Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents.

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 µM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ±â€¯10.85 % (15 µM), and the EC50 was 4.32 µM. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67 kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Bioactivities and Structure-Activity Relationships of Maslinic Acid Derivatives: A Review.

Maslinic acid has a variety of biological activities, such as anti-tumor, hypoglycemic, anti-inflammatory, and anti-parasitic. In order to enhance the biological activity of maslinic acid, scholars have carried out a lot of structural modifications, and found some more valuable maslinic acid derivatives. In this paper, the structural modification, biological activity, and structure-activity relationship of maslinic acid were reviewed, providing references for the development of maslinic acid.

Abyssibius alkaniclasticus gen. nov., sp. nov., a novel member of the family Rhodobacteraceae, isolated from the Mariana Trench.

A Gram-stain-negative bacterium with rod-shaped or irregular cells approximately 0.5-0.9×2.0-3.8 µm in size, designated as 960558T, was isolated from sediment sampled in the Mariana Trench. Strain 960558T grows at 4-37 °C (optimum, 28 °C), pH 6-7 (optimum, pH 7) and in the presence of 1-5 % (w/v) NaCl (optimum, 3 %). Strain 960558T utilizes tetradecane or hexadecane as a sole carbon and energy source, respectively. Phylogenetic trees based on 16S rRNA gene sequences and phylogenomic reconstruction revealed a close phylogenetic relationship between strain 960558T and members of the family Rhodobacteraceae by forming a separate branch within the type species of closely related genera. The validly published species that is most closely related to strain 960558T is Planktotalea lamellibrachiae JAM 119T, which has the highest 16S rRNA gene sequence similarity (93.47 %). Ubiquinone 10 is the predominant ubiquinone, while C16 : 0, 11-methyl C18 : 1 ω7c and C18 : 1 ω7c and/or C18 : 1 ω6c are the predominant fatty acids (>10 %). Additionally, phosphatidylglycerol, glycolipids, diphosphatidylglycerol, unidentified polar lipids and unidentified aminolipids are the major polar lipids. The DNA G+C content of strain 960558T is 61 %. Average nucleotide identity and digital DNA-DNA hybridization results of strain 960558T with other type strains are <70.2 and 22.1 %, respectively. Based on its phylogenetic, chemotaxonomic and other phenotypic properties, strain 960558T is considered to represent a novel genus and species within the family Rhodobacteraceae, for which the name Abyssibius alkaniclasticus gen. nov., sp. nov. is proposed. The type strain of Abyssibius alkaniclasticus is 960558T (=KCTC 82619T=MCCC 1K04727T).

Hoeflea algicola sp. nov. and Hoeflea ulvae sp. nov., isolated from phycosphere of marine algae.

Two Gram-negative, moderately halophilic, and motile rod bacteria, strains G2-23T and J2-29T, showing catalase- and oxidase-positive activities were isolated from species of the marine algae Chondrus and Ulva, respectively. Both strains optimally grew at 30 °C, pH 7.0 and 2% (w/v) NaCl. Both strains contained ubiquinone-10 as the sole isoprenoid quinone. Strain G2-23T contained summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c), C16 : 0 and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1 ω7c/ω6c) as major cellular fatty acids, and phosphatidylethanolamine (PE), phosphatidyl-N-monomethylethanolamine (PME), phosphatidylglycerol (PG), diphosphatidylglycerol and an unidentified phospholipid (PL) as major polar lipids. Strain J2-29T contained summed feature 8, C18 : 1 ω7c 11-methyl and C16 : 0 as major cellular fatty acids and PE, PME, PG and PL as major polar lipids. The genomic DNA G+C contents of strains G2-23T and J2-29T were 59.5 and 62.2 mol%, respectively. Both strains shared 97.9 % 16S rRNA gene sequence similarity, 79.8 % average nucleotide identity (ANI) and 22.8 % digital DNA-DNA hybridization (dDDH) values, indicating that they represent different species. Phylogenetic and phylogenomic analyses by 16S rRNA gene and genome sequences, respectively, revealed that strains G2-23T and J2-29T formed different phylogenic lineages within the genus Hoeflea. ANI and dDDH values between strains G2-23T and J2-29T and other Hoeflea type strains were less than 79.0 and 22.1% and 80.5 and 23.3 %, respectively, suggesting that they represent novel species of the genus Hoeflea. In summary, based on their phenotypic, chemotaxonomic and molecular properties, strains G2-23T and J2-29T represent two different novel species of the genus Hoeflea, for which the names Hoeflea algicola sp. nov. (G2-23T=KACC 22714T=JCM 35548T) and Hoeflea ulvae sp. nov. (J2-29T=KACC 22715T=JCM 35549T), respectively, are proposed.

Synthesis and structure-activity relationship studies of fusidic acid derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) are severe forms of diffuse lung disease that impose a substantial health burden all over the world. In the United States, approximately 190,000 cases per year of ALI each year, with an associated 74,500 deaths per year. Anti-inflammatory therapy has become a reasonable approach for the treatment of patients with ALI. In this study, fusidic acid derivatives were used to design new anti-inflammatory compounds with high pharmacological activity and low toxicity. A total of 30 new fusidic acid derivatives were discovered, synthesized, and screened for their anti-inflammatory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells. Of them, b2 was found to be the most active, with a higher efficiency compared with fusidic acid and celecoxib in 10 µM. In vitro, we further measured b2 inhibited inflammatory factor NO (IC50 = 5.382 ± 0.655 µM), IL-6 (IC50 = 7.767 ± 0.871 µM), and TNF-α (IC50 = 7.089 ± 0.775 µM) and b2 inhibited inflammatory cytokines COX-2 and iNOS, ROS production, NF-κB/MAPK and Bax/Bcl-2 signaling pathway pathway. In vivo,b2 attenuated ALI pathological changes and inhibited inflammatory cytokines COX-2 and iNOS in lung tissue and NF-κB/MAPK and Bax/Bcl-2 signaling pathway. In conclusion, b2 may be a promising anti-inflammatory lead compound.

Research progress of natural products and their derivatives against Alzheimer's disease.

Alzheimer's disease (AD), a persistent neurological dysfunction, has an increasing prevalence with the aging of the world and seriously threatens the health of the elderly. Although there is currently no effective treatment for AD, researchers have not given up, and are committed to exploring the pathogenesis of AD and possible therapeutic drugs. Natural products have attracted considerable attention owing to their unique advantages. One molecule can interact with multiple AD-related targets, thus having the potential to be developed in a multi-target drug. In addition, they are amenable to structural modifications to increase interaction and decrease toxicity. Therefore, natural products and their derivatives that ameliorate pathological changes in AD should be intensively and extensively studied. This review mainly presents research on natural products and their derivatives for the treatment of AD.

Application of the Mannich reaction in the structural modification of natural products.

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.

Application of Quinoline Ring in Structural Modification of Natural Products.

Natural compounds are rich in pharmacological properties that are a hot topic in pharmaceutical research. The quinoline ring plays important roles in many biological processes in heterocycles. Many pharmacological compounds, including saquinavir and chloroquine, have been marketed as quinoline molecules with good anti-viral and anti-parasitic properties. Therefore, in this review, we summarize the medicinal chemistry of quinoline-modified natural product quinoline derivatives that were developed by several research teams in the past 10 years and find that these compounds have inhibitory effects on bacteria, viruses, parasites, inflammation, cancer, Alzheimer's disease, and others.

Natural Products-Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry.

Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.

Deconstructive and Divergent Synthesis of Bioactive Natural Products.

Natural products play a key role in innovative drug discovery. To explore the potential application of natural products and their analogues in pharmacology, total synthesis is a key tool that provides natural product candidates and synthetic analogues for drug development and potential clinical trials. Deconstructive synthesis, namely building new, challenging structures through bond cleavage of easily accessible moieties, has emerged as a useful design principle in synthesizing bioactive natural products. Divergent synthesis, namely synthesizing many natural products from a common intermediate, can improve the efficiency of chemical synthesis and generate libraries of molecules with unprecedented structural diversity. In this review, we will firstly introduce five recent and excellent examples of deconstructive and divergent syntheses of natural products (2021-2023). Then, we will summarize our previous work on the deconstructive and divergent synthesis of natural products to demonstrate the high efficiency and simplicity of these two strategies in the field of total synthesis.

A novel molecular representation with BiGRU neural networks for learning atom.

Molecular representations play critical roles in researching drug design and properties, and effective methods are beneficial to assisting in the calculation of molecules and solving related problem in drug discovery. In previous years, most of the traditional molecular representations are based on hand-crafted features and rely heavily on biological experimentations, which are often costly and time consuming. However, recent researches achieve promising results using machine learning on various domains. In this article, we present a novel method named Smi2Vec-BiGRU that is designed for learning atoms and solving the single- and multitask binary classification problems in the field of drug discovery, which are the basic and also key problems in this field. Specifically, our approach transforms the molecule data in the SMILES format into a set of sample vectors and then feeds them into the bidirectional gated recurrent unit neural networks for training, which learns low-dimensional vector representations for molecular drug. We conduct extensive experiments on several widely used benchmarks including Tox21, SIDER and ClinTox. The experimental results show that our approach can achieve state-of-the-art performance on these benchmarking datasets, demonstrating the feasibility and competitiveness of our proposed approach.

Thalassolituus alkanivorans sp. nov., a hydrocarbon-utilizing bacterium isolated from the Mariana Trench.

Two strains, TMPB967T and TTPB476, were isolated from two different locations in the Mariana Trench. Cells of strains TMPB967T and TTPB476 were Gram-negative, curved rod-shaped (0.35-0.6 µm×2-4 µm) with flagella. Both strains were catalase- and oxidase-positive. Strains TMPB967T and TTPB476 could grow at 4-37 °C (optimum, 37 °C), at pH 6-9 (optimum, pH 6-7) and in the presence of 0-8 % (w/v) NaCl (optimum, 5 %). Both strains could grow with tetradecane or hexadecane as the sole carbon source. The predominant isoprenoid quinone was ubiquinone 9. The major cellular fatty acids of strains TMPB967T and TTPB476 were C18 : 1 ω9c, C16 : 0 and summed feature 3 (C16 : 1 ω7c or ω6c). The polar lipid profile included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and an unknown aminolipid. The DNA G+C contents of strains TMPB967T and TTPB476 were 53.1 and 53.0 mol%, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the most closely related validly published species were Thalassolituus marinus IMCC1826T (97.1 % similarity) and Thalassolituus oleivorans MIL-1T (95.9 % similarity). Digital DNA-DNA hybridization results of strain TMPB967T with TTPB476, T. marinus IMCC1826T and T. oleivorans MIL-1T were 99.9, 20.9 and 20.2 %, respectively. Average nucleotide identity results of strain TMPB967T with TTPB476, T. marinus IMCC1826T and T. oleivorans MIL-1T were 100, 75.8 and 72.0 %, respectively. On the basis of the phenotypic, chemotaxonomic and molecular features, strains TMPB967T and TTPB476 belong to a novel species within the genus Thalassolituus, for which the name Thalassolituus alkanivorans sp. nov. is proposed. The type strain is TMPB967T (=KCTC 82621T=MCCC 1K05476T).

Methylophaga pinxianii sp. nov., isolated from the Mariana Trench.

Two strains, TMB456T and TMB1265, were isolated from different locations in the Mariana Trench. Analysis of the 16S rRNA gene and genomic rRNA sequences indicated that they were from the same novel species and were affiliated with the genus Methylophaga of the class Gammaproteobacteria. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the most closely related validly published species were Methylophaga muralis Kr3T (98.1 % similarity) and Methylophaga nitratireducenticrescens JAM1T (97.3 % similarity). Digital DNA-DNA hybridization values of TMB456T with M. muralis Kr3T and M. nitratireducenticrescens JAM1T were <25 %. The average nucleotide identity value between strain TMB456T and M. muralis Kr3T was 80.9 %. The genomic DNA G+C contents of strains TMB456T and TMB1265 were both 44.9 mol %. Strains TMB456T and TMB1265 could grow at 4-37 °C (optimum at 20-28 °C), at pH 3-10 (optimum at pH 7-9) and in the presence of 0-10 % (w/v) NaCl (optimum at 0-1 %). Cells of strains TMB456T and TMB1265 were Gram-negative rods (0.3-0.6 µm×0.7-1.3 µm). Chemotaxonomic analysis showed that ubiquinone 8 was the sole quinone produced by strain TMB456T and that the major cellular fatty acids were iso-C16 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) and summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c). The polar lipid profile of this strain included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphoglycolipids and two unidentified polar lipids. Based on the phenotypic, chemotaxonomic and molecular features, strains TMB456T and TMB1265 belong to a novel species within the genus Methylophaga, for which the name Methylophaga pinxianii sp. nov. is proposed. The type strain is TMB456T (=KCTC 82622T= MCCC 1K05898T).

Synthesis and Evaluation of Bakuchiol Derivatives as Potent Anti-inflammatory Agents in Vitro and in Vivo.

Bakuchiol, a prenylated phenolic monoterpene derived from the fruit of Psoralen corylifolia L. (Buguzhi), is widely used to treat tumors, viruses, inflammation, and bacterial infections. In this study, we designed and synthesized 30 bakuchiol derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide-induced RAW264.7 cells. To evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO), interleukin-6, and tumor necrosis factor-α production. Based on the screening results, compound 7a displayed more pronounced activity than bakuchiol and celecoxib. Furthermore, the mechanistic studies indicated that 7a inhibited pro-inflammatory cytokine release, which was correlated with activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway and blockade of the nuclear factor-κB/mitogen-activated protein kinase signaling pathway. The in vivo anti-inflammatory activity in zebrafish indicated that 7a inhibited NO and reactive oxygen species production in a dose-dependent manner. These results indicate that 7a is a potential candidate for development as an anti-inflammatory agent.

Design, synthesis and biological evaluation of dehydroabietic acid derivative as potent vasodilatory agents.

Using dehydroabietic acid as the lead compound for structural modification, 25 dehydroabietic acid derivatives were synthesized. Among them, compound D1 not only showed the strongest relaxation effect on the aortic vascular ring in vitro (Emax = 99.5 ± 2.1%, EC50 = 3.03 ± 0.96 µM), but also significantly reduced systolic and diastolic blood pressure in rats at a dose of 2.0 mg/kg in vivo. Next, the vascular protective effect of the best active D1 and its molecular mechanism were further investigated by HUVECs. The results showed that D1 induced endothelium-dependent diastole in the rat thoracic aorta in a concentration-dependent manner. Endothelium removal or aortic ring pretreatment with NG-nitro-l-arginine methylester (l-NAME), 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), and tetraethylammonium (TEA) significantly inhibited D1-induced relaxation. In addition, wortmannin, KT5823, triciribine, diltiazem, BaCl2, 4-aminopyridine, indomethacin, propranolol, and atropine attenuated D1-induced vasorelaxation. D1 increased the phosphorylation of eNOS in HUVECs Furthermore, D1 attenuated the expression of TNF-α-induced cell adhesion molecules such as ICAM-1 and VCAM-1. However, this effect was attenuated by the eNOS inhibitors l-NAME and asymmetric dimethylarginine (ADMA). The findings suggest that D1-induced vasorelaxation through the PI3K/Akt/eNOS/NO/cGMP/PKG pathway by activating the KCa, Kir and KV channels or muscarinic and ß-adrenergic receptors, and inhibiting the l-type Ca2+ channels, which is closely related to the hypotensive action of the agent. Furthermore, D1 exhibits an inhibitory effect on vascular inflammation, which is associated with the observed vascular protective effects.

Arctigenin: pharmacology, total synthesis, and progress in structure modification.

Arctium lappa L. is a prevalent medicinal herb and a health supplement that is commonly used in Asia. Over the last few decades, the bioactive component arctigenin has attracted the attention of researchers because of its anti-inflammatory, antioxidant, immunomodulatory, multiple sclerosis fighting, antitumor, and anti-leukemia properties. After summarising the research and literature on arctigenin, this study outlines the current status of research on pharmacological activity, total synthesis, and structural modification of arctigenin. The purpose of this study is to assist academics in obtaining a more comprehensive understanding of the research progress on arctigenin and to provide constructive suggestions for further investigation of this useful molecule.

The 50% and 95% effective doses of remimazolam tosilate with adjuvant sufentanil for sedation in patients with liver cirrhosis undergoing oesophagogastric varices screening endoscopy.

WHAT IS ALREADY KNOWN AND OBJECTIVE: Sedation is routinely provided for patients undergoing gastrointestinal endoscopy. Remimazolam tosilate is a novel and short-acting sedative agent that has been used for sedation during endoscopic procedures. The optimal dose of remimazolam in gastrointestinal endoscopy for patients with liver cirrhosis has not been elucidated. BACKGROUND: To determine the effective dose of remimazolam tosilate with adjuvant sufentanil for sedation in patients with liver cirrhosis undergoing oesophagogastric varices screening endoscopy. MATERIAL AND METHODS: Patients aged 18-65 years with liver cirrhosis undergoing screening endoscopy for oesophagogastric varices were recruited. Sufentanil 0.15 µg/kg was given intravenously at 2 min before administration of remimazolam tosilate. The initial dose of remimazolam was 0.1 mg/kg and adjusted by 0.025 mg/kg as a step size, based on the Dixon and Massay up-and-down sequential method. Inclusion of patients was stopped after eight crossovers and the calculated median effective dose (ED50 ) of remimazolam for successful endoscopy was obtained by calculating the mean of midpoint of all crossovers. Furthermore, a probit regression was applied to establish the dose-response curve of remimazolam and further assess the 95% effective dose (ED95 ) of remimazolam. RESULTS: The calculated ED50 of remimazolam for successful endoscopy using the mean of midpoint of all crossovers was 0.097 mg/kg (95% CI, 0.004-0.099 mg/kg). Using the probit regression analysis, the ED50 and ED95 of remimazolam for successful endoscopy was 0.097 mg/kg (95% CI, 0.004-0.099 mg/kg) and 0.107 mg/kg (95% CI, 0.103-0.336 mg/kg), respectively. No adverse events were observed throughout the study period. CONCLUSIONS: This pilot study suggests that the ED50 and ED95 of remimazolam tosilate with adjuvant sufentanil for sedation in liver cirrhosis patients undergoing oesophagogastric varices screening endoscopy was 0.097 and 0.107 mg/kg, respectively.

Bioinspired Palladium-Catalyzed Intramolecular C(sp3 )-H Activation for the Collective Synthesis of Proline Natural Products.

Bioinspired palladium-catalyzed intramolecular cyclization of amino acid derivatives containing a vinyl iodide moiety by C-H activation enabled rapid access to a wide range of functionalized proline derivatives with an exocyclic olefin. To demonstrate the practicality of this methodology, the functionalized prolines were used as intermediates for the synthesis of several natural products: lucentamycin A, oxotomaymycin, oxoprothracarcin, and barmumycin.

Cross-phytogroup assessment of foliar epiphytic mycobiomes.

The foliar surface forms one of the largest aboveground habitats on Earth and maintains plant-fungus relationships that greatly affect ecosystem functioning. Despite many studies with particular plant species, the foliar epiphytic mycobiome has not been studied across a large number of plant species from different taxa. Using high-throughput sequencing, we assessed epiphytic mycobiomes on leaf surfaces of 592 plant species in a botanical garden. Plants of angiosperms, gymnosperms, and pteridophytes were involved. Plant taxonomy, leaf side, growing environment, and evolutionary relationships were considered. We found that pteridophytes showed the higher fungal species diversity, stronger mutualistic fungal interactions, and a greater percentage of putative pathogens than gymnosperms and angiosperms. Plant taxonomic group, leaf side, and growing environment were significantly associated with the foliar epiphytic mycobiome, but the similarity of the mycobiomes among plants was not directly related to the distance of the host evolutionary tree. Our results provide a general understanding of the foliar fungal mycobiomes from pteridophytes to angiosperms. These findings will facilitate our understanding of foliar fungal epiphytes and their roles in plant communities and ecosystems.