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Dendrobium Sw. is one of the largest genera in the Orchidaceae. Most species belong to one of two major clades (the Asian and the Australasian clades) based on morphology and phylogenetic analyses using DNA sequences. Several Dendrobium species in the Asian clade are used in traditional herbal medicine, and many compounds have been isolated from them (e.g., phenanthrene derivatives, bibenzyl derivatives, and polysaccharides). Conversely, there are only a few reports on the compounds contained in the Australasian clade species. Due to its size and diversity, the Australasian clade could be expected to contain compounds of potential medicinal value as well. Previously, we constructed the HPLC profile of 18 Dendrobium species and identified the phenanthrene derivative 1,5-dimethoxyphenanthrene-2,7-diol (1) as a characteristic compound in certain species of the Australasian clade. In this study, we performed metabolic analyses based on ¹H-NMR to identify lineage-correlated metabolites for the Australasian clade. NMR profiling analysis also showed that 1 is a characteristic compound of the Australasian clade species. Additionally, pinoresinol (2) was predominantly detected in the Australasian clade. While syringaresinol (3) was widely detected in species from both clades, specimens from the Australasian clade tended to have higher concentrations. The simple ¹H-NMR profiling method enables rapid comparison of metabolites across multiple species, providing new insights into metabolic differences associated with evolutionary lineages that were not detectable by the previous HPLC profiling.

Mucociliary clearance is a unique defense mechanism that forcibly transfers micron-sized substances deposited on the airway epithelium from the lungs, but may interfere with inhalation therapy. The application of mucoadhesive agents to inhaled formulations is expected to improve their efficacy by prolonging the drug residence time in the lungs through inhibited mucociliary clearance. In the present study, we attempted to develop new inhaled spray-freeze-dried (SFD) powders with high deagglomeration and pulmonary retention abilities by combining hydroxypropyl cellulose (HPC) of different molecular weights as a mucoadhesive agent and dileucine (diLeu) as a dispersion enhancer. The incorporation of diLeu into SFD powders resulted in a rough surface structure with large cavities and improved their deagglomeration abilities. In addition, the incorporation of HPC of lower molecular weights resulted in SFD powders with higher deagglomeration abilities. On the other hand, SFD powders with HPC and diLeu showed similar particle size distributions to that with trehalose (Tre) and diLeu after emission from a device regardless of the molecular weight of HPC incorporated. A biodistribution study through intratracheal administration to mice revealed that pulmonary drug retention was longer with SFD powders with HPC and diLeu than with a drug solution or SFD powder with Tre and diLeu, and also that HPC of a high molecular weight (approx.100000) provided the highest pulmonary retention ability of the SFD powder. These results strongly indicate that the molecular weight of HPC incorporated is a critical factor that markedly affects both the deagglomeration and pulmonary retention abilities of SFD powders.

To enhance the efficacy of magnetic resonance imaging (MRI), numerous novel contrast agents have been developed, with peptide modification emerging as a promising strategy. The versatility of peptides renders them particularly useful molecules for the fabrication of new molecule. However, the influence of peptide side chain modification on the imaging performance of contrast agents has not been fully explored in existing studies. Herein, we employed XK (ε-DOTA-Gd) X as a Gd-DOTA-peptide template and the X molecule underwent amino acid block substitution. Six Gd-DOTA-peptide complexes were synthesized and their properties, such as relaxivity, biostability, and biocompatibility, were measured and in vitro MRI assays were carried out. The results demonstrated that the Gd-DOTA-peptides exhibited low hemolysis rates and cytotoxicity. In plasma, the half-lives of the Gd-DOTA-peptide contrast agents exceeded 5 h. Relaxation experiments revealed that the Gd-DOTA-peptide achieved a slightly higher relaxation rate compared with the commercial agent Dotarem. Therefore, the amino acid modularize modification on the gadolinium-based MRI contrast agents were effective and worthy of further investigation.

Targeted protein degradation (TPD) has emerged as an innovative technology in drug development. In this manuscript, we evaluated LJH685 (an RSK2 ligand) and proteolysis targeting chimeras (PROTACs) based on LJH685 as the first degrader targeting ribosomal S6 kinase 2 (RSK2), a serine/threonine kinase associated with cancer progression. LJH685 decreased total RSK2 via the ubiquitin-proteasome system (UPS) in human multiple myeloma cell lines (HMCLs). Four LJH685-based PROTACs, composed of pomalidomide (a cereblon E3 ligase ligand) and different lengths of polyethylene glycol (PEG) linkers, decreased both total RSK2 and phosphorylated RSK2^Ser227 levels in HMCLs. Among these, PROTAC 2, which features 1 PEG unit as a linker, demonstrated the strongest degradation using cereblon (CRBN) and UPS and anti-proliferative activity, which were comparable to those of LJH685. Molecular docking simulations further supported these findings, revealing that PROTACs with PEG linkers formed stable ternary complexes with RSK2 and CRBN, whereas the linkerless PROTAC, which showed lower activity, was unable to form an appropriate complex. These results emphasize the critical role of linker length in optimizing PROTAC efficacy for targeting RSK2. Future exploration of diverse E3 ligases could enable optimization of PROTAC selectivity.

A concise approach is presented for preparing 4'-modified thymidines from oxime imidates using readily generated 4'-carbon radicals. This method produces 4'-modified thymidines from natural thymidine using the Mitsunobu reaction, the protection of 3'-hydroxy group (when necessary), and 1,5-hydrogen atom transfer (1,5-HAT)/intermolecular 1,4-addition with electron-deficient olefins. Moreover, using a one-pot synthesis involving 1,5-HAT/intermolecular 1,4-addition, followed by the hydrolysis of the imidate intermediate under basic conditions, 4'-modified thymidine was diastereoselectively isolated. This is because the 4'-isomer transferred to the water layer in the work-up process.

To search for safe and efficient anti-hypoxia active molecules, 27 derivatives were synthesized by introducing aminoalkyl groups at daidzein's position-7 and position-8. The structures of these derivatives were confirmed by ¹H-NMR, ¹³C-NMR, and mass spectrometry. The anti-hypoxia activity was evaluated in vitro using a cell hypoxia model established with the AnaeroPack-anaero. The results showed that 9 compounds significantly enhanced cell viability under hypoxic conditions, with compounds 2a, 2b, 4d, 5a, and 5d exhibiting in vitro anti-hypoxia activity significantly superior to daidzein. And the drug-like properties prediction results of the target compounds indicated that compounds 2a, 2b, 4d, 5a, and 5d may also demonstrate favorable pharmacokinetic properties. Further, the anti-hypoxia activity in vivo of these 5 derivatives were evaluated via normobaric hypoxia and hypobaric hypoxia models. The results indicated that all of the 5 compounds extended the survival time of mice under normobaric hypoxia to varying degrees, and they also alleviated oxidative stress damage to the brain and heart of mice under hypobaric hypoxia. Among these, compound 2a demonstrated superior anti-hypoxia activity both in vitro and in vivo compared to daidzein, making it worthy of further study as a potential candidate for an anti-hypoxia drug.

3-Acetyl-11-keto-β-boswellic acid is a pentacyclic triterpenoid. It is found in frankincense, which is the resin found in plants from the Boswellia genus. Single crystals of 3-acetyl-11-keto-β-boswellic acid methanol and acetonitrile solvates were obtained from the Boswellia serrata extract. X-Ray crystal structure analysis revealed the coexistence of a brominated derivative, 3-acetyl-11-keto-12-bromo-β-boswellic acid. Mass spectroscopy analysis confirmed the presence of the brominated derivative in the extract. These results provide a structural basis for insights into the chemical reactivity and possibly the biosynthesis of 3-acetyl-11-keto-β-boswellic acid and its related substances in B. serrata.

Density functional theory calculations on the cyclization of di-t-butyl 2-(2-aminophenyl)-2-methyl malonate (1) to t-butyl 3-methyloxindole-3-carboxylate (2) reveal that acetic acid-assisted protonation of the carbonyl oxygen atom reduces the activation Gibbs free energy significantly lower than methanol-assisted pathways. Experimental data confirm that reaction concentration plays a pivotal role in oxindole formation. Experimental results also indicate distinct reaction mechanisms at low and high concentrations. Achieving high enantioselectivity for chiral compound 2 in high-concentration reactions requires discovering a novel chiral acid.