Naphthoquinones can be found in Nature in various formats, both as standalone molecules and as building blocks for larger structures. A study of the fungus, sp. (strain MSX63699), led to the isolation of naphthoquinone analogues (-), including both monomers and heterodimers and seven new compounds─three kirschsteinin analogues (-) and four perenniporides (-). The structures of these were elucidated through analysis of data from 1D and 2D NMR, HRESIMS, and ECD experiments, and several compounds displayed cytotoxic activity against melanoma (MDA-MB-435) and ovarian (OVCAR3) cancer cell lines, with structure-activity trends suggesting key roles for specific substituents in enhancing bioactivity. Notably, compounds -, , , , and had IC values that ranged from about 1 to 5 μM against both cell lines. Overall, this work expands the chemical diversity of fungal naphthoquinones by identifying new heterodimeric and perenniporide-type analogues and underscores the untapped biosynthetic potential of the species.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, limiting treatment options due to the lack of targeted therapies. Survivin (BIRC5), an inhibitor of apoptosis (IAP) protein, is overexpressed in TNBC and contributes to tumor progression, chemoresistance, and poor prognosis. Cephalochromin, a fungal-derived bioactive compound, has demonstrated cytotoxic activity in various cancer models; however, its effects on breast cancer remain unexplored. In this study, we evaluated the antineoplastic potential of cephalochromin in breast cancer cells, focusing on its impact on cell viability, apoptosis, cell cycle regulation, and survivin modulation. Cephalochromin exhibited potent cytotoxic effects in TNBC models, inducing apoptosis, disrupting cell cycle progression, and downregulating survivin expression. Mechanistically, cephalochromin treatment induced PARP1 cleavage and increased the expression of γH2AX, SQSTM1/p62, and LC3BII. Gene expression analysis revealed the broad modulation of key regulators involved in apoptosis, DNA damage response, and macroautophagy. Furthermore, cephalochromin enhanced the cytotoxicity of paclitaxel and doxorubicin, showing additive synergistic interactions. In conclusion, our study provides compelling evidence of cephalochromin's antineoplastic activity in breast cancer, highlighting its potential to improve treatment outcomes. Further preclinical studies are warranted to validate their therapeutic efficacy and safety.

We report a new optically active sulfoxide containing natural product isolated from an Alaskan spp. collection off the shores of the Aleutian Islands which we term aleutianamine B. It was identified and characterized in part via contemporary computational tools. Global Natural Products Social Molecular Networking (GNPS) analysis was a key tool used in identifying aleutianamine B in the crude extract. The relative configuration of the unique stereogenic sulfur atom was determined by DFT computational analysis. We also report the synthesis of aleutianamine B from aleutianamine. Aleutianamine B was evaluated against ovarian cancer and normal cell lines. This revealed that aleutianamine B retained submicromolar potency against A2780 cells while being ≥50-fold less potent on noncancerous cells; this was in stark contrast to the parent compound, aleutianamine, which displayed potent cytotoxicity against normal cell lines. Overall, the pyrroloiminoquinone (PIQ) class increasingly reveals unique selectivity and potency for tumor cell groups that are currently resistant to available chemotherapy, providing significant leads for therapeutics and biochemical probes.

Here we disclose the total synthesis of two regioisomeric ribose-linked 1,2,3,4-tetrahydroquinoxaline-6-carboxylic acids () for the first time. This effort helped to reassign the originally proposed structure of a natural product isolated from a Chinese medicinal plant, and correct the biological activity reported in the patent. The use of commercially available methyl 4-fluoro-2-methyl-5-nitrobenzoate as a starting material to access both regioisomers, installation of the amino-sugar moiety, and construction of the quinoxalinedione ring using diethyl oxalate are the key highlights. In addition, we showed that readily available riboflavin can also be converted to the natural product (revised structure). Evaluation of the antibacterial activity of both target compounds showed no activity (up to 512 μg/mL) under the test conditions employed in this study.

Phytochemical investigation on the aerial parts of resulted in the identification of eight new benzylisoquinoline-derived secondary metabolites, including four unusual C-6-N-17 bond cleaved isopavine alkaloids oreonudines A-D (-), two isopavine alkaloids oreonudines E () and F (), one rhoeadine alkaloid oreonudine G (), and one morphinane alkaloid oreonudine H (), along with 10 previously reported analogues -. Their structures were determined by comprehensive spectroscopic and spectrometric analyses, single-crystal X-ray diffraction, and quantum chemical calculations of ECD spectra. studies using HT22 mouse hippocampal neuronal cells revealed that the previously reported compounds , , and exhibited potent inhibition of serotonin (5-HT) and/or norepinephrine (NE) reuptake. Among them, mecoquitupline () showed significant inhibitory activity against 5-HT (88.0%) and NE (58.8%) reuptake, outperforming the tricyclic antidepressant amitriptyline (53.6% and 35.5%, respectively), and notably activated the neurotrophic BDNF/CREB signaling pathway. Molecular docking and drug affinity responsive target stability (DARTS) assays further confirmed the binding of to both serotonin transporter (SERT) and norepinephrine transporter (NET). In contrast, and selectively inhibited NE and 5-HT reuptake, respectively, by targeting the corresponding transporters. These findings highlight mecoquitupline () as a promising dual-action antidepressant candidate with potent activity.

Thirteen previously unreported ascochlorin-type meroterpenoids, acrocholrins A-M (-), together with seven known analogues (-) were characterized from the deep-sea-derived fungus LW14 guided by LC-MS/MS-based molecular networking. Their structures and absolute configurations were determined unambiguously by spectroscopic analysis, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction experiments. Compounds /, /, /, /, and / are diastereomers isomerized at C-10. Additionally, compounds , , , and represent rare ascochlorin analogues featuring an uncommon 19 configuration in the cyclohexanone ring. Compounds , , and exhibited antifungal activity against 3271G1 with the same minimum inhibitory concentration (MIC) of 4 μg/mL. Preliminary mechanistic studies showed that compound exhibited its anti- activity by inhibiting capsule formation and increasing cell membrane permeability.

Pyrone derivatives, characterized by a six-membered lactone, exhibit multifaceted anticancer activity by targeting PI3K/Akt/mTOR, MAPK/ERK, Wnt/β-catenin, and Hedgehog pathways. They suppress cancer proliferation of various cancer cells, while inducing apoptosis through mitochondrial dysfunction and caspase activation. These compounds arrest cell cycle, downregulate cancer stemness markers, and reverse multidrug resistance and enhance chemosensitivity. Preclinical studies highlight efficacy in xenograft models, particularly against KRAS-mutated and therapy-resistant cancers, with synergistic effects when combined with chemo-/radiotherapy. Pyrone derivatives also impair angiogenesis by suppressing VEGF signaling. However, poor solubility and bioavailability, coupled with off-target toxicity hinder clinical translation. Emerging strategies, such as nanoparticle delivery, structural modifications, and immunotherapy combinations, aim to address these limitations. Their ability to disrupt oncogenic signaling, overcome resistance, and target cancer stem cells underscores their therapeutic potential. Future research should focus on pharmacokinetic refinement, toxicity profiling, and clinical validation to advance their application in precision oncology.

We report the divergent total synthesis of marine natural products nocarterphenyl A (), 2-dehydroxymethylnocarterphenyl A (), and nocarterphenyl D (). The thiazole-fused -terphenyl core was synthesized via Suzuki-Miyaura coupling, and dibrominated precursor was obtained by dibromination of a multisubstituted benzothiazole using NBS/morpholine/HFIP. Nocarterphenyl D () was synthesized through palladium-catalyzed dehydrogenation cross-coupling. Biological evaluation revealed that nocarterphenyl A () inhibited HCT116 cell proliferation by 71% at 10 μM. Preliminary structure-activity relationships are discussed.

We describe a bioinspired approach to the synthesis of the sulfur-containing marine pyridoacridine alkaloids kuanoniamine D and shermilamine B. The reaction sequence introduces a biogenic thia-substituent to -acetyldopamine early in the overall pathway, mimicking the known chemistry of pheomelanin/trichochrome pigment biosynthesis. Subsequent oxidative coupling with kynuramine elaborated the pyridoacridine core, affording the target natural products, spectroscopic data of which were in excellent agreement with those reported for the isolated natural products. The use of mild reaction conditions will enable structure-activity studies of these bioactive alkaloids and open new avenues for the biomimetic synthesis of other structurally related natural products.

Six-heptyl-5,6-dihydro-2-pyran-2-ones and their analogues, named in this work as hyptolactones, are substances that have great antitumor potential because they are structurally related to pironetin, an important natural product with well-established antitumor effects. To investigate the cytotoxic potential and other biological effects of natural hyptolactones, a systematic review was performed according to the PRISMA guidelines. The search was conducted on databases: PubMed Central, ScienceDirect, Scopus and Web of Science. The authors independently evaluated 272 records after insertion into the Rayyan platform, including 61 articles (Cohen's Kappa: 0.94), which indicated the existence of 72 hyptolactones originating from plants and 14 from fungi. Of these, 58 demonstrated some type of biological activity, the main ones being cytotoxic, antibacterial and antifungal effects. The SYRCLE tool was used to assess the risk of bias in animal studies. As only the α,β-unsaturated δ-lactones were cytotoxic, it is assumed that the biological effects of the hyptolactones are due to the α,β-unsaturated lactone group, also present in pironetin. Despite promising results, there is a lack of data regarding the biological effects of these lactones, especially models. Thus, scientific evidence of their therapeutic potential motivates more in-depth biological studies, enabling greater expansion of their potential.

The first asymmetric total synthesis of the bisbenzylisoquinoline alkaloids berbamine () and oxyacanthine () has been accomplished by employing Noyori asymmetric hydrogenation for chirality installation and leveraging copper-mediated Ullmann coupling for macrocycle formation. Our synthesis unequivocally confirmed the sample misidentification of , as indicated in our previous work. Evaluation of anti-inflammatory activities revealed that both synthetic and natural berbamine or oxyacanthine comparably suppressed gene expression of pro-inflammatory cytokines IL-6 and IL-1β in LPS-stimulated RAW 264.7 macrophages. Notably, intermediate displayed potent anti-inflammatory activity coupled with minimal cytotoxicity, emerging as a promising lead candidate for the development of novel anti-inflammatory agents.

Hypecoleptopines B-H (-, , and ), seven pairs of racemic spiro-benzylisoquinoline alkaloids with a complicated ring system, together with four key biosynthetic precursors (-) were isolated from by molecular networking approach. Hypecoleptopines B-H possess a rarely reported 6/6/5/6/6 pentacyclic system with a spirocyclic amide scaffold or fused spironolactone skeleton. Their structures were established by employing a combination of spectroscopic analysis, chiral separation, computational calculations, and X-ray crystal diffraction. The anti-neuroinflammatory effects of all isolates were assessed in lipopolysaccharide (LPS)-stimulated BV-2 microglial model. Remarkably, compounds (+)- and (-)- demonstrated the most significant inhibition effects with IC values of 9.9 and 8.6 μM, compared with the positive control, minocycline (IC: 25 μM). A further mechanistic study revealed that the two compounds exert the effects by inhibiting the release of inflammatory factors and downregulating iNOS and COX-2 protein expression.

Twelve hitherto undescribed -decalinoyltetramic acid derivatives (arengasetins A - L), a unique spiro[2.4]heptendione (spiroarengarone) and two benzoquinones (arengaquinones A and B), together with the highly oxygenated polycyclic molecule, epicolactone, were isolated from the palm fungus TBRC-BCC 32590. Chemical structures were determined by extensive analyses of 2D NMR spectroscopic data and chemical means. The absolute configuration of arengasetin A () was confirmed by X-ray crystallographic information, while the absolute configurations of other related compounds were corroborated by comparison of NMR spectroscopic data and chemical reactions. The isolated compounds exhibited activity against (K1, multidrug-resistant strain, IC 6.42 - > 38.76 μM), (MIC 0.78 - > 50.0 μg/mL), (MIC 1.56 - > 50.0 μg/mL), and (MIC 6.25 - > 50.0 μg/mL). Cytotoxicity against both cancerous (MCF-7 and NCI-H187) and noncancerous (Vero) was also reported.

Spiroconyone B () and C (), two unique steroids bearing rare spiro[4.5]decane and oxaspiro[4.5]decane scaffolds, along with four analogues (-) were isolated from the sea star . Structures were established by comprehensive spectroscopic analysis, quantum-chemical nuclear magnetic resonance calculations, electronic circular dichroism data, and single-crystal X-ray diffraction. Compounds , , and exhibited cytotoxicity toward HL-60 cells with IC values of 7.6 ± 0.3, 3.6 ± 0.1, and 6.0 ± 0.5 μM, respectively. Flow cytometry indicated that induced G/M phase arrest, and annexin V/PI assays showed dose-dependent increases in the level of total apoptosis for and . Western blotting revealed downregulation of cyclin B1 and cdc2 (CDK1) by ; both and decreased Bcl-2 and increased Bax, consistent with mitochondria-mediated apoptosis. Network pharmacology, supported by mechanistic assays, further suggested the engagement of the PI3K/Akt pathway by .

The first total synthesis of one out of four Kikai Island polybrominated C3'-N1 bisindole alkaloids from red alga is described. The key steps involve both dehydration of -hemiaminal and a C2'-methylthiolation of bisindole using dimethyl disulfide through directed metalation, followed by C3-methylthiolation using a -SMe succinimide reagent.

Integrating genome mining with LC-MS/MS-based molecular networking analysis has revealed that the extract of the endophytic fungus represents a promising source for the discovery of new azaphilone analogues. Two rare polyketide derivatives ( and ), along with 11 new sclerotiorin-type azaphilones (-) and eight known compounds (-), were isolated from the macroalga-associated fungus . The structural elucidation of these compounds was achieved using ECD, HR-ESI-MS, and NMR spectroscopic analyses. The absolute configurations of compounds and were determined through X-ray single-crystal diffraction. The antilymphangiogenic potential of these isolates was assessed using human lymphatic endothelial cells (LECs). Compounds and , both nitrogenated azaphilones, exhibited significant inhibitory activity, displaying IC values of 5.7 ± 0.2 and 5.8 ± 0.2 μg/mL, respectively.

A chemical investigation of the basidiomycete led to the isolation of 17 polyoxygenated cyathane diterpenoid xylosides, cyathstrines A-K (-), including 11 new ones sharing five distinct ring skeletons, two sesquiterpenoids ( and ), and two lupane triterpenoids ( and ), as well as three sterols (-), based on the OSMAC (One Strain-Many Compounds) strategy. Among them, compound represents the first example of cyathane diterpenoids with an undescribed 5/6/7/6/5/6/6-fused ring skeleton incorporating an extra 2-pyran moiety, and compound bears an unconventional 9/7/6/5/6-fused pentacyclic ring skeleton. The structures of these compounds were elucidated by means of NMR spectroscopic analyses, HRESIMS and ECD calculations. Compounds and exhibited moderate antibacterial effects against six human pathogenic bacteria, with MIC values ranging from 8 to 32 μg/mL. Meanwhile, compound showed significant neuroprotective activity at 20 μM, with cell viability improved to 82.4% from the MPP-treated cell viability of 51.20%, which was comparable to the positive control. Additionally, compounds , , , and demonstrated notable neuroprotective effects, with cell viabilities of more than 70%. These findings expanded the chemical space of cyathane diterpenoids and provided the new template molecules for the development of anti-infective and neuroprotective drugs.

Two novel macrolide hybrids, cladoescherins A and B ( and ), and a rare macrolide dimer, dithiocladospolide (), were identified from cocultures of sp. and . Compounds and feature a hybrid structural skeleton consisting of a 12-membered macrolide skeleton and a phenolate-thiazole-cysteine moiety. Compound represents a rare example of symmetrical macrocyclic polyketide dimers connected by an intermolecular disulfide bridge. Biosynthetic study revealed that and were derived from the hybridization of the macrolide encoded by a fungal polyketide synthase (PKS) and the siderophore produced by a bacterial nonribosomal peptide synthetase (NRPS) via a spontaneous abiotic reaction. The discovery of cladoescherins reveals an unprecedented nonenzymatic inactivation of an exogenous electrophilic antibiotic by bacterial metabolite.

species, particularly those investigated as biocontrol agents, are known to produce a cocktail of bioactive lipopeptides that act synergistically to shape the ecological function of these beneficial microbes. However, while certain families of lipopeptides are well-characterized, others remain elusive. Herein, we describe the characterization of the kurstakins, a family of lipopeptides associated with promising biocontrol properties but that lack adequate characterization. Metabolomic analyses of a semipurified EM195W extract fraction revealed the presence of approximately 50 cyclic- and linear-peptide analogs. Deeper analyses revealed that the chemical diversity stems from the diverse lipid tails, including linear, -, and -lipid tails ranging from C-C, along with several hydroxylated lipid tails. Isolation and complete structural analysis of two new analogs represented the first kurstakin analogs characterized by NMR and provided the first experimental analyses for deducing their absolute configuration. Finally, analysis of publicly available genomic and MS data provided insights into the true chemical diversity and distribution of the kurstakins. These results expand our understanding of this family of compounds, opening the door for determining their ecological functions and the role they play in the broader activity of biocontrol agents.

Natural products derived from symbiotic microbes remain a rich source of structurally diverse and bioactive molecules. In this study, we report genome sequencing of the termite-associated isolate sp. RB23. Genome mining uncovered a type I polyketide synthase (T1PKS) biosynthetic gene cluster encoding five halogenases, predicted to produce pyrrolomycin-like antimicrobial compounds. Mass-spectrometry-based molecular networking facilitated the identification and isolation of -methylated pyrrolomycin K and mycothiol-adduct, pyrrolomycin L. Structure elucidation was accomplished based on liquid chromatography high-resolution tandem mass spectrometry (LC-HRMS/MS) alongside 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. Based on the evaluated of antimicrobial activity, we propose that -methylation and mycothiol-based conjugation in pyrrolomycins are possible detoxification mechanisms that play a role in enhancing self-tolerance.

Biological screening of marine sponge extracts against transient receptor potential ankyrin 1 (TRPA1) identified as a promising source of secondary metabolites with potential antagonistic activity. A comprehensive investigation yielded 13 nitrogen-containing sesquiterpenoids (-) and eight glycerophosphocholines (-), including four previously undescribed bisabolene-type analogues ( and -) and one new phosphatidylcholine derivative (). Structures were elucidated by extensive NMR and HR-ESIMS/MS analyses. The absolute configuration of was determined via asymmetric synthesis, while that of was assigned from NOE correlations and pyridine-induced deshielding effects. Isolated compounds were evaluated for TRPA1 antagonistic activity using a FLIPR-based calcium mobilization assay, and compounds , , and exhibited moderate inhibitory effects without cytotoxicity against HEK cells. This study represents the first report of secondary metabolites from the genus and highlights bisabolene- and pupukeanane-type scaffolds as novel frameworks for TRPA1 antagonists, thereby expanding the chemical diversity of the underexplored order Tethyida and offering new chemotypes with potential relevance to analgesic drug discovery.