Journal of Natural Products 最新文献

{"title":"Spiro-meroterpenoids, Syzygioblanes D-H, Isolated from Indonesian Medicinal Plant <i>Syzygium oblanceolatum</i>.","authors":"Nona Koga, Kaede Kawashima, Chihiro Ito, Tomoya Nishida, Shuichi Fukuyoshi, Yohei Saito, Katsunori Miyake, Saidanxia Amuti, Abdul Rahim, Ahmad Najib, Gemini Alam, Atsushi Mizokami, Nobuyuki Tanaka, Kyoko Nakagawa-Goto","doi":"10.1021/acs.jnatprod.4c01154","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c01154","url":null,"abstract":"<p><p>Syzygioblanes A-C (<b>1</b>-<b>3</b>), isolated from the Indonesian traditional herbal medicine <i>Syzygium oblanceolatum</i> (<i>S. oblanceolatum</i>), are meroterpenoids with a spiro ring formed through a [4 + 2] cycloaddition of the flavanone desmethoxymatteucinol with cyclic sesquiterpenoids. Our ongoing phytochemical investigation of <i>S. oblanceolatum</i> resulted in the isolation of five additional spiro-meroterpenoids, syzygioblanes D-H (<b>4</b>-<b>8</b>), which are hybrids of the same flavanone with eudesmane/cadinane-type sesquiterpenoids. A possible biosynthetic pathway involves enzymatic dearomative hydroxylation of desmethoxymatteucinol followed by [4 + 2] cyclization of the resulting diene with a cyclic sesquiterpene containing an exocyclic methylene to form the unique spiro ring in the syzygioblane molecule. The isolated syzygioblanes F (<b>6</b>) and G (<b>7</b>) demonstrated collateral sensitivity by inhibiting the growth of multidrug-resistant tumor cell lines more than the related chemosensitive tumor cell lines.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816775","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":"Synthesis and Evaluation of 9-<i>epi</i>-Koshidacin B as Selective Inhibitor of Histone Deacetylase 1.","authors":"Rajat Ghosh, Sima Biswas, Angshuman Bagchi, Shital K Chattopadhyay","doi":"10.1021/acs.jnatprod.4c00913","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00913","url":null,"abstract":"<p><p>A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9-<i>epi</i>-koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC₅₀ value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798722","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":"Total Synthesis of Artapilosine A and Artapilosine B.","authors":"Guangyan Zhang, Beibei Yang, Li Li, Xuan Pan, Zhanzhu Liu","doi":"10.1021/acs.jnatprod.4c01149","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c01149","url":null,"abstract":"<p><p>Artapilosines A and B, isolated from <i>Artabotrys pilosus</i>, demonstrated significant anti-HIV reverse transcriptase activity. In this work, we present the first asymmetric total synthesis of (-)-artapilosine A and of its enantiomer (+)-artapilosine A, achieved in 10 steps with overall yields of 0.9% and 0.7%, respectively, starting from commercially available piperonylic acid. The key step in this synthesis involved a pivotal photocyclization reaction, providing an efficient protocol for constructing the phenanthrene ring system common to many natural products. Additionally, using the same photocyclization strategy, we successfully synthesized artapilosine B in 10 steps with an overall yield of 2.1%.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826623","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":"Divergent Metabolism of <i>Cyclo</i>-l-Trp-l-Leu in <i>Streptomyces albofaciens</i> by Hydroxylation and Nucleobase Transfer with Two Cytochrome P450 Enzymes.","authors":"Yu Dai, Daniel Ostendorff, Shu-Ming Li","doi":"10.1021/acs.jnatprod.4c00837","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00837","url":null,"abstract":"<p><p>A three-gene <i>salb</i> cluster from <i>Streptomyces albofaciens</i> was proven to be responsible for the formation of <i>cyclo</i>-l-Trp-l-Leu (cWL) derivatives. An <i>Escherichia coli</i> strain harboring the cyclodipeptide synthase (CDPS) gene <i>salbA</i> produced cWL. Expression of the whole cluster or genes of various combinations in <i>Streptomyces coelicolor</i> revealed different metabolites of cWL by two cytochrome P450 enzymes. Isolation and structure elucidation proved the conversion of cWL to guatrypleumycine A by nucleobase transfer with SalbB and to <i>cyclo</i>(<i>trans</i>-10-hydroxy-l-Trp-l-Leu) by hydroxylation with SalbC. Incubation with ¹⁵NH₄Cl supported the incorporation of guanine in guatrypleumycine A and an X-ray crystallographic study confirmed the stereospecific hydroxylation at C-10 of the tryptophanyl residue. Cultivation of the <i>salbB</i> or <i>salbC</i> expression strains with different substrates further proved the divergent metabolisms of cWL. To the best of our knowledge, SalbC is the first report of the P450 enzyme from CDPS-associated pathways to catalyze β-hydroxylation at the amino acid side chain.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798671","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":"Cannabichromene (CBC) Shows Matrix-Dependent Thermal Configurational Stability.","authors":"Simone Manetto, Diego Caprioglio, Gianpaolo Grassi, Bruno Botta, Francesco Gasparrini, Giulia Mazzoccanti, Giovanni Appendino","doi":"10.1021/acs.jnatprod.4c00861","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00861","url":null,"abstract":"<p><p>The optical purity of cannabichromene (CBC, <b>1a</b>) is affected by the matrix in which it is generated by thermolysis from its native carboxylated form (cannabichromenic acid, CBCA, <b>1b</b>). Thus, thermolysis at 130 °C <i>in planta</i> caused a marked decrease of the enantiomeric excess (ee), while, under the same conditions, only a modest decrease of optical purity was observed when thermolysis was carried out <i>in extracto</i>. To rationalize these puzzling observations, the kinetics of thermal (100 °C) racemization of enantiopure cannabichromene (<b>1a</b>) was evaluated by enantioselective ultrahigh performance liquid chromatography in solvents (decalin and isopropyl alcohol, neat and acidified with TFA) and surfaces (native and silanized borosilicate glass) of complementary polarity. Optical stability was more than halved in isopropanol compared to decalin (<i>t</i>_1/2 50 h vs 135 h), but acidification had no effect on racemization. However, contact with a solid surface dramatically accelerated the process, with a <i>t</i>_1/2 of only 6 h on both glass surfaces. The overall extent of racemization of enantiopure CBC (<b>1a</b>) was compared under conditions commonly used for decarboxylation (heating at 130 °C) between a decalin solution and a thin film on three different surfaces (native and silanized borosilicate glass and powdered blank cannabis biomass). In line with the kinetic data, a significant erosion of enantiopurity was observed on all solid surfaces compared to the solution. These observations suggest that discrepancies in the reported enantiomeric purity of natural CBC could be not only of biogenetic derivation but also be associated with the decarboxylation protocol of cannabichromenic acid (<b>1b</b>). These findings, while relevant for the exploitation of the bioactivity of natural CBC for human health, should also prompt the adoption of a standardized decarboxylation protocol for the studies on the configurational status of CBC (<b>1a</b>) in cannabis and, in general, of cannabinochromanoids in nature.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794046","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":"Correction to Triterpenoid Saponins from <i>Dianthus versicolor</i>.","authors":"Li Ma, Yu-Cheng Gu, Jian-Guang Luo, Jun-Song Wang, Xue-Feng Huang, Ling-Yi Kong","doi":"10.1021/acs.jnatprod.4c01363","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c01363","url":null,"abstract":"","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764734","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":"Discovery of Ureido-Containing Alteropeptilides and Intramolecular Cyclized Alteramides in <i>Pseudoalteromonas flavipulchra</i> S16 by Promoter Engineering of Cryptic Biosynthetic Gene Clusters.","authors":"Ruiying Feng, Quan Dai, Meina Ma, Shuang Zhao, Zongjie Wang, Huimei Wang, Youming Zhang, Liujie Huo, Fu Yan","doi":"10.1021/acs.jnatprod.4c00965","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00965","url":null,"abstract":"<p><p><i>Pseudoalteromonas</i> are abundant in the oceans and possess great potential in the synthesis of bioactive natural products. Although many secondary metabolite biosynthetic gene clusters have been identified from <i>Pseudoalteromonas</i> genomes, most of their products have not been characterized. In this study, endogenous constitutive promoters with high transcriptional activity were obtained from <i>Pseudoalteromonas flavipulchra</i> S16 through RNA-seq and a fluorescence assay of luciferase gene expression. Through <i>in situ</i> promoter replacement two silent biosynthetic gene clusters (BGCs) were successfully activated, leading to production of intramolecular cyclized alteramides and two novel ureido-containing linear peptides, alteropeptilides. This study provides a feasible approach for the activation of silent BGCs and the mining of novel compounds from marine bacteria.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764754","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":"<i>In Vitro</i> and <i>In Vivo</i> Leishmanicidal Activity of Beauvericin.","authors":"Virlânio A de Oliveira Filho, Juliana R Gubiani, Vitória D Borgonovi, Felipe Hilário, Marcelo R de Amorim, Karen Minori, Vitor K S Bertolini, Antonio G Ferreira, Andressa R Biz, Marcos A Soares, Helder L Teles, Fernanda R Gadelha, Roberto G S Berlinck, Danilo C Miguel","doi":"10.1021/acs.jnatprod.4c01098","DOIUrl":"10.1021/acs.jnatprod.4c01098","url":null,"abstract":"<p><p>Leishmaniasis is a worldwide disease caused by more than 20 species of <i>Leishmania</i> parasites. <i>Leishmania amazonensis</i> and <i>L. braziliensis</i> are among the main causative agents of cutaneous leishmaniasis, presenting a broad spectrum of clinical forms. As these pathologies lead to unsatisfactory treatment outcomes, the discovery of alternative chemotherapeutic options is urgently required. In this investigation, a leishmanicidal bioassay-guided fractionation of the growth media extract produced by <i>Aspergillus terreus</i> P63 led to the isolation of the cyclic depsipeptide beauvericin (<b>1</b>). The viability of <i>L. amazonensis</i>, <i>L. braziliensis</i> and mammalian cells (macrophages and L929 fibroblasts) was assessed in <b>1</b> incubated cultures. <i>Leishmania</i> promastigotes were sensitive to <b>1</b>, with EC₅₀ values ranging from 0.7 to 1.3 μM. Microscopy analysis indicated that <i>Leishmania</i> spp. parasites showed morphological abnormalities in a dose-dependent manner in the presence of <b>1</b>. <i>L. amazonensis</i> intracellular amastigotes were more sensitive to <b>1</b> than promastigotes (EC₅₀ = 0.8 ± 0.1 μM), with a good selectivity index (22-30). <b>1</b> reduced the infectivity index at very low concentrations, maintaining the integrity of the primary murine host cell for up to the highest concentration tested for <b>1</b>. <i>In vivo</i> assays of <b>1</b> conducted using BALB/c mice infected with stationary-phase promastigotes of <i>L. amazonensis</i> in the tail base presented a significant reduction in the lesion parasite load. A second round of <i>in vivo</i> assays was performed to assess the efficacy of the topical use of <b>1</b>. The results demonstrated a significant decrease in the total ulcerated area of mice treated with <b>1</b> when compared with untreated animals. Our results present promising <i>in vitro</i> and <i>in vivo</i> leishmanicidal effects of beauvericin, emphasizing that systemic inoculation of <b>1</b> led to a decrease in the parasite load at the lesion site, whereas topical administration of <b>1</b> delayed the progression of leishmaniasis ulcers, a cure criterion established for cutaneous leishmaniasis management.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764726","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":"Genome Mining of the Marine-Derived Fungus <i>Trichoderma erinaceum</i> F1-1 Unearths Bergamotene-Type Sesquiterpenoids.","authors":"Wencong Yang, Shurong Tian, Yi-Fan Du, Xian-Liang Zeng, Jia-Jing Liang, Wen-Jian Lan, Hang Li","doi":"10.1021/acs.jnatprod.4c00905","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00905","url":null,"abstract":"<p><p>Terpenoids are a vast group of natural products known for their remarkable biological properties and structural diversity. UbiA terpene synthases are increasingly recognized for producing various terpenoids. In this study, we identified a biosynthetic gene cluster (<i>bgt</i>) encoding a UbiA terpene synthase BgtA in the genome of the marine-derived fungus <i>Trichoderma erinaceum</i> F1-1. The gene <i>bgtA</i> was validated to encode the biosynthesis of (-)-α-<i>trans</i>-bergamotene (<b>1</b>). Heterologous expression of the <i>bgt</i> gene cluster in the characterized host <i>Aspergillus nidulans</i> LO8030 activated the biosynthetic pathway, leading to the isolation of eight previously undocumented bergamotene-derived sesquiterpenoids (<b>2</b>-<b>9</b>). Their structures, including the absolute configurations, were elucidated by a combination of spectroscopic analysis, ECD spectra, chemical hydrolysis, single-crystal X-ray diffraction, and biosynthetic considerations. We further demonstrated that the production of these structurally intricate sesquiterpenoids in heterologous expression is attributable to the concerted action of the UbiA terpene synthase BgtA, the cytochrome P450 BgtC, and endogenous enzymes. This study underscores the immense biosynthetic potential of fungal UbiA terpene synthase gene clusters and shows genome mining is a promising strategy for the discovery of novel terpenoids from fungi.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764808","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":"Synthesis, Biological Evaluation, and Mechanistic Insights of Rubrolide Analogues as Antitumor Agents.","authors":"Haoyu Wu, Guangyao Lv, Liying Liu, Ruilin Hu, Feng Zhao, Mingxiang Song, Sisi Zhang, Huaying Fan, Shengjun Dai, Saif Ur Rehman, Hongbo Wang, Xiaofeng Mou","doi":"10.1021/acs.jnatprod.4c00946","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00946","url":null,"abstract":"<p><p>Marine natural products and their analogues have as of now been acknowledged as an important source of bioactive molecules for the treatment of cancer. Rubrolides, a unique group of <i>γ</i>-butenolides derived from marine microorganisms, have shown strong cytotoxic activity against various tumor cells. In this study, we synthesized and characterized 21 rubrolide analogues (including 16 new compounds) and investigated their antitumor activities in order to screen more active molecules and elucidate their mechanism of action. Primary MTT assay showed that compounds <b>1</b> and <b>4</b>-<b>9</b> all exhibited excellent antiproliferative activities. In particular, compound <b>7</b> showed broad-spectrum cytotoxic activity against six tumor cell lines, with IC₅₀ values mostly ranging from 2.5 to 0.2 μM. Further mechanistic studies revealed that compound <b>7</b> could penetrate HCT116 and Hela cells, localize in the endoplasmic reticulum, and upregulate the PERK-eIF2α-CHOP pathway, inducing ER stress and increasing intracellular reactive oxygen species (ROS) levels to ultimately trigger apoptosis in tumor cells. Additionally, compound <b>7</b> was found to upregulate Cyclin B1 protein expression, causing cell cycle reticulum at the G₂/M phase. <i>In vivo</i> studies further demonstrated that liposomal delivery of compound <b>7</b> exhibited a potent antitumor efficacy against Hela xenograft tumors. Based on these results, marine-derived rubrolide analogues show significant potential as novel lead compounds for antitumor drug development.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737786","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}