{"title":"Discovery of Dual-Target Anti-Alzheimer’s Filicinic Acid-Based Meroterpenoids from Hypericum japonicum Thunb.","authors":"Shengfei Zhong, Shoulun He, Junjie Chen, Jingyu Sun, Lulu Fu, Yingting Lin, Yuhang You, Guanghui Wang, Xiaobin Li*, Haifeng Chen* and Wenjing Tian*, ","doi":"10.1021/acs.jnatprod.6c00131","DOIUrl":"10.1021/acs.jnatprod.6c00131","url":null,"abstract":"<p >Seven undescribed filicinic acid-based meroterpenoids, hyperjaponiones A–G (<b>1</b>–<b>7</b>), along with a new natural product (hyperjaponione H, <b>8</b>) and 10 known analogues (<b>9</b>–<b>18</b>), were isolated from <i>Hypericum japonicum</i> Thunb. Chiral separation of compound <b>1</b> afforded a pair of racemates (±)-<b>1</b> (<b>1a</b> and <b>1b</b>). Their structures were elucidated through a comprehensive spectroscopic analysis and quantum chemical calculations. Moreover, biological evaluation revealed that <b>8</b> activated peroxisome proliferator-activated receptor-γ (PPARγ) transcription and upregulated the level of ATP-binding cassette transporter A1 (ABCA1), showing promise in promoting β-amyloid (Aβ) clearance. Surface plasmon resonance analysis indicated that <b>8</b> might interacted with the PPARγ ligand-binding domain, with an estimated binding affinity (<i>K</i><sub>d</sub>) of 5.63 μM. Molecular docking study further predicted the binding mode of <b>8</b> to PPARγ. Additionally, <b>8</b> was found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity, showing potential in reducing Aβ generation. In an <i>in vivo</i> zebrafish model, <b>8</b> exhibited notable anti-Alzheimer’s disease effects with no detectable toxicity or teratogenicity. Thus, <b>8</b> acts as a dual-target agent by both activating PPARγ and inhibiting BACE1, highlighting its potential as a novel therapeutic candidate for Alzheimer’s disease.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1711–1723"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Derbesiamides A–E, Cyclic Depsipeptides from Pedobesia sp.","authors":"Towa Tsukamoto, Yuki Yamazaki, Takeaki Hanyuda, Kazutoshi Yoshitake and Kentaro Takada*, ","doi":"10.1021/acs.jnatprod.6c00400","DOIUrl":"10.1021/acs.jnatprod.6c00400","url":null,"abstract":"<p >Bryopsidales green algae harbor diverse secondary metabolites, yet the family Derbesiaceae remains poorly explored. Herein, we report five cyclic depsipeptides, derbesiamides A–E (<b>1</b>–<b>5</b>), from the green alga <i>Pedobesia</i> sp. The planar structures were established by extensive NMR and HRESI-TOFMS analyses. Absolute configurations of the constituent amino acids were mainly determined by Marfey’s analysis. The configurations of the two threonine residues in <b>3</b> were further resolved by partial hydrolysis coupled with LC–MS/MS analysis and comparison with synthetic diastereomeric peptide fragments. These findings expand the chemical diversity of Derbesiaceae and highlight <i>Pedobesia</i> as a source of distinctive metabolites.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"2023–2028"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial Introducing the Collection in Honor of Valerie J. Paul","authors":"Hendrik Luesch*, and , William Fenical*, ","doi":"10.1021/acs.jnatprod.6c00688","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.6c00688","url":null,"abstract":"","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1625–1630"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148314512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Elesestriterpenoid A, an Unprecedented 5/7/6/6/5 Carbon Skeleton with Neuroprotective Activity from Leaves of Eleutherococcus sessiliflorus","authors":"Yi-Qiang Zhang, Dong Han, Rui Yang, Shu-Jun Zhang, Yan-Ying Li, Lei-Xin Zhuang, Ke-Zhen Chen, Jia-Tong Wu, Juan Pan, Wei Guan, Meng-Meng Li, Qing-Shan Chen, Li−Li Zhang, Hai-Xue Kuang and Yan Liu*, ","doi":"10.1021/acs.jnatprod.6c00058","DOIUrl":"10.1021/acs.jnatprod.6c00058","url":null,"abstract":"<p >One undescribed triterpenoid and four novel triterpenoid saponins, elesestriterpenoids A–E (<b>1</b>–<b>5</b>) were isolated from the leaves of <i>Eleutherococcus sessiliflorus</i> (Rupr. & Maxim.) S. Y. Hu. Their chemical structures were determined using spectroscopic data analysis, with their corresponding absolute configurations measured using single-crystal X-ray diffraction, electronic circular dichroism calculations, and DP4+ technologies. Notably, elesestriterpenoid A (<b>1</b>) represents the first reported lupane-type triterpenoid with a 5/7/6/6/5-fused ring system from nature, and elesestriterpenoids B-E (<b>2</b>–<b>5</b>) feature an unprecedented 7/6/6/5-fused carbon skeleton. The neuroprotective potential of these isolates was evaluated using an in vitro model of oxidative stress in <span>l</span>-glutamate-induced HT22 mouse hippocampal neuron cells. The results revealed significant neuroprotective activity for compounds <b>1</b>, <b>3</b>, and <b>4</b>. Particularly noteworthy, compound <b>1</b> demonstrated pronounced efficacy in mitigating oxidative damage through modulation of the Keap1/Nrf2/HO-1 signaling pathway in HT22 cells, indicating its potential for treating nerve injuries.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1671–1685"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147830839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Activation of a Silent Type II PKS Pathway in Streptomyces avermitilis via a Reintroduction Strategy","authors":"Tengfei Zhao, Zengguang Zhang, Jinfen Yuan, Shaofei Wang, Guangtao Zhang* and Chunshuai Huang*, ","doi":"10.1021/acs.jnatprod.6c00382","DOIUrl":"10.1021/acs.jnatprod.6c00382","url":null,"abstract":"<p >Genome mining of the industrially important bacterium <i>Streptomyces avermitilis</i> was performed via antiSMASH prediction and Protein BLAST analysis, which uncovered a previously uncharacterized cryptic type II polyketide synthase (PKS) biosynthetic gene cluster (BGC) designated <i>spy</i>. To activate this silent biosynthetic pathway in its native genomic background, we employed a gene cluster reintroduction strategy in which the <i>spy</i> cluster was captured and reintroduced into the optimized chassis strain <i>S. avermitilis</i> SUKA17. This approach successfully activated the silent pathway, leading to the isolation and characterization of six new griseusin analogues, spiromycins A–F (<b>1</b>–<b>6</b>), together with two anthraquinone derivatives, spoanthraquinones A (<b>7</b>) and B (<b>8</b>). Bioactivity evaluation revealed that spiromycins A–F exhibit potent antibacterial activities, with MIC values as low as 0.5 μM, whereas spoanthraquinones A (<b>7</b>) and B (<b>8</b>) display significant antioxidant activity in a DPPH· radical scavenging assay, with IC<sub>50</sub> values of 27.23 ± 1.69 μM and 61.65 ± 1.37 μM, respectively. Overall, this work validates that reintroduction of endogenous BGCs represents a robust genome mining approach to activate silent metabolic pathways and accelerate the discovery of bioactive novel natural products.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1902–1912"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adrian Dennis Podlesny, Josefine Brindöpke, Stephanie Schulz, David Mross, David Tymann, Ljuba Iovkova* and Martin Hiersemann*,
{"title":"Structural Assignment of Daucane Sesquiterpenoids by Low-Effort Total Synthesis and X-ray Crystallography","authors":"Adrian Dennis Podlesny, Josefine Brindöpke, Stephanie Schulz, David Mross, David Tymann, Ljuba Iovkova* and Martin Hiersemann*, ","doi":"10.1021/acs.jnatprod.6c00467","DOIUrl":"10.1021/acs.jnatprod.6c00467","url":null,"abstract":"<p >Total synthesis is an indispensable tool for structural elucidation and thus a cornerstone of natural product research. Lasidiol esters are daucane sesquiterpenoids that have been isolated from various plant genera, particularly from the families <i>Asteraceae</i> and <i>Apiaceae</i>. The structure of lasidiol and one of its esters, lasidiol angelate, was assigned in 1981 by chemical correlation with carotol from <i>Daucus carota</i>. The structural assignment of three other natural lasidiol esters is based on spectral data comparison with lasidiol angelate. In this publication, we validate the previously reported structural characterization of three natural lasidiol esters through a combination of total synthesis and X-ray crystallography. The molecular structures of lasidiol and lasidiol angelate were determined by X-ray crystallography. During the process of structural validation, we were compelled to correct the previously proposed structure of a lasidiol ester derived from <i>Ambrosia trifida</i>. To enable a plant-independent supply of lasidiol and its esters, we devise a seven-step ex-chiral-pool total synthesis to (−)-lasidiol, thereby enabling straightforward access to a wide variety of lasidiol derivatives.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1963–1971"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuling Zeng, Jing Nie, Haiyan Lan, Yichao Zhang, Yufang Dai, Xiaojie Cao, Liang Zhang and Jianjian Hu*,
{"title":"Analysis of the Expression Profiles of Borneol Dehydrogenase Genes and Its Catalytic Function in Camphor Biosynthesis in Lavender","authors":"Yuling Zeng, Jing Nie, Haiyan Lan, Yichao Zhang, Yufang Dai, Xiaojie Cao, Liang Zhang and Jianjian Hu*, ","doi":"10.1021/acs.jnatprod.6c00239","DOIUrl":"10.1021/acs.jnatprod.6c00239","url":null,"abstract":"<p >Camphor is a key quality determinant of lavender oil. Bornyl dehydrogenase (BDH) catalyzes the final camphor biosynthesis step, yet its gene family and mechanism in lavender remain uncharacterized. We phylogenetically classified 154 short-chain dehydrogenase/reductase (<i>SDR</i>) genes into six clades and screened 17 <i>BDH</i> genes. Integrated transcriptomic and metabolomic analyses revealed that camphor biosynthesis primarily occurs via the plastidic 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, with coordinated expression of geranyl diphosphate synthase (<i>GPPS</i>), bornyl diphosphate synthases (<i>BPPS</i>), bornyl-diphosphate diphosphatase (<i>BDD</i>), and <i>BDH</i> genes. Most biosynthetic genes, especially <i>BDH</i> and <i>BPPS</i>, were significantly upregulated in <i>L. × intermedia</i> “Xinxun 4”, correlating with its highest camphor content. Subcellular localization showed BDH1 resides in the cytoplasm, suggesting plastid-cytoplasm collaboration. In vitro assays demonstrated that BDH1 and BDH2 both oxidize (+)- and (−)-borneol to camphor. Molecular dynamics simulations revealed that BDH1’s active site exhibits conformational flexibility, accommodating both enantiomers with similar binding affinities, which was confirmed by enzyme kinetics. Asn90 was identified as a key catalytic residue. These findings reveal BDH family expansion, coordinated gene expression driving camphor accumulation, and BDH1’s catalytic flexibility, offering key genetic resources and mechanistic insights for optimizing lavender camphor content via metabolic engineering and molecular breeding.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1785–1801"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chalcone-Terpene Hybrids from Fissistigma litseifolium (King) Merr as Potential Carbapenemase Inhibitors","authors":"Isabel Ramón Martínez, Cécile Apel, Saoussen Oueslati, Gaëtan Herbette, Jean-François Gallard, Emily Cioni, Azeana Zahari, Thierry Naas, Sandy Desrat and Fanny Roussi*, ","doi":"10.1021/acs.jnatprod.6c00338","DOIUrl":"10.1021/acs.jnatprod.6c00338","url":null,"abstract":"<p >Resistance to carbapenems in Gram-negative bacteria is a major public health concern. This resistance is primarily mediated by carbapenemase enzymes, which hydrolyze and inactivate carbapenem antibiotics. These enzymes fall into two main categories: serine carbapenemases (e.g., OXA-48 and KPC-2) and zinc-dependent metallo-β-lactamases (e.g., NDM-1). Over recent years, their dissemination has dramatically increased worldwide, accompanied by the continuous emergence of novel variants. Notably, KPC-2 and OXA-48 are among the most prevalent carbapenemases. The current combinations of antibiotics and inhibitors available are insufficient to counteract the rapid spread of these enzyme variants. In this context, the bark extract of the Malasyan <i>Fissistigma litseifolium</i> (King) Merr, was selected following the screening of a large collection of plant extracts. This study describes and compares the metabolomic profile of this extract, for which no previous studies have been reported, with those of 13 other <i>Fissistigma</i> species. Phytochemical investigation resulted in the isolation of nine compounds, including three unreported natural products. Of these, fissisteifolin, a quinone, features a unique tetracyclic structure deriving from a chalcone and an uncommon monoterpene. Finally, fissistidin, an original chalcone-sesquiterpene dimer, exhibited 83% reduction in KPC-2 enzyme activity, establishing its potential as a candidate for developing novel carbapenemase inhibitors.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1883–1892"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148100696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Magda Škaloudová, Jan Blahut, Jan Hájek, Alan Kádek, Peter Mojzeš, Jana Pilátová, Dominika Tučková, Petra Divoká, Antonín Střížek, Martin Lukeš, Eva Kotabová, Petra Bittnerová, Kumar Saurav, Pavel Hrouzek and Petra Urajová*,
{"title":"Cytotoxic Synurins A–C: Chlorinated Naphthoquinone Pigments from the Freshwater Alga Synura sphagnicola","authors":"Magda Škaloudová, Jan Blahut, Jan Hájek, Alan Kádek, Peter Mojzeš, Jana Pilátová, Dominika Tučková, Petra Divoká, Antonín Střížek, Martin Lukeš, Eva Kotabová, Petra Bittnerová, Kumar Saurav, Pavel Hrouzek and Petra Urajová*, ","doi":"10.1021/acs.jnatprod.6c00417","DOIUrl":"10.1021/acs.jnatprod.6c00417","url":null,"abstract":"<p ><i>Synura sphagnicola</i>, a peat bog chrysophyte, forms conspicuous red cytoplasmic droplets. These droplets previously showed an unidentified pigment, prompting a detailed chemical investigation. Large-scale cultivation and chromatographic purification yielded three structurally related orange-to-red compounds, previously undescribed chlorinated naphthoquinone pigments─synurin A (<b>1</b>), synurin B (<b>2</b>), and synurin C (<b>3</b>)─whose identities were established using HPLC-HRMS, FT-ICR MS, NMR spectroscopy, FTIR, fluorescence spectroscopy, and Raman microscopy. The compounds were identified as 2,3-dichloro-5,8-dihydroxy-6-propylnaphthalene-1,4-dione (<b>1</b>) and its two O-methylated regioisomers (<b>2</b>, <b>3</b>). Raman spectra revealed strong environment-dependent vibrational differences, particularly for <b>1</b> and <b>2</b>. <i>In vitro</i> assays demonstrated potent but nonselective cytotoxicity toward cancerous and nontransformed cell lines (IC<sub>50</sub> in the low micromolar range), while only <b>1</b> exhibited ferric-reducing antioxidant activity.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"1932–1941"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jnatprod.6c00417","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148024896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Overexpression of Global Regulator ShCrp Leads to the Discovery of Polycyclic Tetramate Macrolactams in Streptomyces hebeiensis HDN10-293","authors":"Ruojin Liu, Chuanteng Ma, Yueling Teng, Wenxue Wang, Xiaomin Zhang, Dehai Li, Tianjiao Zhu* and Qian Che*, ","doi":"10.1021/acs.jnatprod.6c00138","DOIUrl":"10.1021/acs.jnatprod.6c00138","url":null,"abstract":"<p >Two new polycyclic tetramate macrolactams (PTMs), shebamides A and B (<b>1</b> and <b>2</b>), were isolated from <i>Streptomyces hebeiensis</i> HDN10-293 following the activation of cryptic biosynthetic gene clusters by overexpression of the global regulator Crp. Their structures were elucidated via comprehensive spectroscopic analysis and electronic circular dichroism calculations, revealing a C-30 ketone─an oxidative modification rarely observed in the PTMs. Compound <b>1</b> exhibited significant cytotoxicity against 4 human cancer cell lines (IC<sub>50</sub> 6.45–12.30 μM). Their biosynthetic pathway was further proposed through functional gene cluster comparison. This study underscores the efficacy of global regulation-based genome mining for discovering structurally unique metabolites.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":"89 6","pages":"2008–2014"},"PeriodicalIF":3.7,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}