Marine natural product-inspired discovery of novel BRD4 inhibitors with anti-inflammatory activity.

Bromodomain-containing protein 4 (BRD4) has been identified as a promising target in drug discovery, and the development of novel specific BRD4 bromodomain inhibitors will benefit anti-inflammatory drug discovery as well as bromodomain function role disclose. Herein, inspired by marine quinazolinone alkaloid penipanoid C, we designed and synthesized a series of quinazolin-4(3H)-ones with diverse linkers between two aromatic ring systems. Among them, compound 25 possessed good in vitro BRD4 inhibitory activities (IC = 3.

One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors.

The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets.

New Sulfurated Butyrolactones from the Fungus Penicillium janthinellum.

Deep-sea derived fungi are considered as significant resources to discovery structurally diverse and biologically active natural compounds. In this study, four new sulfurated butyrolactones, penijanthiones A-D (1-4), together with four known analogues (5-8), were isolated from a Mariana Trench-derived fungus Penicillium janthinellum SH0301. Compounds 1-4 were the undescribed examples for natural butyrolactones coupling with a mercaptolactate moiety.

Pleiotropically activation of azaphilone biosynthesis by overexpressing a pathway-specific transcription factor in marine-derived Aspergillus terreus RA2905.

The genome sequencing of Aspergillus terreus reveals that the vast number of predicted biosynthetic gene clusters have not reflected by the metabolic profile observed under conventional culture conditions. In this study, a silent azaphilone biosynthetic gene cluster was activated by overexpressing a pathway-specific transcription factor gene2642 in marine-derived fungus A. terreus RA2905.

Synthetic Nicotinamide Cofactors as Alternatives to NADPH in Imine Reductase-Catalyzed Reactions.

This study demonstrates the effectiveness of synthetic nicotinamide cofactors as cost-effective alternatives to NADPH in imine reductase (IRED) catalysis. The synthetic cofactors maintained catalytic activity and stereoselectivity, achieving high conversion rates. Molecular docking studies revealed key structural interactions influencing performance.

Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway.

Marine natural product (MNP) pretrichodermamide B (Pre B, ) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, ) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC value of 0.

Screening and genetic engineering of marine-derived Aspergillus terreus for high-efficient production of lovastatin.

Background: Lovastatin has widespread applications thanks to its multiple pharmacological effects. Fermentation by filamentous fungi represents the major way of lovastatin production. However, the current lovastatin productivity by fungal fermentation is limited and needs to be improved.

An unexpected role of EasD: catalyzing the conversion of chanoclavine aldehyde to chanoclavine acid.

Ergot alkaloids (EAs) are a diverse group of indole alkaloids known for their complex structures, significant pharmacological effects, and toxicity to plants. The biosynthesis of these compounds begins with chanoclavine-I aldehyde (CC aldehyde, 2), an important intermediate produced by the enzyme EasD or its counterpart FgaDH from chanoclavine-I (CC, 1). However, how CC aldehyde 2 is converted to chanoclavine-I acid (CC acid, 3), first isolated from Ipomoea violacea several decades ago, is still unclear.

Folium crataegi boosts skin regeneration for burn injury in rats through multiple ways.

Appropriate topical dressings for burn treatments are important to accelerate skin wound recovery and prevent external infections. This study aimed to evaluate the effect and investigate the mechanism of folium crataegi (Crataegus pinnatifida Bge.) for the treatment of burn wounds, as well as to compare the therapeutic effects of aqueous extracts (HLW) and alcoholic extracts (HLE) from folium crataegi.

Meta-analysis reveals variations in microbial communities from diverse stony coral taxa at different geographical distances.

Coral-associated microbial communities play a vital role in underpinning the health and resilience of reef ecosystems. Previous studies have demonstrated that the microbial communities of corals are affected by multiple factors, mainly focusing on host species and geolocation. However, up-to-date, insight into how the coral microbiota is structured by vast geographic distance with rich taxa is deficient.

Opportunities and challenges in drug discovery targeting the orphan receptor GPR12.

G-protein-coupled receptor 12 (GPR12) is a brain-specific expression orphan G-protein-coupled receptor (oGPCR) that regulates various physiological processes. It is an emerging therapeutic target for central nervous system (CNS) disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), attention deficit hyperactivity disorder (ADHD), and schizophrenia, as well as other human diseases, such as cancer, obesity, and metabolic disorders. GPR12 remains a less extensively investigated oGPCR, particularly in terms of its biological functions, signaling pathways, and ligand discovery.

Hierarchical Macroporous Agarose Materials with Polyethyleneimine-Assisted Multiple Boronate Affinity Binding Sites for the Separation of Neomycin.

Quantification of neomycin residues in food samples demands an efficient purification platform. Herein, hierarchical macroporous agarose monoliths with multiple boronate affinity sites were established for selective separation of neomycin. The silica core was synthesized by "one-step" Stöber procedures followed by modification with amino group and incorporation of polyethyleneimine.

Structure-Based Design and Characterization of the Highly Potent and Selective Covalent Inhibitors Targeting the Lysine Methyltransferases G9a/GLP.

Protein lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3K9 and nonhistone proteins, play important roles in diverse cellular processes. Overexpression or dysregulation of G9a and GLP has been identified in various types of cancer. Here, we report the discovery of a highly potent and selective covalent inhibitor of G9a/GLP via the structure-based drug design approach following structure-activity relationship exploration and cellular potency optimization.

Sclerotioloids A-C: Three New Alkaloids from the Marine-Derived Fungus ST0501.

Alkaloids, as one of the largest classes of natural products with diverse structures, are an important source of innovative medicines. Filamentous fungi, especially those derived from the marine environment, are one of the major producers of alkaloids. In this study, three new alkaloids, sclerotioloids A-C (-), along with six known analogs (-), were obtained under the guidance of the MS/MS-based molecular networking from the marine-derived fungus, ST0501, collected from the South China Sea.

Identification of marine natural product Pretrichodermamide B as a STAT3 inhibitor for efficient anticancer therapy.

Unlabelled: The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) regulates the expression of various critical mediators of cancer and is considered as one of the central communication nodes in cell growth and survival. Marine natural products (MNP) represent great resources for discovery of bioactive lead compounds, especially anti-cancer agents. Through the medium-throughput screening of our in-house MNP library, Pretrichodermamide B, an epidithiodiketopiperazine, was identified as a JAK/STAT3 signaling inhibitor.

Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities.

A series of quinazolin-4(3H)-one derivatives was designed through scaffold-hopping strategy and synthesized as novel multifunctional anti-AD agents demonstrating both cholinesterase inhibition and anti-inflammatory activities. Their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were evaluated, and the enzyme kinetics study as well as detailed binding mode via molecular docking were performed for selected compounds. MR2938 (B12) displayed promising AChE inhibitory activity with an IC value of 5.

Semi-Synthesis and Biological Evaluation of 25(-26-Acetoxy-3,5-Dihydroxycholest-6-One.

Previously, we identified a series of steroids (-) that showed potent anti-virus activities against respiratory syncytial virus (RSV), with IC values ranging from 3.23 to 0.19 µM.

Analogues of natural products yaequinolones as potential inflammatory inhibitors: Design, synthesis and biological evaluation.

Inflammation is connected with a variety of diseases and there is still a need to develop more effective and safer anti-inflammatory drugs. Herein, we synthesized, resolved, and characterized eight enantiopure isomers of yaequinolone J1 (1), yaequinolone J2 (2), 4'-desmethoxyyaequinolone J1 (3), and 4'-desmethoxyyaequinolone J2 (4). The key synthetic steps were extended and 34 racemic analogues modified at the 4-aryl, the N-position, and the pyran ring were designed and synthesized.

Targeted isolation of prenylated indole alkaloids from the marine-derived fungus HK1‑6 using molecular networking.

Four prenylated indole alkaloids (-) were targeted isolated from the mangrove rhizosphere soil-derived fungus HK1-6 by using molecular networking strategies. Among them, the planar structure and relative configuration of notoamide X () were elucidated by detailed analysis of the spectroscopic data especially the NOESY spectrum for the first time and its absolute configuration was determined by ECD spectrum. Furthermore, curated molecular networks of MS/MS data were generated with GNPS which allowed highlighting six prenylated indole alkaloids (, , , , , ) that had not previously been identified in this fungus and two (, ) that had never been observed in any fungus.

Targeted isolation of antitubercular cycloheptapeptides and an unusual pyrroloindoline-containing new analog, asperpyrroindotide A, using LC-MS/MS-based molecular networking.

Unlabelled: Further insights on the secondary metabolites of a soft coral-derived fungus under the guidance of MS/MS-based molecular networking led to the isolation of seven known cycloheptapeptides, namely, asperversiamides A-C (-) and asperheptatides A-D (-) and an unusual pyrroloindoline-containing new cycloheptapeptide, asperpyrroindotide A (). The structure of was elucidated by comprehensive spectroscopic data analysis, and its absolute configuration was determined by advanced Marfey's method. The semisynthetic transformation of into was successfully achieved and the reaction conditions were optimized.

Scalable total synthesis of (+)-aniduquinolone A and its acid-catalyzed rearrangement to aflaquinolones.

The strong antibacterial, antiviral and anticancer activities demonstrated by quinolones make them promising lead structures and important synthetic targets for drug discovery. Here, we report, to the best of our knowledge, the first scalable total synthesis of antiviral (+)-aniduquinolone A, possessing a 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one skeleton. This synthetic strategy explores E-stereoselective Horner-Wadsworth-Emmons (HWE) olefination as the key step to assemble isopropenyl substituted tetrahydrofuran onto the 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one core, which is built by highly diastereoselective intramolecular aldol reaction.

Discovery, total syntheses and potent anti-inflammatory activity of pyrrolinone-fused benzoazepine alkaloids Asperazepanones A and B from Aspergillus candidus.

Natural products are well established as an important resource and play an important role in drug discovery. Here, two pyrrolinone-fused benzoazepine alkaloids, (+)-asperazepanones A (1) and B (2) with a 6/7/5 ring system, together with the artifact (-)-asperazepanone A (1), were isolated from the coral-derived Aspergillus candidus fungus. Their structures including absolute configurations were elucidated by extensive spectroscopic methods, single crystal X-ray diffraction, and ECD calculations.