Simple and Efficient Enantioselective α-Deuteration Method of α-Amino Acids without External Chiral Sources.

Deuterium-labeled α-amino acids are useful in research related to drug discovery and biomedical science. However, a high degree of site selectivity and stereoselectivity in the deuterium incorporation process is still difficult to achieve. Herein, we report a new enantioselective deuteration method at the α-position of several amino acids without external chiral sources. The proposed deuteration methods (NaOEt and EtOD) are highly selective and simple. Additionally, we provide a mechanistic study for this enantioretentive deuteration.

A phytosphingosine derivative mYG-II-6 inhibits histamine-mediated TRPV1 activation and MRGPRX2-dependent mast cell degranulation.

BACKGROUND: Phytosphingosine and its derivative are known for their skin-protective properties. While mYG-II-6, a phytosphingosine derivative, has shown anti-inflammatory and antipsoriatic effects, its potential antipruritic qualities have yet to be explored. This study aimed to investigate mYG-II-6's antipruritic properties. METHODS: The calcium imaging technique was employed to investigate the activity of ion channels and receptors. Mast cell degranulation was confirmed through the ß-hexosaminidase assay. Additionally, in silico molecular docking and an in vivo mouse scratching behavior test were utilized. RESULTS: Using HEK293T cells transfected with H1R and TRPV1, we examined the impact of mYG-II-6 on histamine-induced intracellular calcium rise, a key signal in itch-mediating sensory neurons. Pretreatment with mYG-II-6 significantly reduced histamine-induced calcium levels and inhibited TRPV1 activity, suggesting its role in blocking the calcium influx channel. Additionally, mYG-II-6 suppressed histamine-induced calcium increase in primary cultures of mouse dorsal root ganglia, indicating its potential antipruritic effect mediated by histamine. Interestingly, mYG-II-6 exhibited inhibitory effects on human MRGPRX2, a G protein-coupled receptor involved in IgE-independent mast cell degranulation. However, it did not inhibit mouse MrgprB2, the ortholog of human MRGPRX2. Molecular docking analysis revealed that mYG-II-6 selectively interacts with the binding pocket of MRGPRX2. Importantly, mYG-II-6 suppressed histamine-induced scratching behaviors in mice. CONCLUSIONS: Our findings show that mYG-II-6 can alleviate histamine-induced itch sensation through dual mechanisms. This underscores its potential as a versatile treatment for various pruritic conditions.

Integrated Machine Learning Approach for the Early Prediction of Pressure Ulcers in Spinal Cord Injury Patients.

(1) Background: Pressure ulcers (PUs) substantially impact the quality of life of spinal cord injury (SCI) patients and require prompt intervention. This study used machine learning (ML) techniques to develop advanced predictive models for the occurrence of PUs in patients with SCI. (2) Methods: By analyzing the medical records of 539 patients with SCI, we observed a 35% incidence of PUs during hospitalization. Our analysis included 139 variables, including baseline characteristics, neurological status (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI]), functional ability (Korean version of the Modified Barthel Index [K-MBI] and Functional Independence Measure [FIM]), and laboratory data. We used a variety of ML methods-a graph neural network (GNN), a deep neural network (DNN), a linear support vector machine (SVM_linear), a support vector machine with radial basis function kernel (SVM_RBF), K-nearest neighbors (KNN), a random forest (RF), and logistic regression (LR)-focusing on an integrative analysis of laboratory, neurological, and functional data. (3) Results: The SVM_linear algorithm using these composite data showed superior predictive ability (area under the receiver operating characteristic curve (AUC) = 0.904, accuracy = 0.944), as demonstrated by a 5-fold cross-validation. The critical discriminators of PU development were identified based on limb functional status and laboratory markers of inflammation. External validation highlighted the challenges of model generalization and provided a direction for future research. (4) Conclusions: Our study highlights the importance of a comprehensive, multidimensional data approach for the effective prediction of PUs in patients with SCI, especially in the acute and subacute phases. The proposed ML models show potential for the early detection and prevention of PUs, thus contributing substantially to improving patient care in clinical settings.

Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing SF5-Cyclobutanes.

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5-CBs) are now synthetically accessible through strain-release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone-based BCBs are detailed herein, as well as proof-of-concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three-component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5-CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti-stereoselective variant of SF5Cl addition across sulfone-based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5-CB "hybrid isosteres" were then contextualized using SC-XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl-containing BCBs, we also observed rare instances whereby radical addition to the 1-position of a BCB occurs. The nature of the key C(sp3)-SF5 bond formation step - among other mechanistic features of the methods we disclose - was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5-CBs with various downstream functionalizations.

Targeting HMG-CoA synthase 2 suppresses tamoxifen-resistant breast cancer growth by augmenting mitochondrial oxidative stress-mediated cell death.

AIMS: In this study, we aimed to investigate previously unrecognized lipid metabolic perturbations in tamoxifen-resistant breast cancer (BC) by conducting comprehensive metabolomics and transcriptomics analysis. We identified the role of 3-hydroxy-3-methylglutary-coenzyme-A-synthase 2 (HMGCS2), a key enzyme responsible for ketogenesis, in tamoxifen-resistant BC growth. MAIN METHODS: Comprehensive metabolomics (CE-TOFMS, LC-TOFMS) and transcriptiomics analysis were performed to characterize metabolic pathways in tamoxifen-resistant BC cells. The upregulation of HMGCS2 were verified thorugh immunohistochemistry (IHC) in clinical samples obtained from patients with recurrent BC. HMGCS2 inhibitor was discovered through surface plasmon resonance analysis, enzyme assay, and additional molecular docking studies. The effect of HMGCS2 suppression on tumor growth was studied thorugh BC xenograft model, and intratumoral lipid metabolites were analyzed via MALDI-TOFMS imaging. KEY FINDINGS: We revealed that the level of HMGCS2 was highly elevated in both tamoxifen-resistant T47D sublines (T47D/TR) and clinical refractory tumor specimens from patients with ER+ breast cancer, who had been treated with adjuvant tamoxifen. Suppression of HMGCS2 in T47D/TR resulted in the accumulation of mitochondrial reactive oxygen species (mtROS) and apoptotic cell death. Further, we identified alphitolic acid, a triterpenoid natural product, as a novel HMGCS2-specific inhibitor that elevated mtROS levels and drastically retarded the growth of T47D/TR in in vitro and in vivo experiments. SIGNIFICANCE: Enhanced ketogenesis with upregulation of HMGCS2 is a potential metabolic vulnerability of tamoxifen-resistant BC that offers a new therapeutic opportunity for treating patients with ER+ BC that are refractory to tamoxifen treatment.

Facile One-Pot Synthesis of Polysubstituted Pyridinium Salts by Annulation of Enamines with Alkynes.

An efficient and facile synthesis of highly substituted pyridinium salts through the annulation of enamines with alkynes is reported herein. A Ag2 CO3 /HNTf2 synergistically acting catalyst system was developed and used in a condensation reaction between carbonyl substrates and propargylamine to afford structurally diverse pyridinium salts. A mechanistic investigation shows that this one-pot transformation proceeded via selective 6-endo-dig cyclization of the in situ generated propargylenamine and protonolysis of the resulting vinyl-silver intermediate. The reaction conditions are mild, and the substrate scope is broad. During the cyclization, an unusual inversion of the normal reactivity of α,ß-unsaturated carbonyl systems was observed.

Evolution of a Strategy for Concise Enantioselective Total Synthesis of the Salinosporamide Family of Natural Products.

Our first strategy for rapidly accessing pyrrolidinone cores of salinosporamides involved combined use of memory of chirality and dynamic kinetic resolution principles in aldol reactions of the serine-derived 5-oxazolidinone substrate, which was ultimately unsuccessful with respect to enantioselectivity. This failure led us to the revised strategy. The influence of the stereocenter in 5-oxazolidinone enabled selective installation of the C-2 stereocenter. The intramolecular aldol reaction of the C-2 stereodefined aldol substrate was successful. An unexpected hydrolytic dynamic kinetic resolution was observed in hydrolyses of the bicyclic aldol products. This unprecedented substrate-driven hydrolytic dynamic kinetic resolution was utilized in preparing the pyrrolidinone core with excellent efficiency. Through this strategy, the concise total syntheses of salinosporamides A and B as well as cinnabaramides A, E, and F were achieved with high selectivity.

Synthesis of Bridged Oxabicycles via Cascade Reactions involving O-Acyloxocarbenium Ion Intermediates.

Compared to related electrophilic species, O-acyloxocarbenium ions (AOIs) have been much less utilized in organic synthesis due to the lack of an efficient formation method. Here, we present a facile and simple approach for the generation of AOI from ester and acetal groups. Based on our AOI system with a pendant nucleophile, we obtained a unique bridged bicyclic system via an epoxonium-like transition state. The proposed mechanism is based on experimental and computational studies.

Collective Asymmetric Total Synthesis of C-11 Oxygenated Cephalotaxus Alkaloids.

While numerous studies pertaining to the total synthesis of Cephalotaxus alkaloids have been reported, only two strategies have been reported to date for the successful synthesis of the C-11 oxygenated subset, due to the additional synthetic challenge posed by the remote C-11 stereocenter. Herein, we report the collective asymmetric total synthesis of C-11 oxygenated Cephalotaxus alkaloids using a chiral proline both as a starting material and as the only chirality source. A tetracyclic advanced intermediate was synthesized in a highly stereoselective manner from l-proline in 8 steps involving sequential chirality transfer steps such as a diastereoselective N-alkylation, stereospecific Stevens rearrangement and intramolecular Friedel-Crafts reaction via an unusual O-acyloxocarbenium intermediate. From a common intermediate, the asymmetric total synthesis of six C-11 oxygenated Cephalotaxus alkaloids was completed by a series of oxidation state adjustments.

Carbocyclization of Heterosubstituted Alkynes via the Memory of Chirality: Access to Cα-Substituted Proline Derivatives.

An efficient strategy for the asymmetric synthesis of Cα-substituted proline derivatives from acyclic α-amino acids has been established. The 5-exo-dig asymmetric cyclization of α-amino ester enolates onto heterosubstituted alkynes provided a product with excellent enantioselectivity via the memory of chirality concept. Density functional theory calculations indicated that a heteroatom is crucial for the success of the asymmetric cyclization because a more stabilized vinyl carbanion is produced. This new method has the potential to enable the rapid asymmetric construction of bioactive molecules containing the pyrrolidine skeleton.

Enantioselective Synthesis of Homoisoflavanones by Asymmetric Transfer Hydrogenation and Their Biological Evaluation for Antiangiogenic Activity.

Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel antiangiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases. We have previously reported the therapeutic potential of anti-angiogenic homoisoflavanone derivatives with efficacy in retinal and choroidal neovascularization models, although these are racemic compounds due to the C3-stereogenic center in the molecules. This work presents asymmetric synthesis and structural determination of anti-angiogenic homoisoflavanones and pharmacological characterization of the stereoisomers. We describe an enantioselective synthesis of homoisoflavanones by virtue of ruthenium-catalyzed asymmetric transfer hydrogenation accompanying dynamic kinetic resolution, providing a basis for the further development of these compounds into novel experimental therapeutics for neovascular eye diseases.

Memory of Chirality in Bromoalkyne Carbocyclization: Applications in Asymmetric Total Synthesis of Hasubanan Alkaloids.

A transition-metal-free 5- exo- dig asymmetric cyclization of α-amino ester enolates onto bromoalkynes provided a product with excellent enantioselectivity via the memory of chirality concept. This strategy was applied to a concise total synthesis of (-)-runanine and a formal synthesis of (-)-8-demethoxyrunanine and (-)-cepharatine D.

Asymmetric Synthesis of Cα-Substituted Prolines through Curtin-Hammett-Controlled Diastereoselective N-Alkylation.

Asymmetric synthesis of α-substituted proline derivatives has been accomplished by an efficient chirality-transfer method. High diastereoselectivity of the N-alkylation of the proline ester (C→N chirality transfer) was achieved when a 2,3-disubstituted benzyl group was used as the N-substituent. DFT calculations provided a mechanistic rationale for the high degree of stereoselectivity. The generated N-chirality of the quaternary ammonium salt was transferred back to the α-carbon through a stereoselective [2,3]-Stevens rearrangement (N→C chirality transfer) to give α-substituted proline ester.

Asymmetric Cα-Alkylation of Proline via Chirality Transfers of Conformationally Restricted Proline Derivative: Application to the Total Synthesis of (-)-Amathaspiramide F.

An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (-)-amathaspiramide F.

Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing.

Cervical small cell neuroendocrine tumors (CSCNETs) are rare, aggressive neuroendocrine tumors (NETs). Reliable diagnostic and prognostic CSCNET markers are lacking, making diagnosis and prognosis prediction difficult, and treatment strategies limited. Here we provide mutation profiles for five tumor-normal paired CSCNETs using whole exome sequencing (WES). We expanded our assessment of frequently mutated genes to include publicly available data from 55 small intestine neuroendocrine tumors, 10 pancreatic neuroendocrine tumors, 42 small cell lung cancers, six NET cell lines, and 188 cervical cancers, along with our five CSCNETs. We identified 1,968 somatic mutations, including 1,710 missense, 106 nonsense, 144 splice site, 4 lncRNA, 3 nonstop, and 1 start codon mutation. We assigned functions to the 114 most frequently mutated genes based on gene ontology. ATRX, ERBB4, and genes in the Akt/mTOR pathway were most frequently mutated. Positive cytoplasmic ERBB4 immunohistochemical staining was detected in all CSCNET tumors tested, but not in adjacent normal tissues. To our knowledge, this study is the first to utilize WES in matched CSCNET and normal tissues to identify somatic mutations. Further studies will improve our understanding of how ATRX and ERBB4 mutations and AKT/mTOR signaling promote CSCNET tumorigenesis, and may be leveraged in novel anti-cancer treatment strategies.

Prediction of miRNA-mRNA associations in Alzheimer's disease mice using network topology.

BACKGROUND: Little is known about the relationship between miRNA and mRNA expression in Alzheimer's disease (AD) at early- or late-symptomatic stages. Sequence-based target prediction algorithms and anti-correlation profiles have been applied to predict miRNA targets using omics data, but this approach often leads to false positive predictions. Here, we applied the joint profiling analysis of mRNA and miRNA expression levels to Tg6799 AD model mice at 4 and 8 months of age using a network topology-based method. We constructed gene regulatory networks and used the PageRank algorithm to predict significant interactions between miRNA and mRNA. RESULTS: In total, 8 cluster modules were predicted by the transcriptome data for co-expression networks of AD pathology. In total, 54 miRNAs were identified as being differentially expressed in AD. Among these, 50 significant miRNA-mRNA interactions were predicted by integrating sequence target prediction, expression analysis, and the PageRank algorithm. We identified a set of miRNA-mRNA interactions that were changed in the hippocampus of Tg6799 AD model mice. We determined the expression levels of several candidate genes and miRNA. For functional validation in primary cultured neurons from Tg6799 mice (MT) and littermate (LM) controls, the overexpression of ARRDC3 enhanced PPP1R3C expression. ARRDC3 overexpression showed the tendency to decrease the expression of miR139-5p and miR3470a in both LM and MT primary cells. Pathological environment created by Aß treatment increased the gene expression of PPP1R3C and Sfpq but did not significantly alter the expression of miR139-5p or miR3470a. Aß treatment increased the promoter activity of ARRDC3 gene in LM primary cells but not in MT primary cells. CONCLUSIONS: Our results demonstrate AD-specific changes in the miRNA regulatory system as well as the relationship between the expression levels of miRNAs and their targets in the hippocampus of Tg6799 mice. These data help further our understanding of the function and mechanism of various miRNAs and their target genes in the molecular pathology of AD.

ISO/IEEE 11073 PHD message generation toolkit to standardize healthcare device.

As senior population increases, various healthcare devices and services are developed such as fall detection device, home hypertension management service, and etc. However, to vitalize healthcare devices and services market, standardization for interoperability between device and service must precede. To achieve the standardization goal, the IEEE 11073 Personal Health Device (PHD) group has been standardized many healthcare devices, but until now there are few devices compatible with the PHD standard. One of main reasons is that it isn't easy for device manufactures to implement standard communication module by analyzing standard documents of over 600 pages. In this paper, we propose a standard message generation toolkit to easily standardize existing non-standard healthcare devices. The proposed toolkit generates standard PHD messages using inputted device information, and the generated messages are adapted to the device with the standard state machine file. For the experiments, we develop a reference H/W, and test the proposed toolkit with three healthcare devices: blood pressure, weighting scale, and glucose meter. The proposed toolkit has an advantage that even if the user doesn't know the standard in detail, the user can easily standardize the non-standard healthcare devices.

Home healthcare settop-box for senior chronic care using ISO/IEEE 11073 PHD standard.

As the number of seniors with chronic disease increases, the need of home healthcare settop-box is increased to manage their chronic disease in their home environment. Using the home healthcare settop-box, the patients can regularly check their health data, and finally, it can lead the decrease of medical expenses. For the home healthcare settop-box, the most important factor is the standard compatibility, which can interoperate with standard devices of any other companies. In this paper, we propose a home healthcare settop-box using ISO/IEEE 11073 PHD standard. It collects health data according to the PHD standard, and provides a chronic-care service based on the collected data. The proposed settop-box is connected with 3 devices of weigh scale, blood pressure monitor, and glucose meter, and tested at 10 homes for a month. Lastly, the proposed settop-box can be used for various healthcare services such as Google Health and Telemedicine Services using a healthcare platform server.

Dynamic activity classification based on automatic adaptation of postural orientation.

We propose a dynamic activity classification system with tri-axial accelerometer sensor using adaptation of user's postural orientation. In general, the sensor module is worn at a fixed position such as waist, head, wrist, thigh, and so on. However, in reality, the tilt of the attached sensor could be changed from time to time in actions such as sitting down, standing up, lying, walking or running. Moreover, most of the users want to wear the sensor at their own favorite positions instead of a recommended position. In these cases, the activity detection methods based on fixed tilt value may produce serious problem in their performance. Therefore, we propose a user adapted activity classification method which enables users to freely wear the sensor everywhere on their torso. In order to decide tilt values corresponding user's postural orientation, we focused on tilt-free activities such as walking and running. While walking, the algorithm tries to modify the predefined reference tilt values for the three axes, X, Y and Z. From an experiment, we have achieved 88% of the activity classification accuracy even though the tilt angle is changed while wearing sensors.

Design of a context-aware model to enhance medication adherence.

Medication adherence is important to patients who suffer from chronic disease. Regular medication activity reduces the cost of caring disease and prohibits the worsening of disease condition. To support patients taking medicine correctly, we developed a medication assistance system which alarms medication situation through multimedia messages and help patients to take a medicine. To enable the system copes with various situations related to a medication service, we designed a medication context model and implemented a state based context aware application. We also applied our system to patients and saw a little improvement in medication adherence.