Pub Date : 2024-04-09DOI: 10.1021/acs.jnatprod.4c00029
Manar Magdy Mahmoud Mohamed, Maria Mahmoud Abboud, Matiss Maleckis, Luciano D. O. Souza, José M. A. Moreira, Charlotte H. Gotfredsen, Tilmann Weber* and Ling Ding*,
Cinnamoyl moiety containing nonribosomal peptides represented by pepticinnamin E are a growing family of natural products isolated from different Streptomyces species and possess diverse bioactivities. The soil bacterium Streptomyces mirabilis P8-A2 harbors a cryptic pepticinnamin biosynthetic gene cluster, producing azodyrecins as major products. Inactivation of the azodyrecin biosynthetic gene cluster by CRISPR-BEST base editing led to the activation and production of pepticinnamin E (1) and its analogues, pepticinnamins N, O, and P (2–4), the structures of which were determined by detailed NMR spectroscopy, HRMS data, and Marfey’s reactions. These new compounds did not show a growth inhibitory effect against the LNCaP and C4-2B prostate cancer lines, respectively.
{"title":"Pepticinnamins N, O, and P, Nonribosomal Peptides from the Soil-Derived Streptomyces mirabilis P8-A2","authors":"Manar Magdy Mahmoud Mohamed, Maria Mahmoud Abboud, Matiss Maleckis, Luciano D. O. Souza, José M. A. Moreira, Charlotte H. Gotfredsen, Tilmann Weber* and Ling Ding*, ","doi":"10.1021/acs.jnatprod.4c00029","DOIUrl":"10.1021/acs.jnatprod.4c00029","url":null,"abstract":"<p >Cinnamoyl moiety containing nonribosomal peptides represented by pepticinnamin E are a growing family of natural products isolated from different <i>Streptomyces</i> species and possess diverse bioactivities. The soil bacterium <i>Streptomyces mirabilis</i> P8-A2 harbors a cryptic pepticinnamin biosynthetic gene cluster, producing azodyrecins as major products. Inactivation of the azodyrecin biosynthetic gene cluster by CRISPR-BEST base editing led to the activation and production of pepticinnamin E (<b>1</b>) and its analogues, pepticinnamins N, O, and P (<b>2</b>–<b>4</b>), the structures of which were determined by detailed NMR spectroscopy, HRMS data, and Marfey’s reactions. These new compounds did not show a growth inhibitory effect against the LNCaP and C4-2B prostate cancer lines, respectively.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593332","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}
Pub Date : 2024-04-08DOI: 10.1021/acs.jnatprod.3c01272
Jakia Jerin Mehjabin, Chin-Soon Phan and Tatsufumi Okino*,
A chemical investigation of the hydrophilic fraction of a cultured Nodularia sp. (NIES-3585) afforded six new cyclic lipopeptides, noducyclamides A1–A4 (1–4) containing 10 amino acid residues and dodecapeptides noducyclamides B1 and B2 (5 and 6). The planar structures of these lipopeptides were elucidated based on the combination of HRMS and 1D and 2D NMR spectroscopic data analyses. These peptides are structurally analogous to laxaphycins and contain the nonproteinogenic amino acids 3-hydroxyvaline and 3-hydroxyleucine and a β-amino decanoic acid residue. The absolute configurations of the noducyclamides (1–6) were determined by acid hydrolysis, followed by advanced Marfey’s analysis. Noducyclamide B1 (5) showed cytotoxic activities against MCF7 breast cancer cell lines with an IC50 value of 3.0 μg/mL (2.2 μM).
{"title":"Noducyclamides A1–A4, B1, and B2 from the Cyanobacterium Nodularia sp. NIES-3585","authors":"Jakia Jerin Mehjabin, Chin-Soon Phan and Tatsufumi Okino*, ","doi":"10.1021/acs.jnatprod.3c01272","DOIUrl":"10.1021/acs.jnatprod.3c01272","url":null,"abstract":"<p >A chemical investigation of the hydrophilic fraction of a cultured <i>Nodularia</i> sp. (NIES-3585) afforded six new cyclic lipopeptides, noducyclamides A1–A4 (<b>1</b>–<b>4</b>) containing 10 amino acid residues and dodecapeptides noducyclamides B1 and B2 (<b>5</b> and <b>6</b>). The planar structures of these lipopeptides were elucidated based on the combination of HRMS and 1D and 2D NMR spectroscopic data analyses. These peptides are structurally analogous to laxaphycins and contain the nonproteinogenic amino acids 3-hydroxyvaline and 3-hydroxyleucine and a β-amino decanoic acid residue. The absolute configurations of the noducyclamides (<b>1</b>–<b>6</b>) were determined by acid hydrolysis, followed by advanced Marfey’s analysis. Noducyclamide B1 (<b>5</b>) showed cytotoxic activities against MCF7 breast cancer cell lines with an IC<sub>50</sub> value of 3.0 μg/mL (2.2 μM).</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593231","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}
Pub Date : 2024-04-08DOI: 10.1021/acs.jnatprod.3c01216
Anatoly Fedorov, Vsevolod Dubovik, Sergey Smirnov, Leonid Chisty, Victor Khrustalev, Anton Slukin, Alena Alekseeva, Elena Stepanycheva, Igor Sendersky, Alexander Berestetskiy and Anna Dalinova*,
Fungal 10-membered lactones (TMLs), such as stagonolide A, herbarumin I, pinolidoxin, and putaminoxin, are promising candidates for the development of nature-derived herbicides. The aim of this study was to analyze the structure–activity relationships (SAR) of C-9-methyl-substituted TMLs with a multitarget bioassay approach to reveal compounds with useful (phytotoxic, entomotoxic, antimicrobial) or undesirable (cytotoxic) bioactivities. A new TML, stagonolide L (1), along with five known compounds (stagonolides D (2) and E (3), curvulides A (4) and B1/B2 (5a,b), and pyrenolide C (6)), were purified from cultures of the phytopathogenic fungus Stagonospora cirsii, and five semisynthetic derivatives of 3 and 4 (7–11) were obtained. The absolute configuration of 4 was revised to 2Z, 4S, 5S, 6R, and 9R. The identity of 5a,b and stagonolide H is discussed. The phytotoxicity of compound 4, the entomotoxicity of 5a,b, and nonselective toxicity of compound 6 are demonstrated. The latter confirms the hypothesis that the α,β-unsaturated carbonyl group is associated with the high general toxicity of TML, regardless of its position in the ring and other substituents. The epoxide in compound 4 is important for phytotoxicity. The revealed SAR patterns will be useful for further rational design of TML-based herbicides including curvulide A analogs with a 4,5-epoxy group.
{"title":"Structure–Activity Relationships of Natural C-9-Methyl-Substituted 10-Membered Lactones and Their Semisynthetic Derivatives","authors":"Anatoly Fedorov, Vsevolod Dubovik, Sergey Smirnov, Leonid Chisty, Victor Khrustalev, Anton Slukin, Alena Alekseeva, Elena Stepanycheva, Igor Sendersky, Alexander Berestetskiy and Anna Dalinova*, ","doi":"10.1021/acs.jnatprod.3c01216","DOIUrl":"10.1021/acs.jnatprod.3c01216","url":null,"abstract":"<p >Fungal 10-membered lactones (TMLs), such as stagonolide A, herbarumin I, pinolidoxin, and putaminoxin, are promising candidates for the development of nature-derived herbicides. The aim of this study was to analyze the structure–activity relationships (SAR) of C-9-methyl-substituted TMLs with a multitarget bioassay approach to reveal compounds with useful (phytotoxic, entomotoxic, antimicrobial) or undesirable (cytotoxic) bioactivities. A new TML, stagonolide L (<b>1</b>), along with five known compounds (stagonolides D (<b>2</b>) and E (<b>3</b>), curvulides A (<b>4</b>) and B<sub>1</sub>/B<sub>2</sub> (<b>5a</b>,<b>b</b>), and pyrenolide C (<b>6</b>)), were purified from cultures of the phytopathogenic fungus <i>Stagonospora cirsii</i>, and five semisynthetic derivatives of <b>3</b> and <b>4</b> (<b>7</b>–<b>11</b>) were obtained. The absolute configuration of <b>4</b> was revised to 2<i>Z</i>, 4<i>S</i>, 5<i>S</i>, 6<i>R</i>, and 9<i>R.</i> The identity of <b>5a</b>,<b>b</b> and stagonolide H is discussed. The phytotoxicity of compound <b>4</b>, the entomotoxicity of <b>5a</b>,<b>b</b>, and nonselective toxicity of compound <b>6</b> are demonstrated. The latter confirms the hypothesis that the α,β-unsaturated carbonyl group is associated with the high general toxicity of TML, regardless of its position in the ring and other substituents. The epoxide in compound <b>4</b> is important for phytotoxicity. The revealed SAR patterns will be useful for further rational design of TML-based herbicides including curvulide A analogs with a 4,5-epoxy group.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593238","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}
Pub Date : 2024-04-05DOI: 10.1021/acs.jnatprod.3c01288
Ivan Kiganda, Jonathan Bogaerts, Lianne H. E. Wieske, Tsegaye Deyou, Yoseph Atilaw, Colores Uwamariya, Masum Miah, Joanna Said, Albert Ndakala, Hoseah M. Akala, Wouter Herrebout, Edward Trybala, Tomas Bergström*, Abiy Yenesew* and Mate Erdelyi*,
Three new (1–3) and six known rotenoids (5–10), along with three known isoflavones (11–13), were isolated from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14–18), and one known chalcone (19) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC50 values of 0.7 and 3.4 μg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC50 values of 0.4–10 μM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC50 of 4.2 μM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3, 11, and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.
{"title":"Antiviral Rotenoids and Isoflavones Isolated from Millettia oblata ssp. teitensis","authors":"Ivan Kiganda, Jonathan Bogaerts, Lianne H. E. Wieske, Tsegaye Deyou, Yoseph Atilaw, Colores Uwamariya, Masum Miah, Joanna Said, Albert Ndakala, Hoseah M. Akala, Wouter Herrebout, Edward Trybala, Tomas Bergström*, Abiy Yenesew* and Mate Erdelyi*, ","doi":"10.1021/acs.jnatprod.3c01288","DOIUrl":"10.1021/acs.jnatprod.3c01288","url":null,"abstract":"<p >Three new (<b>1</b>–<b>3</b>) and six known rotenoids (<b>5</b>–<b>10</b>), along with three known isoflavones (<b>11</b>–<b>13</b>), were isolated from the leaves of <i>Millettia oblata</i> ssp. <i>teitensis</i>. A new glycosylated isoflavone (<b>4</b>), four known isoflavones (<b>14</b>–<b>18</b>), and one known chalcone (<b>19</b>) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC<sub>50</sub> values of 0.7 and 3.4 μg/mL, respectively. Compounds <b>6</b>, <b>8</b>, <b>10</b>, <b>11</b>, and <b>14</b> showed anti-RSV activity with IC<sub>50</sub> values of 0.4–10 μM, while compound <b>3</b> exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC<sub>50</sub> of 4.2 μM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds <b>3</b>, <b>11</b>, and <b>14</b> exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jnatprod.3c01288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593237","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}
Pub Date : 2024-04-04DOI: 10.1021/acs.jnatprod.3c00843
Jaeyoun Lee, Soohyun Um, Eun-Hee Kim and Seung Hyun Kim*,
Nine bacteria were isolated from the episphere of Suaeda maritima (L.) Dumort. Among them, the bacterial strain YSL2 displayed the highest antimicrobial activity on agar plates and exhibited significant novelty compared with other bacteria based on 16S rRNA analysis. Consequently, Nocardiopsis maritima YSL2T was subjected to phenotypic characterization and whole-genome sequencing. Phylogenetic analysis revealed its close association with Nocardiopsis aegyptia SNG49T. Furthermore, genomic analysis of strain YSL2T revealed the presence of various gene clusters, indicating its potential for producing antimicrobial secondary metabolites. Upon cultivation on a large scale, maritiamides A and B (1 and 2) were isolated and characterized as cyclic hexapeptides based on nuclear magnetic resonance, ultraviolet, infrared, and mass spectrometric data. The absolute configurations of the amino acid residues in the maritiamides were determined through chiral derivatization, utilizing FDAA and GITC. Maritiamides 1 and 2 exhibited promising antibacterial activities against Staphylococcus epidermidis and weakly inhibited the growth of Escherichia coli and Pseudomonas fluorescens.
{"title":"Genomic and Metabolomic Analyses of Nocardiopsis maritima YSL2 as the Mycorrhizosphere Bacterium of Suaeda maritima (L.) Dumort","authors":"Jaeyoun Lee, Soohyun Um, Eun-Hee Kim and Seung Hyun Kim*, ","doi":"10.1021/acs.jnatprod.3c00843","DOIUrl":"10.1021/acs.jnatprod.3c00843","url":null,"abstract":"<p >Nine bacteria were isolated from the episphere of <i>Suaeda maritima</i> (L.) Dumort. Among them, the bacterial strain YSL2 displayed the highest antimicrobial activity on agar plates and exhibited significant novelty compared with other bacteria based on 16S rRNA analysis. Consequently, <i>Nocardiopsis maritima</i> YSL2<sup>T</sup> was subjected to phenotypic characterization and whole-genome sequencing. Phylogenetic analysis revealed its close association with <i>Nocardiopsis aegyptia</i> SNG49<sup>T</sup>. Furthermore, genomic analysis of strain YSL2<sup>T</sup> revealed the presence of various gene clusters, indicating its potential for producing antimicrobial secondary metabolites. Upon cultivation on a large scale, maritiamides A and B (<b>1</b> and <b>2</b>) were isolated and characterized as cyclic hexapeptides based on nuclear magnetic resonance, ultraviolet, infrared, and mass spectrometric data. The absolute configurations of the amino acid residues in the maritiamides were determined through chiral derivatization, utilizing FDAA and GITC. Maritiamides <b>1</b> and <b>2</b> exhibited promising antibacterial activities against <i>Staphylococcus epidermidis</i> and weakly inhibited the growth of <i>Escherichia coli</i> and <i>Pseudomonas fluorescens</i>.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593329","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}
Pub Date : 2024-04-04DOI: 10.1021/acs.jnatprod.3c01233
Amila Agampodi Dewa, Zeinab G. Khalil, Waleed M. Hussein, Shengbin Jin, Yanan Wang, Pablo Cruz-Morales and Robert J. Capon*,
We report on the use of nitric oxide-mediated transcriptional activation (NOMETA) as an innovative means to detect and access new classes of microbial natural products encoded within silent biosynthetic gene clusters. A small library of termite nest- and mangrove-derived fungi and actinomyces was subjected to cultivation profiling using a miniaturized 24-well format approach (MATRIX) in the presence and absence of nitric oxide, with the resulting metabolomes subjected to comparative chemical analysis using UPLC-DAD and GNPS molecular networking. This strategy prompted study of Talaromyces sp. CMB-TN6F and Coccidiodes sp. CMB-TN39F, leading to discovery of the triterpene glycoside pullenvalenes A–D (1–4), featuring an unprecedented triterpene carbon skeleton and rare 6-O-methyl-N-acetyl-d-glucosaminyl glycoside residues. Structure elucidation of 1–4 was achieved by a combination of detailed spectroscopic analysis, chemical degradation, derivatization and synthesis, and biosynthetic considerations.
{"title":"Pullenvalenes A–D: Nitric Oxide-Mediated Transcriptional Activation (NOMETA) Enables Discovery of Triterpene Aminoglycosides from Australian Termite Nest-Derived Fungi","authors":"Amila Agampodi Dewa, Zeinab G. Khalil, Waleed M. Hussein, Shengbin Jin, Yanan Wang, Pablo Cruz-Morales and Robert J. Capon*, ","doi":"10.1021/acs.jnatprod.3c01233","DOIUrl":"10.1021/acs.jnatprod.3c01233","url":null,"abstract":"<p >We report on the use of <u>n</u>itric <u>o</u>xide-<u>me</u>diated <u>t</u>ranscriptional <u>a</u>ctivation (NOMETA) as an innovative means to detect and access new classes of microbial natural products encoded within silent biosynthetic gene clusters. A small library of termite nest- and mangrove-derived fungi and actinomyces was subjected to cultivation profiling using a miniaturized 24-well format approach (MATRIX) in the presence and absence of nitric oxide, with the resulting metabolomes subjected to comparative chemical analysis using UPLC-DAD and GNPS molecular networking. This strategy prompted study of <i>Talaromyces</i> sp. CMB-TN6F and <i>Coccidiodes</i> sp. CMB-TN39F, leading to discovery of the triterpene glycoside pullenvalenes A–D (<b>1</b>–<b>4</b>), featuring an unprecedented triterpene carbon skeleton and rare 6-<i>O</i>-methyl-<i>N</i>-acetyl-<span>d</span>-glucosaminyl glycoside residues. Structure elucidation of <b>1</b>–<b>4</b> was achieved by a combination of detailed spectroscopic analysis, chemical degradation, derivatization and synthesis, and biosynthetic considerations.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593507","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}
Pub Date : 2024-04-01DOI: 10.1021/acs.jnatprod.4c00037
Shengxin Sun, Xiaodan He, Juan Yang, Xia Wang and Shengkun Li*,
As an important bioactive molecular backbone, drimane meroterpenoids have drawn a great deal of attention from both pharmacologists and chemists. Inspired by the prevalidated success of conformational restriction in the discovery of novel pharmaceutical leads, two distinct tetracyclic drimane meroterpenoids, (−)-pelorol and (+)-aureol, were synthesized from the inexpensive starting material (−)-sclareol through 10 and 8 steps with 5.6% and 5.4% overall yield, respectively. The mild conditions, operational facility, and scalability enabled the expedient synthesis and biological exploration of not only natural products themselves but also their mimics. The first agrochemical exploration showed (−)-pelorol and (+)-aureol possessed good antifungal activity against Rhizoctonia solani, with EC50 values of 7.7 and 6.9 μM, respectively. This revealed that tetracyclic drimane meroterpenoids are valuable models for antifungal lead discovery.
{"title":"Facile Synthesis and First Antifungal Exploration of Tetracyclic Meroterpenoids: (+)-Aureol, (−)-Pelorol, and Its Analogs","authors":"Shengxin Sun, Xiaodan He, Juan Yang, Xia Wang and Shengkun Li*, ","doi":"10.1021/acs.jnatprod.4c00037","DOIUrl":"10.1021/acs.jnatprod.4c00037","url":null,"abstract":"<p >As an important bioactive molecular backbone, drimane meroterpenoids have drawn a great deal of attention from both pharmacologists and chemists. Inspired by the prevalidated success of conformational restriction in the discovery of novel pharmaceutical leads, two distinct tetracyclic drimane meroterpenoids, (−)-pelorol and (+)-aureol, were synthesized from the inexpensive starting material (−)-sclareol through 10 and 8 steps with 5.6% and 5.4% overall yield, respectively. The mild conditions, operational facility, and scalability enabled the expedient synthesis and biological exploration of not only natural products themselves but also their mimics. The first agrochemical exploration showed (−)-pelorol and (+)-aureol possessed good antifungal activity against <i>Rhizoctonia solani</i>, with EC<sub>50</sub> values of 7.7 and 6.9 μM, respectively. This revealed that tetracyclic drimane meroterpenoids are valuable models for antifungal lead discovery.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333860","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}
Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A–G (1–7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E–G (5–7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C–E (3–5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8–8.8 μM) with no cytotoxicity (CC50 of >200 μM).
{"title":"Acremosides A–G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species","authors":"Xiaomeng Hao, Shasha Li, Jianrui Li, Guiyang Wang, Jiao Li, Zonggen Peng* and Maoluo Gan*, ","doi":"10.1021/acs.jnatprod.4c00015","DOIUrl":"10.1021/acs.jnatprod.4c00015","url":null,"abstract":"<p >Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A–G (<b>1</b>–<b>7</b>), were isolated from the cultures of the sponge-associated fungus <i>Acremonium</i> sp. IMB18-086 cultivated with heat-killed <i>Pseudomonas aeruginosa</i>. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by <i>J</i>-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E–G (<b>5</b>–<b>7</b>) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (<b>1</b>) and C–E (<b>3</b>–<b>5</b>) showed significant inhibitory activities against hepatitis C virus (EC<sub>50</sub> values of 4.8–8.8 μM) with no cytotoxicity (CC<sub>50</sub> of >200 μM).</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333859","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}
Pub Date : 2024-04-01DOI: 10.1021/acs.jnatprod.4c00127
Meiting Wu, Daniel J. Janzen, Zhenhua Guan, Ying Ye, Yonghui Zhang and Shu-Ming Li*,
The potential of natural products as pharmaceutical and agricultural agents is based on their large structural diversity, resulting in part from modifications of the backbone structure by tailoring enzymes during biosynthesis. Flavin-dependent monooxygenases (FMOs), as one such group of enzymes, play an important role in the biosynthesis of diverse natural products, including cyclodipeptide (CDP) derivatives. The FMO PboD was shown to catalyze C-3 hydroxylation at the indole ring of cyclo-l-Trp-l-Leu in the biosynthesis of protubonines, accompanied by pyrrolidine ring formation. PboD substrate promiscuity was investigated in this study by testing its catalytic activity toward additional tryptophan-containing CDPs in vitro and biotransformation in Aspergillus nidulans transformants bearing a truncated protubonine gene cluster with pboD and two acetyltransferase genes. High acceptance of five CDPs was detected for PboD, especially of those with a second aromatic moiety. Isolation and structure elucidation of five pyrrolidine diketopiperazine products, with two new structures, proved the expected stereospecific hydroxylation and pyrrolidine ring formation. Determination of kinetic parameters revealed higher catalytic efficiency of PboD toward three CDPs consisting of aromatic amino acids than of its natural substrate cyclo-l-Trp-l-Leu. In the biotransformation experiments with the A. nidulans transformant, modest formation of hydroxylated and acetylated products was also detected.
{"title":"The Promiscuous Flavin-Dependent Monooxygenase PboD from Aspergillus ustus Increases the Structural Diversity of Hydroxylated Pyrroloindoline Diketopiperazines","authors":"Meiting Wu, Daniel J. Janzen, Zhenhua Guan, Ying Ye, Yonghui Zhang and Shu-Ming Li*, ","doi":"10.1021/acs.jnatprod.4c00127","DOIUrl":"10.1021/acs.jnatprod.4c00127","url":null,"abstract":"<p >The potential of natural products as pharmaceutical and agricultural agents is based on their large structural diversity, resulting in part from modifications of the backbone structure by tailoring enzymes during biosynthesis. Flavin-dependent monooxygenases (FMOs), as one such group of enzymes, play an important role in the biosynthesis of diverse natural products, including cyclodipeptide (CDP) derivatives. The FMO PboD was shown to catalyze C-3 hydroxylation at the indole ring of <i>cyclo</i>-<span>l</span>-Trp-<span>l</span>-Leu in the biosynthesis of protubonines, accompanied by pyrrolidine ring formation. PboD substrate promiscuity was investigated in this study by testing its catalytic activity toward additional tryptophan-containing CDPs <i>in vitro</i> and biotransformation in <i>Aspergillus nidulans</i> transformants bearing a truncated protubonine gene cluster with <i>pboD</i> and two acetyltransferase genes. High acceptance of five CDPs was detected for PboD, especially of those with a second aromatic moiety. Isolation and structure elucidation of five pyrrolidine diketopiperazine products, with two new structures, proved the expected stereospecific hydroxylation and pyrrolidine ring formation. Determination of kinetic parameters revealed higher catalytic efficiency of PboD toward three CDPs consisting of aromatic amino acids than of its natural substrate <i>cyclo</i>-<span>l</span>-Trp-<span>l</span>-Leu. In the biotransformation experiments with the <i>A. nidulans</i> transformant, modest formation of hydroxylated and acetylated products was also detected.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140333861","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}
Pub Date : 2024-03-31DOI: 10.1021/acs.jnatprod.4c00082
Kevin Seipp, Claudia Kammler, Nils Ole Rossdam, Paul Eckhardt, Anna Maria Kiefer, Gerhard Erkel and Till Opatz*,
Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV–vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.
本文首次报道了天然13-羟基-14-脱氧氧杂环十二烷二酮的全合成以及对拟议构型的修订。这种天然产物最初发现于2018年,属于氧杂环十二烷二酮家族,以其显著的抗炎和抗纤维化活性而闻名。合成路线涉及酯化/Friedel-Crafts-酰化方法,并使用了各种三醇片段。它可以制备出不同的立体异构体,包括(修正的)天然产物、两种三醇衍生物以及内环 C═C 双键的两种 Z 异构体。此外,C-13 立体中心的后期反转可将最初提出的结构转化为修正后的天然产物。有了这组完整的化合物和之前制备的 (13R,14S,15R) 异构体,我们对它们的结构特性和生物活性有了更深入的了解。利用光谱学(核磁共振、红外光谱、紫外-可见光谱)和 X 射线晶体学对最终的大内酯进行了详细分析,从而获得了新的认识,例如光学旋转对阐明其构型的重要意义以及光诱导的 E/Z 双键光异构化。在抑制细胞炎症反应的生物学实验中,这些化合物的 IC50 值非常低,这凸显了它们的药理潜力。
{"title":"Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione","authors":"Kevin Seipp, Claudia Kammler, Nils Ole Rossdam, Paul Eckhardt, Anna Maria Kiefer, Gerhard Erkel and Till Opatz*, ","doi":"10.1021/acs.jnatprod.4c00082","DOIUrl":"10.1021/acs.jnatprod.4c00082","url":null,"abstract":"<p >Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two <i>threo</i>-derivatives, and two <i>Z</i>-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13<i>R</i>,14<i>S</i>,15<i>R</i>)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV–vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced <i>E</i>/<i>Z</i> double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC<sub>50</sub> values in biological assays addressing the inhibition of cellular inflammatory responses.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329391","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}