquid crystal dimers.

A number of liquid crystal dimers have been synthesised and characterised containing secondary or tertiary (N-methyl) benzanilide-based mesogenic groups. The secondary amides all form nematic phases, and we present the first example of an amide to show the twist-bend nematic (NTB) phase. Only two of the corresponding N-methylated dimers formed a nematic phase and with greatly reduced nematic-isotropic transition temperatures. Characterisation using 2D ROESY NMR experiments, DFT geometry optimisation and X-ray diffraction reveal that there is a change in the preferred conformation of the benzanilide core on methylation, from Z to E. The rotational barrier around the N-C(O) bond has been measured using variable temperature 1H NMR spectroscopy. This dramatic change in shape accounts for the remarkable difference in liquid crystalline behaviour between these secondary and tertiary amide-based materials.

The Chiral Twist-Bend Nematic Phase (N*TB ).

The twist-bend nematic, NTB , phase has been observed for chiral materials in which chirality is introduced through a branched 2-methylbutyl terminal tail. The chiral twist-bend nematic phase, N*TB , is completely miscible with the NTB phase of the standard achiral material, CB6OCB. The N*TB phase exhibits optical textures with lower birefringence than those observed for the achiral NTB phase, suggesting an additional mechanism of averaging molecular orientations. The N*-N*TB transition temperatures for the chiral materials are higher than the NTB -N transition temperatures seen for the corresponding racemic materials. This suggests the double degeneracy of helical twist sense in the N T B * phase is removed by the intrinsic molecular chirality. A square lattice pattern is observed in the N* phase over a temperature range of several degrees above the N*TB -N phase transition, which may be attributed to a non-monotonic dependence of the bend elastic constant.

Molecular curvature, specific intermolecular interactions and the twist-bend nematic phase: the synthesis and characterisation of the 1-(4-cyanobiphenyl-4'-yl)-6-(4-alkylanilinebenzylidene-4'-oxy)hexanes (CB6O.m).

The syntheses and characterisation of the first ten homologues of the 1-(4-cyanobiphenyl-4'-yl)-6-(4-alkylanilinebenzylidene-4'-oxy)hexanes (CB6O.m) are reported. All ten members of the series exhibit an enantiotropic nematic, N, phase, and a monotropic twist-bend nematic, NTB, phase. Only CB6O.10 shows a smectic phase. The assignment of both nematic phases was confirmed using X-ray diffraction. For short chain lengths (m = 1-6) the local packing in both nematic phases is an intercalated arrangement, for intermediate chain lengths a frustrated local structure is seen and for the longest chain length, a bilayer arrangement is observed. This change in the local structure on increasing m has no apparent effect on the stability of either nematic phase, and TNTBN and TNI show a regular dependence on m. Specifically, TNTBN and TNI decrease on increasing m and superimposed upon this is a weak odd-even effect in which the odd members show the higher values. TNI decreases more rapidly than TNTBN on increasing m such that the ratio TNTBN/TNI increases. The lower temperature liquid crystal phase shown by 1-(4-cyanobiphenyl-4'-yloxy)-5-(4-butylanilinebenzylidene-4'-oxy)pentane (CBO5O.4) is reassigned as a twist-bend nematic phase. The transitional properties of the CB6O.m, CB6O.Om and CBO5O.m series are compared.

Spherical-cap droplets of a photo-responsive bent liquid crystal dimer.

Using a photo-responsive dimer exhibiting the transition between nematic (N) and twist-bend nematic (NTB) phases, we prepared spherical cap-shaped droplets on solid substrates exposed to air. The internal director structures of these droplets vary depending on the phase and on the imposed boundary conditions. The structural switching between the N and NTB phases was successfully performed either by temperature control or by UV light-irradiation. The N phase is characterized by an extremely small bend elastic constant K3, and surprisingly, we found that the droplet-air interface induces a planar alignment, in contrast to that seen for typical calamitic liquid crystals. As a consequence, the director configuration was stabilized in a structure substantially different from that normally found in conventional nematic liquid crystalline droplets. In the twist-bend nematic droplets characteristic structures with macroscopic length scales were formed, and they were well controlled by the droplet size. These results indicated that a continuum theory is effective in describing the stabilization mechanism of the macroscopic structure even in the twist-bend nematic liquid crystal droplets exhibiting director modulations on a scale of several molecular lengths.

Electrically tunable laser based on oblique heliconical cholesteric liquid crystal.

A cholesteric liquid crystal (CLC) formed by chiral molecules represents a self-assembled one-dimensionally periodic helical structure with pitch [Formula: see text] in the submicrometer and micrometer range. Because of the spatial periodicity of the dielectric permittivity, a CLC doped with a fluorescent dye and pumped optically is capable of mirrorless lasing. An attractive feature of a CLC laser is that the pitch [Formula: see text] and thus the wavelength of lasing [Formula: see text] can be tuned, for example, by chemical composition. However, the most desired mode to tune the laser, by an electric field, has so far been elusive. Here we present the realization of an electrically tunable laser with [Formula: see text] spanning an extraordinarily broad range (>100 nm) of the visible spectrum. The effect is achieved by using an electric-field-induced oblique helicoidal (OH) state in which the molecules form an acute angle with the helicoidal axis rather than align perpendicularly to it as in a field-free CLC. The principal advantage of the electrically controlled CLCOH laser is that the electric field is applied parallel to the helical axis and thus changes the pitch but preserves the single-harmonic structure. The preserved single-harmonic structure ensures efficiency of lasing in the entire tunable range of emission. The broad tuning range of CLCOH lasers, coupled with their microscopic size and narrow line widths, may enable new applications in areas such as diagnostics, sensing, microscopy, displays, and holography.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

BACKGROUND: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. METHODS: We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). FINDINGS: Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. INTERPRETATION: The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. FUNDING: TauRx Therapeutics.

Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease.

Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 µM. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 µM. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 µM) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 µM) required to reverse behavioral deficits and pathology in Tau transgenic mice.

Reversible Isothermal Twist-Bend Nematic-Nematic Phase Transition Driven by the Photoisomerization of an Azobenzene-Based Nonsymmetric Liquid Crystal Dimer.

The liquid crystal nonsymmetric dimer, 1-(4-butoxyazobenzene-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl) hexane (CB6OABOBu), shows enantiotropic twist-bend nematic, NTB, and nematic, N, phases. The NTB phase has been confirmed using polarized light microscopy, freeze fracture transmission electron microscopy, and X-ray diffraction. The helicoidal pitch in the NTB phase is 18 nm. The NTB-N (TNTBN) and N-I (TNI) transition temperatures are reduced upon UV light irradiation, with the reduction in TNTBN being much larger than that in TNI. An isothermal, reversible NTB-N transition may be driven photochemically. These observations are attributed to a trans-cis photoisomerization of the azobenzene fragment on UV irradiation, with the cis isomers stabilizing the standard nematic phase and the trans isomers stabilizing the NTB phase. The dramatic changes in TNTBN provide evidence that the transition between the normal nematic and twist-bend nematic with spontaneous breaking of chiral symmetry is crucially dependent on the shape of molecular dimers, which changes greatly during the trans-cis isomerization.

Understanding the twist-bend nematic phase: the characterisation of 1-(4-cyanobiphenyl-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl)hexane (CB6OCB) and comparison with CB7CB.

The synthesis and characterisation of the nonsymmetric liquid crystal dimer, 1-(4-cyanobiphenyl-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl)hexane (CB6OCB) is reported. An enantiotropic nematic (N)-twist-bend nematic (NTB) phase transition is observed at 109 °C and a nematic-isotropic phase transition at 153 °C. The NTB phase assignment has been confirmed using polarised light microscopy, freeze fracture transmission electron microscopy (FFTEM), (2)H-NMR spectroscopy, and X-ray diffraction. The effective molecular length in both the NTB and N phases indicates a locally intercalated arrangement of the molecules, and the helicoidal pitch length in the NTB phase is estimated to be 8.9 nm. The surface anchoring properties of CB6OCB on a number of aligning layers is reported. A Landau model is applied to describe high-resolution heat capacity measurements in the vicinity of the NTB-N phase transition. Both the theory and heat capacity measurements agree with a very weak first-order phase transition. A complementary extended molecular field theory was found to be in suggestive accord with the (2)H-NMR studies of CB6OCB-d2, and those already known for CB7CB-d4. These include the reduced transition temperature, TNTBN/TNI, the order parameter of the mesogenic arms in the N phase close to the NTB-N transition, and the order parameter with respect to the helix axis which is related to the conical angle for the NTB phase.

Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease.

Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT(+)) forms; as a chloride salt [methylthioninium chloride (MTC), "methylene blue"], it is stabilized in its MT(+) form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT(+) form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.