Dynamic molecular crystals combining multiple and finely tunable functionalities are attracting and an increasing attention due to their potential applications in a broad range of fields as efficient energy transducers and stimuli-responsive materials. In this context, a multicomponent organic salt, piperazinium trifluoroacetate (PZTFA), endowed with an unusual multidimensional responsive landscape is reported. Crystals of the salt undergo smooth plastic deformation under mechanical stress and thermo-induced jumping. Furthermore, via controlled crystal bending and release of trifluoroacetic acid from the lattice, which is anticipated from the design of the material, both the mechanical response and the thermoresponsive behavior are efficiently tuned while partially preserving the crystallinity of the system. In particular, mechanical deformation hampers guest release and hence the macroscopic jumping effect, while trifluoroacetic acid release stiffens the crystals. These complex adaptive responses establish a new crystal engineering strategy to gain further control over dynamic organic crystals.
Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Previously, we demonstrated that a ketogenic diet (KD) combined with metronomic cyclophosphamide (CP) delayed tumor growth in MYCN-amplified NB xenografts. The anti-diabetic drug metformin (MET) also targets complex I of the OXPHOS system. Therefore, MET-induced disruptions of mitochondrial respiration may enhance the anti-tumor effect of CP when combined with a KD. In this study, we found that MET decreased cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines, while the combination of KD, MET, and low-dose CP (triple therapy) also reduced tumor growth and improved survival in vivo in MYCN-amplified NB xenografts. Gene ontology enrichment analysis revealed that this triple therapy had the greatest effect on the transcription of genes involved in fatty acid ß-oxidation, which was supported by the increased protein expression of CPT1A, a key mitochondrial fatty acid transporter. We suspect that alterations to ß-oxidation alongside the inhibition of complex I may hamper mitochondrial energy production, thus explaining these augmented anti-tumor effects, suggesting that the combination of MET and KD is an effective adjuvant therapy to CP in MYCN-amplified NB xenografts.
Chiral molecules are known to behave as spin filters due to the chiral induced spin selectivity (CISS) effect. Chirality can be implemented in molecular semiconductors in order to study the role of the CISS effect in charge transport and to find new materials for spintronic applications. In this study, the design and synthesis of a new class of enantiopure chiral organic semiconductors based on the well-known dinaphtho[2,3-b:2,3-f]thieno[3,2-b]thiophene (DNTT) core functionalized with chiral alkyl side chains is presented. When introduced in an organic field-effect transistor (OFET) with magnetic contacts, the two enantiomers, (R)-DNTT and (S)-DNTT, show an opposite behavior with respect to the relative direction of the magnetization of the contacts, oriented by an external magnetic field. Each enantiomer displays an unexpectedly high magnetoresistance over one preferred orientation of the spin current injected from the magnetic contacts. The result is the first reported OFET in which the current can be switched on and off upon inversion of the direction of the applied external magnetic field. This work contributes to the general understanding of the CISS effect and opens new avenues for the introduction of organic materials in spintronic devices.
BACKGROUND: Neuroblastoma is a paediatric malignancy of incredibly complex aetiology. Oncogenic protein kinase signalling in neuroblastoma has conventionally focussed on transduction through the well-characterised PI3K/Akt and MAPK pathways, in which the latter has been implicated in treatment resistance. The discovery of the receptor tyrosine kinase ALK as a target of genetic alterations in cases of familial and sporadic neuroblastoma, was a breakthrough in the understanding of the complex genetic heterogeneity of neuroblastoma. However, despite progress in the development of small-molecule inhibitors of ALK, treatment resistance frequently arises and appears to be a feature of the disease. Moreover, since the identification of ALK, several additional protein kinases, including the PIM and Aurora kinases, have emerged not only as drivers of the disease phenotype, but also as promising druggable targets. This is particularly the case for Aurora-A, given its intimate engagement with MYCN, a driver oncogene of aggressive neuroblastoma previously considered 'undruggable.' SCOPE OF REVIEW: Aided by significant advances in structural biology and a broader understanding of the mechanisms of protein kinase function and regulation, we comprehensively outline the role of protein kinase signalling, emphasising ALK, PIM and Aurora in neuroblastoma, their respective metabolic outputs, and broader implications for targeted therapies. MAJOR CONCLUSIONS: Despite massively divergent regulatory mechanisms, ALK, PIM and Aurora kinases all obtain significant roles in cellular glycolytic and mitochondrial metabolism and neuroblastoma progression, and in several instances are implicated in treatment resistance. While metabolism of neuroblastoma tends to display hallmarks of the glycolytic "Warburg effect," aggressive, in particular MYCN-amplified tumours, retain functional mitochondrial metabolism, allowing for survival and proliferation under nutrient stress. Future strategies employing specific kinase inhibitors as part of the treatment regimen should consider combinatorial attempts at interfering with tumour metabolism, either through metabolic pathway inhibitors, or by dietary means, with a view to abolish metabolic flexibility that endows cancerous cells with a survival advantage.
Neuroblastoma , Protein Kinases , Signal Transduction , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Neuroblastoma/metabolism , Neuroblastoma/pathology , Protein Kinases/metabolism , Humans , Drug Resistance, Neoplasm , Genetic Heterogeneity
We combine temperature-dependent low-frequency Raman measurements and first-principles calculations to obtain a mechanistic understanding of the order-disorder phase transition of 2,7-di-tert-butylbenzo[b]benzo[4,5]thieno[2,3-d]thiophene (ditBu-BTBT) and 6,13-bis(triisopropylsilylethynyl) pentacene (TIPS-pentacene) semiconducting amphidynamic crystals. We identify the lattice normal modes associated with the phase transition by following the position and width of the Raman peaks with temperature and identifying peaks that exhibit nonlinear dependence toward the phase transition temperature. Our findings are interpreted according to the "hardcore mode" model previously used to describe order-disorder phase transitions in inorganic and hybrid crystals with a Brownian sublattice. Within the framework of this model, ditBu-BTBT exhibits an ideal behavior where only one lattice mode is associated with the phase transition. TIPS-pentacene deviates strongly from the model due to strong interactions between lattice modes. We discuss the origin of the different behaviors and suggest side-chain engineering as a tool to control polymorphism in amphidynamic crystals.
Molecular packing controls optoelectronic properties in organic molecular nanomaterials. Here we report a donor-acceptor organic molecule (2,6-bis(4-cyanophenyl)-4-(9-phenyl-9H-carbazol-3-yl)pyridine-3,5-dicarbonitrile) that exhibits two aggregate states in aqueous dispersions: amorphous nanospheres and ordered nanofibres with π-π molecular stacking. The nanofibres promote sacrificial photocatalytic H2 production (31.85 mmol g-1 h-1) while the nanospheres produce hydrogen peroxide (H2O2) (3.20 mmol g-1 h-1 in the presence of O2). This is the first example of an organic photocatalyst that can be directed to produce these two different solar fuels simply by changing the molecular packing. These different packings affect energy band levels, the extent of excited state delocalization, the excited state dynamics, charge transfer to O2 and the light absorption profile. We use a combination of structural and photophysical measurements to understand how this influences photocatalytic selectivity. This illustrates the potential to achieve multiple photocatalytic functionalities with a single organic molecule by engineering nanomorphology and solid-state packing.
A porous molecular crystal (TSCl) was found to crystallise from dichloromethane and water during the synthesis of tetrakis(4-sulfophenylmethane). Crystal structure prediction (CSP) rationalises the driving force behind the formation of this porous TSCl phase and the intermolecular interactions that direct its formation. Gas sorption analysis showed that TSCl is permanently porous with selective adsorption of CO2 over N2, H2 and CH4 and a maximum CO2 uptake of 74 cm3 g-1 at 195 K. Calculations revealed that TSCl assembles via a combination of weak hydrogen bonds and strong dispersion interactions. This illustrates that CSP can underpin approaches to crystal engineering that do not involve more intuitive directional interactions, such as hydrogen bonding.
BACKGROUND: Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system. METHODS: Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo. RESULTS: We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors. CONCLUSIONS: Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.
Dynamic organic crystals are rapidly gaining traction as a new class of smart materials for energy conversion, however, they are only capable of very small strokes (<12%) and most of them operate through energetically cost-prohibitive processes at high temperatures. We report on the exceptional performance of an organic actuating material with exceedingly large stroke that can reversibly convert energy into work around room temperature. When transitioning at 295-305 K on heating and at 265-275 K on cooling the ferroelectric crystals of guanidinium nitrate exert a linear stroke of 51%, the highest value observed with a reversible operation of an organic single crystal actuator. Their maximum force density is higher than electric cylinders, ceramic piezoactuators, and electrostatic actuators, and their work capacity is close to that of thermal actuators. This work demonstrates the hitherto untapped potential of ionic organic crystals for applications such as light-weight capacitors, dielectrics, ferroelectric tunnel junctions, and thermistors.
The outstanding performance and facile processability turn hybrid organic-inorganic perovskites into one of the most sought-after classes of semiconducting materials for optoelectronics. Yet, their translation into real-world applications necessitates that challenges with their chemical stability and poor mechanical robustness are first addressed. Here, centimeter-size single crystals of methylammoniumlead(II) iodide (MAPbI3 ) are reported to be capable of autonomous self-healing under minimal compression at ambient temperature. When crystals are halved and the fragments are brought in contact, they can readily self-repair as a result of a liquid-like behavior of their lattice at the contact surface, which leads to a remarkable healing with an efficiency of up to 82%. The successful reconstitution of the broken single crystals is reflected in recuperation of their optoelectronic properties. Testing of the healed crystals as photodetectors shows an impressive 74% recovery of the generated photocurrent relative to pristine crystals. This self-healing capability of MAPbI3 single crystals is an efficient strategy to overcome the poor mechanical properties and low wear resistance of these materials, and paves the way for durable and stable optoelectronic devices based on single crystals of hybrid perovskites.
We report the first organic semiconductor crystal with a unique combination of properties that can be used as a multifunctional optoelectronic device. Mechanically flexible single crystals of 9,10-bis(phenylethynyl)anthracene (BPEA) can function as a phototransistor, photoswitch, and an optical waveguide. The material can exist as two structurally different solid phases, with single crystals of one of the phases being elastic at room temperature while those of the other are brittle and become plastic at higher temperature. The output and transfer characteristics of the devices were characterized by measuring the generation and temporal response of the switching of the photogenerated current. The current-voltage characteristics of both phases exhibit linearity and symmetry about the positive and negative voltages. The crystals transmit light in the telecommunications range with significantly low optical loss for an organic crystalline material.
Organic crystals are emerging as mechanically compliant, light-weight and chemically versatile alternatives to the commonly used silica and polymer waveguides. However, the previously reported organic crystals were shown to be able to transmit visible light, whereas actual implementation in telecommunication devices requires transparency in the near-infrared spectral range. Here we demonstrate that single crystals of the amino acid L-threonine could be used as optical waveguides and filters with high mechanical and thermal robustness for transduction of signals in the telecommunications range. On their (00[Formula: see text]) face, crystals of this material have an extraordinarily high Young's modulus (40.95 ± 1.03 GPa) and hardness (1.98 ± 0.11 GPa) for an organic crystal. First-principles density functional theory calculations, used in conjunction with analysis of the energy frameworks to correlate the structure with the anisotropy in the Young's modulus, showed that the high stiffness arises as a consequence of the strong charge-assisted hydrogen bonds between the zwitterions. The crystals have low optical loss in the O, E, S and C bands of the spectrum (1250-1600 nm), while they effectively block infrared light below 1200 nm. This property favors these and possibly other related organic crystals as all-organic fiber-optic waveguides and filters for transduction of information.
Amino Acids/chemistry , Communication , Fiber Optic Technology/methods , Transducers , Anisotropy , Crystallization , Crystallography, X-Ray , Elastic Modulus , Hardness , Hydrogen Bonding , Threonine/chemistry
Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.
Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer.
Anticarcinogenic Agents/pharmacology , Melanoma/drug therapy , Mitochondria/drug effects , Oxidative Phosphorylation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Fibroblasts/drug effects , Glycolysis/drug effects , Humans , Melanoma/metabolism , Melanoma/pathology , Mitochondria/genetics , Mitochondria/physiology , Oxidative Stress/drug effects , Pyrvinium Compounds/pharmacology
The anticipated shift in the focal point of interest of solid-state chemists, crystal engineers, and crystallographers from structure to properties to function parallels the need to apply our accumulated understanding of the intricacies of crystal structure to explaining the related properties, with the ultimate goal of harnessing that knowledge in applications that require soft, lightweight, or biocompatible organic solids. In these developments, the adaptive molecular crystals warrant particular attention as an alternative choice of materials for light, flexible, and environmentally benign devices, primarily memories, capacitors, sensors, and actuators. Some of the outstanding requirements for the application of these dynamic materials as high-efficiency energy-storage devices are strongly induced polarization, a high switching field, and narrow hysteresis in the case of reversible dynamic processes. However, having been studied almost exclusively by chemists, molecular crystals still lack the appropriate investigations that reliably evaluate their reproducibility, scalability, and actuating performance, and some important drawbacks have diverted the interest of engineers from these materials in applications. United under the umbrella term crystal adaptronics, the recent research efforts aim to realistically assess the appositeness of dynamic crystals for applications that require fast, reversible, and continuous operation over prolonged periods of time. With the aim of highlighting the most recent developments, this Perspective discusses their assets and pitfalls. It also provides some hints on the likely future developments that capitalize on the untapped, sequestered potential of this distinct materials class for applications.
Flexible organic single crystals are evolving as new materials for optical waveguides that can be used for transfer of information in organic optoelectronic microcircuits. Integration in microelectronics of such crystalline waveguides requires downsizing and precise spatial control over their shape and size at the microscale, however that currently is not possible due to difficulties with manipulation of these small, brittle objects that are prone to cracking and disintegration. Here we demonstrate that atomic force microscopy (AFM) can be used to reshape, resize and relocate single-crystal microwaveguides in order to attain spatial control over their light output. Using an AFM cantilever tip, mechanically compliant acicular microcrystals of three N-benzylideneanilines were bent to an arbitrary angle, sliced out from a bundle into individual crystals, cut into shorter crystals of arbitrary length, and moved across and above a solid surface. When excited by using laser light, such bent microcrystals act as active optical microwaveguides that transduce their fluorescence, with the total intensity of transduced light being dependent on the optical path length. This micromanipulation of the crystal waveguides using AFM is non-invasive, and after bending their emissive spectral output remains unaltered. The approach reported here effectively overcomes the difficulties that are commonly encountered with reshaping and positioning of small delicate objects (the "thick fingers" problem), and can be applied to mechanically reconfigure organic optical waveguides in order to attain spatial control over their output in two and three dimensions in optical microcircuits.
BACKGROUND: Cancer is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of standard anticancer therapies. The ketogenic diet, a high-fat, low-carbohydrate diet with adequate amounts of protein, appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells, making the diet a promising candidate as an adjuvant cancer therapy. SCOPE OF REVIEW: To critically evaluate available preclinical and clinical evidence regarding the ketogenic diet in the context of cancer therapy. Furthermore, we highlight important mechanisms that could explain the potential antitumor effects of the ketogenic diet. MAJOR CONCLUSIONS: The ketogenic diet probably creates an unfavorable metabolic environment for cancer cells and thus can be regarded as a promising adjuvant as a patient-specific multifactorial therapy. The majority of preclinical and several clinical studies argue for the use of the ketogenic diet in combination with standard therapies based on its potential to enhance the antitumor effects of classic chemo- and radiotherapy, its overall good safety and tolerability and increase in quality of life. However, to further elucidate the mechanisms of the ketogenic diet as a therapy and evaluate its application in clinical practice, more molecular studies as well as uniformly controlled clinical trials are needed.
Diet, Carbohydrate-Restricted/methods , Diet, High-Fat/methods , Diet, Ketogenic/methods , Neoplasms/diet therapy , Diet, High-Fat/adverse effects , Diet, Ketogenic/adverse effects , Humans , Neoplasms/metabolism , Neoplasms/pathology , Quality of Life , Tumor Microenvironment/drug effects
Although we have entered the era of personalized medicine and tailored therapies, drugs that target a large variety of cancers regardless of individual patient differences would be a major advance nonetheless. This review article summarizes current concepts and therapeutic opportunities in the area of targeting aerobic mitochondrial energy metabolism in cancer. Old drugs previously used for diseases other than cancer, such as antibiotics and antidiabetics, have the potential to inhibit the growth of various tumor entities. Many drugs are reported to influence mitochondrial metabolism. However, here we consider only those drugs which predominantly inhibit oxidative phosphorylation.
Antineoplastic Agents/pharmacology , Energy Metabolism/drug effects , Mitochondria/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Drug Repositioning , Humans , Mitochondria/metabolism
The versatility in mechanical properties and the capability of optical waveguiding of molecular crystals have attracted research on the potential application of these materials in optomechanical transduction. Here, we demonstrate spatial photocontrol over the optical output from slender single crystals of an azo compound, 3',4'-dimethyl-4-(dimethylamino)azobenzene that can be used as a crystalline optical waveguide. The position of the free end of a single crystal can be controlled through reversible photoswitching between the trans and cis isomers at the irradiated crystal surface. The passive optical waveguiding capability of the crystal remains unaffected by its deformation induced by exposure to UV light. Moreover, the response time of the material by bending upon irradiation can be thermally regulated to control the positioning of the tip of the crystal. These single-crystal organic actuators with dual (optical and photomechanical) response deliver on the long sought for dynamic all-organic optical elements to be incorporated in microcircuits.
Halogen bonding has recently gained well deserved attention in present-day research for its importance in many fields of supramolecular science and crystal engineering. Although generally overlooked in comprehensive studies in the past, halogen bonding has become an important tool also in the field of materials science. An increased number of scientific reports are published every year where halogen bonding is exploited in soft materials rather than in crystal engineering. Here, we focus on a description of the most exciting contemporary developments in the field of halogen-bonded functional soft materials, assembled using the guiding principles of crystal engineering. We give a particular emphasis to those published in the past few years.
