Synthesis and biological evaluation of atropisomeric tetrahydroisoquinolines overcoming docetaxel resistance in triple-negative human breast cancer cells.

Herein, atropisomeric 8-aryltetrahydroisoquinolines have been synthesized and biologically evaluated. Based on our structure-activity relationship study, a highly bioactive racemic compound has been produced, and it exhibited high antiproliferative activities against various cancer cell lines, including docetaxel-resistant breast cancer cell lines. Each enantiomer can be synthesized in an enantioselective manner by employing the chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler cyclization. An axially (R)-configured enantiomer showed a higher biological activity compared with the axially (S)-configured enantiomer. Further biological studies suggested that the (R)-enantiomer overcomes docetaxel resistance via the downregulation of signal transducer and activator of transcription 3 activation and consequently induces cellular apoptosis in docetaxel-resistant triple-negative breast cancer cell lines.

Distributed Detour Routing Scheme for Link Failure with Minimized Overhead in LEO Satellite Networks.

The mobility of low Earth orbit (LEO) satellites causes the LEO satellite network to experience topology changes. Topology change includes periodic topology change that occurs naturally and unpredictable topology change that occurs due to instability of the inter-satellite link between satellites. Periodic and unpredictable topology change causes frequent topology change, requiring massive communications throughout the network due to frequent route convergence. LEO satellites have limited onboard power because they operate on batteries. The waste of limited satellite onboard resources shortens the lifespan of the satellite, and achieving stable end-to-end transmission is challenging for the network. In this regard, minimizing communication overhead is a fundamental consideration when designing a routing scheme. In this paper, we propose a distributed detour routing scheme with minimal communication overhead. This routing scheme consists of a rapid detour, selective flooding, and link recovery procedures. When a link failure occurs in the network, a rapid detour can detect link failure using only a precalculated routing table. Subsequently, selective flooding searches for the optimal detour point within the minimum hop region and flood to detour point. After link recovery, a procedure is defined to traverse the pre-detour path and switch it back to the original path. The simulation results show that the proposed routing scheme achieves a reduction of communication overhead by 97.6% compared with the n-hop flooding approach.

Privacy Preservation in Patient Information Exchange Systems Based on Blockchain: System Design Study.

BACKGROUND: With the increasing sophistication of the medical industry, various advanced medical services such as medical artificial intelligence, telemedicine, and personalized health care services have emerged. The demand for medical data is also rapidly increasing today because advanced medical services use medical data such as user data and electronic medical records (EMRs) to provide services. As a result, health care institutions and medical practitioners are researching various mechanisms and tools to feed medical data into their systems seamlessly. However, medical data contain sensitive personal information of patients. Therefore, ensuring security while meeting the demand for medical data is a very important problem in the information age for which a solution is required. OBJECTIVE: Our goal is to design a blockchain-based decentralized patient information exchange (PIE) system that can safely and efficiently share EMRs. The proposed system preserves patients' privacy in the EMRs through a medical information exchange process that includes data encryption and access control. METHODS: We propose a blockchain-based EMR-sharing system that allows patients to manage their EMRs scattered across multiple hospitals and share them with other users. Our PIE system protects the patient's EMR from security threats such as counterfeiting and privacy attacks during data sharing. In addition, it provides scalability by using distributed data-sharing methods to quickly share an EMR, regardless of its size or type. We implemented simulation models using Hyperledger Fabric, an open source blockchain framework. RESULTS: We performed a simulation of the EMR-sharing process and compared it with previous works on blockchain-based medical systems to check the proposed system's performance. During the simulation, we found that it takes an average of 0.01014 (SD 0.0028) seconds to download 1 MB of EMR in our proposed PIE system. Moreover, it has been confirmed that data can be freely shared with other users regardless of the size or format of the data to be transmitted through the distributed data-sharing technique using the InterPlanetary File System. We conducted a security analysis to check whether the proposed security mechanism can effectively protect users of the EMR-sharing system from security threats such as data forgery or unauthorized access, and we found that the distributed ledger structure and re-encryption-based data encryption method can effectively protect users' EMRs from forgery and privacy leak threats and provide data integrity. CONCLUSIONS: Blockchain is a distributed ledger technology that provides data integrity to enable patient-centered health information exchange and access control. PIE systems integrate and manage fragmented patient EMRs through blockchain and protect users from security threats during the data exchange process among users. To increase safety and efficiency in the EMR-sharing process, we used access control using security levels, data encryption based on re-encryption, and a distributed data-sharing scheme.

Catalytic and Enantioselective Control of the C-N Stereogenic Axis via the Pictet-Spengler Reaction.

An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-ß-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

Tumor suppressive function of Matrin 3 in the basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity.

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.

Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration.

Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often explored for other types of reactions, frequently under the auspices of different mechanisms. As successes mount, a unique catalyst scaffold may become viewed as "privileged". However, the mechanistic hallmarks of privileged catalysts are not easily enumerated or readily generalized to genuinely different classes of reactions or substrates. We explored the concept of scaffold uniqueness with two catalyst types for an unusual atropisomer-selective cyclodehydration: (a) C2-symmetric chiral phosphoric acids and (b) phosphothreonine-embedded, peptidic phosphoric acids. Pragmatically, both catalyst scaffolds proved fertile for enantioselective/atroposelective cyclodehydrations. Mechanistic studies revealed that the determinants of often equivalent and high atroposelectivity are different for the two catalyst classes. A data-descriptive classification of these asymmetric catalysts reveals an increasingly broad set of catalyst chemotypes, operating with different mechanistic features, that creates new opportunities for broad and complementary application of catalyst scaffolds in diverse substrate space.

Synthesis and Biological Evaluation of BODIPY-PF-543.

Sphingosine-1-phosphate (S1P) regulates the proliferation of various cells and promotes the growth of cancer cells. Sphingosine kinase (SK), which transforms sphingosine into S1P, has two isotypes: SK1 and SK2. To date, both isotypes are known to be involved in the proliferation of cancer cells. PF-543, an SK1 inhibitor developed by Pfizer, strongly inhibits SK1. However, despite its strong SK1 inhibitory effect, PF-543 shows low anticancer activity in vitro. Therefore, additional biological evidence on the anticancer activity of SK1 inhibitor is required. The present study aimed to investigate the intracellular localization of PF-543 and identify its association with anticancer activity by introducing a fluoroprobe into PF-543. Boron-dipyrromethene (BODIPY)-introduced PF-543 has a similar SK1 inhibitory effect as PF-543. These results indicate that the introduction of BODIPY does not significantly affect the inhibitory effect of SK1. In confocal microscopy after BODIPY-PF-543 treatment, the compound was mainly located in the cytosol of the cells. This study demonstrated the possibility of introducing fluorescent material into an SK inhibitor and designing a synthesized compound that is permeable to cells while maintaining the SK inhibitory effect.

Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C-N Bond-Forming Cross-Coupling and Catalyst-Controlled Atroposelective Cyclodehydration.

Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon centers and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl copper complexes catalyze an unprecedented remote desymmetrization involving enantioselective C-N bond-forming cross-coupling. Then, chiral phosphoric acid catalysts set an axis of chirality through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral copper complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.

Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst.

We report a series of enantioselective C-O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence of an intervening tBu group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective reactions are possible when there are phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse complex molecular settings.

Synthesis and biological evaluation of carbocyclic analogues of pachastrissamine.

A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1.

Divergent total synthesis of the tricyclic marine alkaloids lepadiformine, fasicularin, and isomers of polycitorols by reagent-controlled diastereoselective reductive amination.

We describe a flexible and divergent route to the pyrrolo-/pyrido[1,2-j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester-enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (-)-lepadiformine and (-)-fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate-controlled manner. The key step in these total syntheses was the reagent-dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b. Aziridinium-mediated carbon homologation of the hindered C-10 group to the homoallylic group facilitated the synthesis.

Nitro-Enabled Atroposelective Dynamic Kinetic Resolution of 2-Arylindoles by Phase-Transfer Catalysis.

This study presents the atroposelective alkylation of 2-arylindoles catalyzed by a substituted cinchonium salt as a phase-transfer catalyst. Under the optimized reaction conditions, various substrates are employed to yield products with high enantioselectivity. The presence of an ortho-nitro group at the aromatic ring is essential for high atroposelectivity, because it facilitates favorable interactions between the catalyst and substrate. The origin of the enantioselectivity reveals favorable π-π interactions for both enantiomers and unfavorable steric strains for undesired enantiomers.

Development of cooking method for senior-friendly food using fruits suitable for older adults with masticatory dysfunction.

BACKGROUND/OBJECTIVES: The purpose of this study was to establish a fruit-cooking method suitable for older adults with masticatory dysfunction. MATERIALS/METHODS: Five types of fruits were selected to make fruit jelly and puree: apple, sweet persimmon, mandarin, Korean melon, and watermelon. Recipes were selected based on the Korean Industrial Standard (KS) for senior-friendly foods (KS H 4897), which classifies foods into 3 levels (L1-L3) based on their hardness and viscosity. RESULTS: In South Korea, senior-friendly foods are classified into 3 stages based on their hardness. Stage 1 is for foods that are able to eat with teeth (hardness greater than 50,000 N and less than 500,000 N), Stage 2 is for foods that are able to eat with gums (hardness greater than 20,000 N and less than 50,000 N), and Stage 3 is for foods that are able to eat with the tongue (hardness less than 20,000 N). As a result of measuring the hardness by varying the shape of the fruit, it was found that nearly all fruits could be eaten fresh by chewing with the teeth (L1) but did not meet the KS for mastication using the gums (L2) or tongue (L3), so the cooking method was selected as fruit jelly and fruit puree. Only sweet persimmon, which had a hardness of 61,624-496,393 N, was not suitable for consumption in fresh fruit, unprocessed form. Based on their hardness measurements, fruit jellies (27,869 to 36,343 N) and fruit purees (315 to 1,156 N) met the L2 and L3 requirements, respectively. The viscosity results of all fruit purees met the L3 requirement. CONCLUSION: These results offer a simple cooking method to prepare texture-modified fruits suitable for safe consumption by older adults living with masticatory difficulties in general households and nursing facilities.

Affinity-Directed Site-Specific Protein Labeling and Its Application to Antibody-Drug Conjugates.

Chemically modified proteins have diverse applications; however, conventional chemo-selective methods often yield heterogeneously labeled products. To address this limitation, site-specific protein labeling holds significant potential, driving extensive research in this area. Nevertheless, site-specific modification of native proteins remains challenging owing to the complexity of their functional groups. Therefore, a method for site-selective labeling of intact proteins is aimed to design. In this study, a novel approach to traceless affinity-directed intact protein labeling is established, which leverages small binding proteins and genetic code expansion technology. By applying this method, a site-specific antibody labeling with a drug, which leads to the production of highly effective antibody-drug conjugates specifically targeting breast cancer cell lines is achieved. This approach enables traceless conjugation of intact target proteins, which is a critical advantage in pharmaceutical applications. Furthermore, small helical binding proteins can be easily engineered for various target proteins, thereby expanding their potential applications in diverse fields. This innovative approach represents a significant advancement in site-specific modification of native proteins, including antibodies. It also bears immense potential for facilitating the development of therapeutic agents for various diseases.

Design, synthesis, and evaluation of a water-soluble antofine analogue with high antiproliferative and antitumor activity.

New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.

What Is the Relationship between the Chewing Ability and Nutritional Status of the Elderly in Korea?

This study aims to determine the relationship between chewing ability and the nutritional status of the elderly in Korea. This study utilized the data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted from 2013-2018 for persons who were ≥65 years of age. Of the 7835 subjects, 43.2% had chewing difficulty. Compared to the normal group, the chewing difficulty group had more stress, lower exercise frequency, less snack intake, a lower frequency of eating out, and a higher proportion of food insecurity. The chewing difficulty group had significantly lower food intake compared to the normal group, including various food groups such as cereals and grain, potatoes, fruits, meat, and milks and dairy products. The intake of fresh fruits was 24.5% lower and the intake of plant food (fresh fruits and nonstarchy vegetables) was 17.8% lower in the chewing difficulty group compared to the normal group. In addition, the intake of most nutrients (carbohydrates, fat, calcium, phosphorus, sodium, potassium, vitamin A, riboflavin, niacin, and vitamin C) was significantly lower in the chewing difficulty group than in the normal group. The chewing difficulty was significantly associated with undernutrition (OR = 1.63). In conclusion, chewing ability is closely related to food and nutrient intake among the elderly, which can decrease the quantity and quality of diet and is also related to undernutrition. Therefore, it is necessary to develop customized nutrition programs and aging-friendly food products that consider the chewing ability of the elderly.

How Does the Frequency of Eating-Alone among Older People in Korea Affect Their Health and Dietary Behavior?

This study examined the relationship between general population characteristics and diet-related factors pertaining to eating alone for older adults (65 years and older) in Korea. This study used the Korea National Health and Nutrition Examination Survey (KNHANES), 2016-2020, and the target population was 7037 Koreans aged 65 years or older who participated in the nutritional survey and health interview. Eating alone variables were classified as follows. Eating together all day means "eating together", eating only one meal a day means "1/day", eating two meals a day alone means "2/day", and "3/day" means eating three meals a day alone. The main results are as follows. The rate of moderate or severe food insecurity was 3.41% in the "eating together" group to 7.86% in the "3/day" group, which was 4.45% higher in the "3/day" group. Fruit + vegetable intake among food intake lowered by about 35 g from 301.2 g in the "eating together" group to 266.2 g in the "3 day" group. In addition, as a result of analyzing the prevalence of depression using the PHQ-9 score, the "3/day" group had a 1.775 to 2.464 times higher risk of depression than the "eating together" group. Finally, EQ-5D variables and quality of life scores were significantly lowered from the "eating together" group to the "3/day" group. Overall, higher frequency of eating alone was associated with food safety, essential food intake, and quality of life. Based on these results, it is thought that a dietary life support program such as the eating together program is necessary to improve the quality of life of the older people who eat alone.

All-round catalytic and atroposelective strategy via dynamic kinetic resolution for N-/2-/3-arylindoles.

As the complexity of organic molecules utilized by mankind increases, the phenomenon of atropisomerism is more frequently encountered. While a variety of well-established methods enable the control of a stereogenic center, a catalytic method for controlling a stereogenic axis in one substrate is typically unavailable for controlling axial chirality in other substrates with a similar structure. Herein, we report o-amidobiaryl as a flexible platform for chiral phosphoric acid-catalyzed atroposelective dynamic kinetic resolution. To demonstrate our strategy, three distinct types of arylindoles were utilized and reacted intermolecularly with ketomalonate in the presence of chiral phosphoric acid. An investigation of 46 substrates having an aromatic ring in different positions yields the desired products with excellent enantioselectivities. Computational investigation into the origin of enantioselectivity highlights the importance of the NH group. Given the biological significance of indoles, antiproliferative effects have been investigated; our scaffold exhibits good efficacy in this regard.

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation.

Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.