Structures of the human dopamine D3 receptor-Gi complexes.

The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for Gi protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.

Activation of ERß hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.

Chromene-chromene Schiff base as a fluorescent chemosensor for Th4+ and its application in bioimaging of Caenorhabditis elegans.

The manuscript presents the synthesis of a new di-chromene Schiff base (COM-CH) by combining 7-(diethylamino)-2-oxo-2H-chromene-3-carbohydrazide and 4-oxo-4H-chromene-3-carbaldehyde, and its characterization using various analytical techniques. The probe COM-CH functional group contains a hard donor atom that selectively complexes with Th4+ ions. This report investigated COM-CH's sensing ability towards Th4+ chromogenic and fluorogenic methods in ACN: H2O (8:2, v/v) with Th4+ ions. The COM-CH-Th4+ complex was excited at 430 nm, resulting in a bright emission band at 475 nm with a 45 nm Stokes shift. The COM-CH probe demonstrated the highest performance at pH 4.0 to 8.0, with a sensitivity of 18.7 nM. The complex formation of COM-CH with Th4+ was investigated using NMR, FTIR spectrometry, and density functional theory calculations. The COM-CH and Th4+ are bound with 2:1 stoichiometry and an association constant of 1.92 × 108 M-2. The probe's performance enabled the analysis of monazite sand and water samples for Th4+ content. The probe successfully detected Th4+ content in Caenorhabditis elegans, marking the first Th4+ detection in animal models.

From musk to body odor: Decoding olfaction through genetic variation.

The olfactory system combines input from multiple receptor types to represent odor information, but there are few explicit examples relating olfactory receptor (OR) activity patterns to odor perception. To uncover these relationships, we performed genome-wide scans on odor-perception phenotypes for ten odors in 1000 Han Chinese and validated results for six of these odors in an ethnically diverse population (n = 364). In both populations, consistent with previous studies, we replicated three previously reported associations (ß-ionone/OR5A1, androstenone/OR7D4, cis-3-hexen-1-ol/OR2J3 LD-band), but not for odors containing aldehydes, suggesting that olfactory phenotype/genotype studies are robust across populations. Two novel associations between an OR and odor perception contribute to our understanding of olfactory coding. First, we found a SNP in OR51B2 that associated with trans-3-methyl-2-hexenoic acid, a key component of human underarm odor. Second, we found two linked SNPs associated with the musk Galaxolide in a novel musk receptor, OR4D6, which is also the first human OR shown to drive specific anosmia to a musk compound. We noticed that SNPs detected for odor intensity were enriched with amino acid substitutions, implying functional changes of odor receptors. Furthermore, we also found that the derived alleles of the SNPs tend to be associated with reduced odor intensity, supporting the hypothesis that the primate olfactory gene repertoire has degenerated over time. This study provides information about coding for human body odor, and gives us insight into broader mechanisms of olfactory coding, such as how differential OR activation can converge on a similar percept.

A Platform for the Synthesis of Corynantheine-Type Corynanthe Alkaloids.

Corynantheine-type alkaloids are major components of the Mitragyna speciosa, also known as kratom, that exhibit unique pharmacological activity. However, no universal method to prepare these alkaloids has been reported. Disclosed herein is a catalytic, asymmetric platform that enables rapid access to corynantheine alkaloids. The first enantioselective total synthesis of (-)-corynantheidine pseudoindoxyl is described. The first asymmetric syntheses of (+)-corynoxine and (-)-corynoxine B were also achieved, along with enantioselective syntheses of (-)-corynantheidol and (-)-corynantheidine. Through this work, all series of corynantheine alkaloids including indole, spirooxindole, and pseudoindoxyl can now be accessed in the laboratory, enabling comprehensive biological investigation of kratom alkaloids to be undertaken.

Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated. METHODS: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose. RESULTS: Kinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion. CONCLUSIONS: T-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

Near-Infrared Spontaneously Blinking Fluorophores for Live Cell Super-Resolution Imaging with Minimized Phototoxicity.

Single-molecule localization microscopy (SMLM) requires high-intensity laser irradiation, typically exceeding kW/cm2, to yield a sufficient photon count. However, this intense visible light exposure incurs substantial cellular toxicity, hindering its use in living cells. Here, we developed a class of near-infrared (NIR) spontaneously blinking fluorophores for SMLM. These NIR fluorophores are a combination of rhodamine spirolactams and merocyanine derivatives, where the rhodamine spirolactam component converts between a bright and dark state based on pH-dependent spirocyclization and merocyanine derivatives shift the excitation wavelength into the infrared. Single-molecule characterizations demonstrated their potential for SMLM. At a moderate power density of 3.93 kW/cm2, these probes exhibit duty cycle as low as 0.18% and an emission rate as high as 26,700 photons/s. Phototoxicity assessment under single-molecule imaging conditions reveals that NIR illumination (721 nm) minimizes harm to living cells. Employing these NIR fluorophores, we successfully captured time-lapse super-resolution tracking of mitochondria at a Fourier ring correlation (FRC) resolution of 69.4 nm and reconstructed the ultrastructures of endoplasmic reticulum (ER) in living cells.

Fulvic acid foliar application: a novel approach enhancing antioxidant capacity and nutritional quality of pistachio (Pistacia vera L.).

BACKGROUND: The global growth of pistachio production has prompted exploration into sustainable agricultural practices, on the application of humic substances such as fulvic acid in enhancing the quality of horticultural crops. The present study was carried out in Qom province, Iran, on 20 years old pistachio (Pistacia vera L. cv. Kaleh-Ghoochi) trees and investigated the impact of foliar spraying of fulvic acid at varying concentrations (1.5, 3, and 4.5 g L- 1) on the antioxidant and quality properties of pistachio. The different concentrations of fulvic acid were applied at two key stages: at the initiation of pistachio kernel formation (late June) and the development stage of pistachio kernel (late August), as well as at both time points. Following harvest at the horticulturally mature phase, various parameters, including total phenols, flavonoids, soluble proteins, soluble carbohydrate content, antioxidant capacity, and antioxidant enzyme activity, were assessed. RESULTS: Results indicated that foliar application of fulvic acid, particularly at 1.5 g L- 1 during both late June and August, effectively increased phenolic compounds (31.8%) and flavonoid content (24.53%). Additionally, this treatment also augmented antioxidant capacity and heightened the activity of catalase (CAT) (37.56%), ascorbate peroxidase (APX) (63.86%), and superoxide dismutase (SOD) (76.45%). Conversely, peroxidase (POX) (41.54%) activity was reduced in fulvic acid-treated nuts compared with controls. Moreover, the content of chlorophyll (45%) and carotenoids (46.7%) was enhanced using this organic fertilizer. In terms of mineral elements, the increment was observed in zinc (Zn) (58.23%) and potassium (K) (28.12%) amounts in treated nuts. Additionally, foliar application of fulvic acid led to elevated levels of soluble carbohydrates and proteins in treated nuts. CONCLUSIONS: In the present study, application of fulvic acid resulted in enhancement of antioxidant activity and quality traits of pistachio nut through an increase in total phenol, flavonoids, chlorophyll, carotenoids, K, Zn, and also activity of antioxidant enzymes. Therefore, use of fulvic acid emerges as a promising strategy to enhance the quality and nutritional attributes of pistachios, contributing to sustainable agricultural practices and improved crop outcomes.

Applications of humic and fulvic acid under saline soil conditions to improve growth and yield in barley.

BACKGROUND: Enriching the soil with organic matter such as humic and fulvic acid to increase its content available nutrients, improves the chemical properties of the soil and increases plant growth as well as grain yield. In this study, we conducted a field experiment using humic acid (HA), fulvic acid (FA) and recommended dose (RDP) of phosphorus fertilizer to treat Hordeum vulgare seedling, in which four concentrations from HA, FA and RDP (0.0 %, 50 %, 75 % and 100%) under saline soil conditions . Moreover, some agronomic traits (e.g. grain yield, straw yield, spikes weight, plant height, spike length and spike weight) in barley seedling after treated with different concentrations from HA, FA and RDP were determined. As such the beneficial effects of these combinations to improve plant growth, N, P, and K uptake, grain yield, and its components under salinity stress were assessed. RESULTS: The findings showed that the treatments HA + 100% RDP (T1), HA + 75% RDP (T2), FA + 100% RDP (T5), HA + 50% RDP (T3), and FA + 75% RDP (T6), improved number of spikes/plant, 1000-grain weight, grain yield/ha, harvest index, the amount of uptake of nitrogen (N), phosphorous (P) and potassium (K) in straw and grain. The increase for grain yield over the control was 64.69, 56.77, 49.83, 49.17, and 44.22% in the first season, and 64.08, 56.63, 49.19, 48.87, and 43.69% in the second season,. Meanwhile, the increase for grain yield when compared to the recommended dose was 22.30, 16.42, 11.27, 10.78, and 7.11% in the first season, and 22.17, 16.63, 11.08, 10.84, and 6.99% in the second season. Therefore, under salinity conditions the best results were obtained when, in addition to phosphate fertilizer, the soil was treated with humic acid or foliar application the plants with fulvic acid under one of the following treatments: HA + 100% RDP (T1), HA + 75% RDP (T2), FA + 100% RDP (T5), HA + 50% RDP (T3), and FA + 75% RDP (T6). CONCLUSIONS: The result of the use of organic amendments was an increase in the tolerance of barley plant to salinity stress, which was evident from the improvement in the different traits that occurred after the treatment using treatments that included organic amendments (humic acid or fulvic acid).

Fulvic acid application increases rice seedlings performance under low phosphorus stress.

BACKGROUND: Fulvic acid enhances plant growth and interacts synergistically with phosphate fertilizer to alleviate the agricultural production problem of low phosphorus fertilizer utilization efficiency. However, the underlying mechanism of its action remains poorly understood. In this study, we investigated the impact of fulvic acid application with varying concentrations (0, 40, 60, 80 and 120 mg/L) on rice performance in plants grown in a hydroponic system subjected to low phosphorus stress. The rice growth phenotypes, biomass, root morphology, phosphorus uptake, and the impact of fulvic acid on the rhizosphere environment of rice, were assessed. RESULTS: The findings showed that adding appropriate concentrations of exogenous fulvic acid could promote the growth performance of rice under low phosphorus stress. Particularly at T1 (40 mg/L) and T2 (60 mg/L) over the control effectively increased rice biomass by 25.42% and 24.56%, respectively. Fulvic acid treatments stimulated root morphogenesis, up-regulated phosphate transporter genes, and facilitated phosphorus absorption and accumulation. Especially T1 (20.52%), T2 (18.10%) and T3 (20.48%) treatments significantly increased phosphorus uptake in rice, thereby alleviating low phosphorus stress. Additionally, fulvic acid elevated organic acids concentration in roots and up-regulated plasma membrane H+-ATPase genes, promoting organic acids secretion. This metabolic alteration can also alleviate low phosphorus stress in rice. CONCLUSIONS: The effect of exogenous fulvic acid on physiological indicators is concentration-dependent under low phosphorus stress, enhances rice performance and reduces reliance on phosphorus fertilizer. This provides new insights to shed light on the mechanism of alleviating low phosphorus stress in rice through fulvic acid application, an eco-friendly tool.

Altered Serotonin 1B Receptor Binding After Escitalopram for Depression Is Correlated With Treatment Effect.

BACKGROUND: Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. METHODS: Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10 mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. RESULTS: We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment. CONCLUSIONS: Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.

Spiropyran-Based Photoisomerizable α-Amino Acid for Membrane-Active Peptide Modification.

Photoisomerizable peptides are promising drug candidates in photopharmacology. While azobenzene- and diarylethene-containing photoisomerizable peptides have already demonstrated their potential in this regard, reports on the use of spiropyrans to photoregulate bioactive peptides are still scarce. This work focuses on the design and synthesis of a spiropyran-derived amino acid, (S)-2-amino-3-(6'-methoxy-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin-6-yl])propanoic acid, which is suitable for the preparation of photoisomerizable peptides. The utility of this amino acid is demonstrated by incorporating it into the backbone of BP100, a known membrane-active peptide, and by examining the photoregulation of the membrane perturbation by the spiropyran-containing peptides. The toxicity of the peptides (against the plant cell line BY-2), their bacteriotoxicity (E. coli), and actin-auxin oscillator modulation ability were shown to be significantly dependent on the photoisomeric state of the spiropyran unit.

Characterizing fibril morphological changes by spirooxindoles for neurodegenerative disease application.

Fibrillation of proteins and polypeptides, which leads to the deposition of plaques in cells and tissues has been widely associated with many neuropathological diseases. Inhibition of protein misfolding and aggregation is crucial for the prevention and treatment of these conditions. The growing interest in identifying inhibitor molecules to prevent the formation of fibrils in vivo has led to the results highlighted in this study. Due to their hydrophobic structure and potential to readily cross the blood brain barrier, a library of spirooxindole compounds were synthesized with those labelled Hd-63, Hd-66 and Hd-74 proving to be the most potent against fibril formation. Our spectroscopic analysis provides detailed insight, that the introduction of these spirooxindole compounds leads to morphological changes in the mechanism of fibril formation which prevent the formation of highly ordered fibrils, instead results in the formation of disordered aggregates which are not fibrillar in nature.

Chromenone: An emerging scaffold in anti-Alzheimer drug discovery.

Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD.

Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects.

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.

Fulvic acid alleviates the stress of low nitrogen on maize by promoting root development and nitrogen metabolism.

The potential of fulvic acid (FA) to improve plant growth has been acknowledged, but its effect on plant growth and nutrient uptake under nutrient stress remains unclear. This study investigated the effects of different FA application rates on maize growth and nitrogen utilization under low nitrogen stress. The results showed that under low nitrogen stress, FA significantly stimulated maize growth, particularly root development, biomass, and nitrogen content. The enhanced activity levels of key enzymes in nitrogen metabolism were observed, along with differential gene expression in maize, which enriched nitrogen metabolism, amino acid metabolism and plant hormone metabolism. The application of FA regulated the hormones' level, reduced abscisic acid content in leaves and Me-JA content in roots, and increased auxin and zeatin ribose content in leaves. This study concludes that, by promoting root development, nitrogen metabolism, and hormone metabolism, an appropriate concentration of FA can enhance plant tolerance to low nitrogen conditions and improve nitrogen use efficiency.

Chitosan-fulvic acid nanoparticles enhance drought tolerance in maize via antioxidant defense and transcriptional reprogramming.

Nanoparticles are promising alternatives to synthetic fertilizers in the context of climate change and sustainable agriculture. Maize plants were grown under gradient concentrations (50 µM, 100 µM, 200 µM, 500 µM, and 1 mM) of chitosan (Ch), fulvic acid (FA) or chitosan-fulvic acid nanoparticles (Ch-FANPs). Based on the overall phenotypic assessment, 100 µM was selected for downstream experiments. Maize plants grown under this optimized concentration were thereafter subjected to drought stress by water withholding for 14 days. Compared to the individual performances, the combined treatment of Ch-FANPs supported the best plant growth over chitosan, fulvic acid, or sole watered plants and alleviated the adverse effects of drought by enhancing root and shoot growth, and biomass by an average 20%. In addition, Ch-FANPs-treated plants exhibited a significant reduction in hydrogen peroxide (H2O2) content (~10%), with a concomitant increase in ascorbate peroxidase (APX) activity (>100%) while showing a reduced lipid peroxidation level observed by the decrease in malondialdehyde (MDA) content (~100%) and low electrolyte leakage level. Furthermore, chlorophyll content increased significantly (>100%) in maize plants treated with Ch-FANPs compared to Ch or FA and control in response to drought. The expression of drought-induced transcription factors, ZmDREB1A, ZmbZIP1, and ZmNAC28, and the ABA-dependent ZmCIPK3 was upregulated by Ch-FANPs. Owing to the above, Ch-FANPs are proposed as a growth-promoting agent and elicitor of drought tolerance in maize via activation of antioxidant machinery and transcriptional reprogramming of drought-related genes.

Isocyanide-based multicomponent reactions for the synthesis of benzopyran derivatives with biological scaffolds.

Benzopyrans (BZPs) are among the most privileged and influential small O-heterocycles that form the core of many natural compounds, commercial drugs, biological compositions, agrochemicals, and functional materials. BZPs are divided into six general categories including coumarins, chromans, 2H-chromenes, 4H-chromenes, chromones, and 4-chromanones, each of which is abundant in many plants and foods. These oxygenated heterocyclic compounds are fascinating motifs and have extensive applications in biology and materials science. Hence, numerous efforts have been made to develop innovative approaches for their extraction and synthesis. However, most of them are step-by-step or multi-step strategies that suffer from waste material generation and a tedious extraction process. Isocyanide-based multicomponent reactions (I-MCRs) offer a highly efficient method for overcoming these problems. The I-MCR is a simple and environmentally friendly one-pot domino procedure that does not require intermediate isolation or workup and is generally more efficient in material usage. This review covers all research articles related to I-MCRs for synthesizing BZP derivatives from the beginning to the middle of the year 2023. This strategy will be useful for organic and pharmaceutical chemists to design new drugs and optimize the synthesis steps of biological compounds and commercial drugs with benzopyran cores.

Neuroprotective azaphilones from a deep-sea derived fungus Penicillium sp. SCSIO41030.

Ten azaphilones including one pair of new epimers and three new ones, penineulones A-E (1-5) with the same structural core of angular deflectin, were obtained from a deep-sea derived Penicillium sp. SCSIO41030 fermented on a liquid medium. Their structures including absolute configurations were elucidated using chiral-phase HPLC analysis, extensive NMR spectroscopic and HRESIMS data, ECD and NMR calculations, and by comparing NMR data with literature data. Biological assays showed that the azaphilones possessed no antitumor and anti-viral (HSV-1/2) activities at concentrations of 5.0 µM and 20 µM, respectively. In addition, azaphilones 8 and 9 showed neuroprotective effects against Aß25-35-induced neurotoxicity in primary cultured cortical neurons at a concentration of 10 µM. Azaphilones 8 and 9 dramatically promoted axonal regrowth against Aß25-35-induced axonal atrophy. Our study indicated that azaphilones could be promising lead compounds for neuroprotection.

A water mediated multicomponent reaction for the synthesis of novel spirooxindole derivatives and their antifungal activity.

A water mediated three-component reaction of isatin, 4-aminocoumarin, and 1,3-cyclodicarbonyl compounds is reported for the synthesis of spiro[chromeno[4,3-b]cyclopenta[e]pyridine-7,3'-indoline]trione and the spiro[chromeno[4,3-b]quinoline 7,3'-indoline]trione. Up to 27 different spirooxindole derivatives were synthesized by this method. The bioactivity of these spirooxindole derivatives was evaluated and they were found to show antifungal activity against Cercospora arachidicola, Physalospora piricola, Rhizoctonia cerealis, and Fusarium moniliforme.