Pub Date : 2024-11-06DOI: 10.1021/acs.jnatprod.4c00847
Andreas Wasilewicz, Alexander Areesanan, Benjamin Kirchweger, Sven Nicolay, Eva Waltenberger, Mehdi A Beniddir, Carsten Gründemann, Judith M Rollinger, Ulrike Grienke
Biochemometrics has emerged as promising strategy for the targeted identification of bioactive constituents from natural sources. It is based on the correlation of bioactivity data with chemical data to reveal constituents contributing to activity. Providing complementary data and structural information, MS- and NMR-based biochemometric approaches have both been separately applied in the past. The herein presented study is dedicated to the evaluation of a combined MS- and NMR-based biochemometric workflow for the unambiguous identification of bioactives. As an example, a flower extract of Buddleja officinalis Maxim. was selected to unravel bioactive constituents in the context of dry eye disease pathology. While NMR-based biochemometrics relies on heterocovariance analysis (HetCA) of 1H NMR spectra using the previously established ELINA approach, a biochemometric molecular network was generated for the MS-based approach. Both analyses were performed in parallel and were ultimately combined to increase their power to identify the bioactive constituents from the complex mixture. As a result, phenylethanoid glycosides and triterpene saponins were discovered as main contributors for the antioxidant and cytotoxic effects of the extract. This article illustrates the advantages, opportunities, and limitations of MS and NMR in the context of biochemometrics.
生物化学计量学已成为从天然资源中有针对性地鉴定生物活性成分的一种有前途的策略。它基于生物活性数据与化学数据的相关性,以揭示促成活性的成分。基于 MS 和 NMR 的生物化学计量方法可提供互补数据和结构信息,在过去已被分别应用。本文介绍的研究致力于对基于 MS 和 NMR 的生物化学计量工作流程进行评估,以明确鉴定生物活性成分。例如,研究人员选择了百日草花提取物来揭示干眼症病理学中的生物活性成分。基于 NMR 的生物化学计量学依赖于使用先前建立的 ELINA 方法对 1H NMR 光谱进行异方差分析 (HetCA),而基于 MS 的方法则生成了生物化学计量学分子网络。两种分析同时进行,并最终结合在一起,以提高从复杂混合物中鉴定生物活性成分的能力。结果发现,苯乙醇苷和三萜皂甙是提取物抗氧化和细胞毒性作用的主要成分。本文说明了 MS 和 NMR 在生物化学计量学方面的优势、机遇和局限性。
{"title":"Combining the Strengths of MS and NMR in Biochemometrics: A Case Study on <i>Buddleja officinalis</i>.","authors":"Andreas Wasilewicz, Alexander Areesanan, Benjamin Kirchweger, Sven Nicolay, Eva Waltenberger, Mehdi A Beniddir, Carsten Gründemann, Judith M Rollinger, Ulrike Grienke","doi":"10.1021/acs.jnatprod.4c00847","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00847","url":null,"abstract":"<p><p>Biochemometrics has emerged as promising strategy for the targeted identification of bioactive constituents from natural sources. It is based on the correlation of bioactivity data with chemical data to reveal constituents contributing to activity. Providing complementary data and structural information, MS- and NMR-based biochemometric approaches have both been separately applied in the past. The herein presented study is dedicated to the evaluation of a combined MS- and NMR-based biochemometric workflow for the unambiguous identification of bioactives. As an example, a flower extract of <i>Buddleja officinalis</i> Maxim. was selected to unravel bioactive constituents in the context of dry eye disease pathology. While NMR-based biochemometrics relies on heterocovariance analysis (HetCA) of <sup>1</sup>H NMR spectra using the previously established ELINA approach, a biochemometric molecular network was generated for the MS-based approach. Both analyses were performed in parallel and were ultimately combined to increase their power to identify the bioactive constituents from the complex mixture. As a result, phenylethanoid glycosides and triterpene saponins were discovered as main contributors for the antioxidant and cytotoxic effects of the extract. This article illustrates the advantages, opportunities, and limitations of MS and NMR in the context of biochemometrics.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580834","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}
A chemical investigation of the coral-derived fungus Talaromyces sp. TJ403-AL05 led to the isolation of 18 duclauxin analogues (1-18), 14 of which, taladuxins A-N (1-14), are new and consist of the first example of duclauxin fused with one 1,6-dioxaspiro[4.5]decan-2-one moiety (1), as well as its biosynthetic product (2), and 12 6/6/6/5/6/6/6 heptacyclic derivatives (3-14). Comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, DP4+ probability analyses, single-crystal X-ray diffraction, and vibrational circular dichroism (VCD) calculations were employed to characterize their structures and revise the published structure of verruculosin B. An efficient 1H NMR method was established to discriminate 1R and 1S configurations at C-1 of 6/6/6/5/6/6/6 heptacyclic duclauxins according to chemical shift differences of diastereotopic methylene H2-11 or H2-12 (ΔδH-11 or ΔδH-12). Compounds 4, 7-8, 13-15, and 18 exhibited moderate inhibition of Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD), with IC50 values ranging from 17.1 to 71.3 μM.
{"title":"Structurally Diverse Duclauxins from a Coral-Derived <i>Talaromyces</i> sp. and Insight into Determining the Configuration at C-1 of Heptacyclic Duclauxins by <sup>1</sup>H NMR.","authors":"Hanxiao Zeng, Yaxing Wang, Chenyang Wang, Yahui Huang, Shuang Lin, Jiangchun Wei, Weiguang Sun, Fei Cao, Yonghui Zhang, Zhengxi Hu","doi":"10.1021/acs.jnatprod.4c00709","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00709","url":null,"abstract":"<p><p>A chemical investigation of the coral-derived fungus <i>Talaromyces</i> sp. TJ403-AL05 led to the isolation of 18 duclauxin analogues (<b>1</b>-<b>18</b>), 14 of which, taladuxins A-N (<b>1</b>-<b>14</b>), are new and consist of the first example of duclauxin fused with one 1,6-dioxaspiro[4.5]decan-2-one moiety (<b>1</b>), as well as its biosynthetic product (<b>2</b>), and 12 6/6/6/5/6/6/6 heptacyclic derivatives (<b>3</b>-<b>14</b>). Comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, DP4+ probability analyses, single-crystal X-ray diffraction, and vibrational circular dichroism (VCD) calculations were employed to characterize their structures and revise the published structure of verruculosin B. An efficient <sup>1</sup>H NMR method was established to discriminate 1<i>R</i> and 1<i>S</i> configurations at C-1 of 6/6/6/5/6/6/6 heptacyclic duclauxins according to chemical shift differences of diastereotopic methylene H<sub>2</sub>-11 or H<sub>2</sub>-12 (Δδ<sub>H-11</sub> or Δδ<sub>H-12</sub>). Compounds <b>4</b>, <b>7</b>-<b>8</b>, <b>13</b>-<b>15</b>, and <b>18</b> exhibited moderate inhibition of <i>Arabidopsis thaliana</i> 4-hydroxyphenylpyruvate dioxygenase (<i>At</i>HPPD), with IC<sub>50</sub> values ranging from 17.1 to 71.3 μM.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574985","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}
Chemical investigation of the cyanobacterium Microcystis aeruginosa NIES-4285 led to the isolation of six new natural products, microginins 705 (1), 719 (2), 733A (3), 733B (4), and 733C (5), and anabaenopeptin 885 (7), and three known compounds, anabaenopeptins 871 (6), B (8), and F (9). Planar structures and absolute configurations for 1-7 were determined by 2D NMR, HRMS, and Marfey's analyses. Microginin 733C (5), and anabaenopeptins 871 (6) and 885 (7) contained a unique residue of 2-amino-5-(4-hydroxyphenyl)pentanoic acid (Ahppa): doubly homologated tyrosine (di-hTyr). The biosynthetic origin of this nonproteinogenic amino acid di-hTyr was investigated, and it was found that MaHphABCDE are involved in the production of di-hTyr. In addition, biochemical characterization of aminotransferase MaHphE showed that it is a promiscuous enzyme. This result expanded the biocatalytic toolbox for amino acid homologation.
{"title":"Doubly Homologated Tyrosine-Containing Peptides from the Cyanobacterium <i>Microcystis aeruginosa</i> NIES-4285 and Their Biosynthesis.","authors":"Chin-Soon Phan, Zhengyi Ling, Jakia Jerin Mehjabin, Kenichi Matsuda, Nurcahyo Iman Prakoso, Taiki Umezawa, Toshiyuki Wakimoto, Tatsufumi Okino","doi":"10.1021/acs.jnatprod.4c00972","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00972","url":null,"abstract":"<p><p>Chemical investigation of the cyanobacterium <i>Microcystis aeruginosa</i> NIES-4285 led to the isolation of six new natural products, microginins 705 (<b>1</b>), 719 (<b>2</b>), 733A (<b>3</b>), 733B (<b>4</b>), and 733C (<b>5</b>), and anabaenopeptin 885 (<b>7</b>), and three known compounds, anabaenopeptins 871 (<b>6</b>), B (<b>8</b>), and F (<b>9</b>). Planar structures and absolute configurations for <b>1</b>-<b>7</b> were determined by 2D NMR, HRMS, and Marfey's analyses. Microginin 733C (<b>5</b>), and anabaenopeptins 871 (<b>6</b>) and 885 (<b>7</b>) contained a unique residue of 2-amino-5-(4-hydroxyphenyl)pentanoic acid (Ahppa): doubly homologated tyrosine (di-hTyr). The biosynthetic origin of this nonproteinogenic amino acid di-hTyr was investigated, and it was found that MaHphABCDE are involved in the production of di-hTyr. In addition, biochemical characterization of aminotransferase MaHphE showed that it is a promiscuous enzyme. This result expanded the biocatalytic toolbox for amino acid homologation.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542874","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 : 2024-10-29DOI: 10.1021/acs.jnatprod.4c00439
James G Graham, Jonathan Bisson, Guy H Harris, Zaijie Jim Wang, Donald P Waller, Guido F Pauli
Natural products (NPs) continue to inform the discovery and development of a diversity of drugs, both marketed and investigational. Pain, one of the most common of human experiences and profound challenges in medicine and biology, has emerged at the core of an urgent societal problem, in the United States and globally. The present study employs a retrospective analysis of an extensive set of published literature curated in the NAPRALERT database to identify NPs with experimental evidence of bioactivity supporting the selection and prioritization of NP leads with promise in pain management. The NAPRALERT pain data set currently documents >38,000 pain-relevant experiments reported in >1,750 distinct journals. The evidence presented here was annotated from >10,000 distinct scientific publications identifying NP extracts and isolates with experimental biological data indicating positive mitigation of pain, inflammation, and/or modulation of nociceptive signaling targets. Correlation of ethnomedical uses with experimental data represents a value-added approach to the selection and prioritization of leads. Dissemination of this unique NP/pain data set, with experimental data and information applicable to basic, translational, and clinical science stakeholders alike, furnishes practical evidence in support of a rational selection of NPs for directed pain research. A large portion of the NAPRALERT pain-relevant data set, along with a set of query tools designed to assist user-directed selection and prioritization of leads, are presented as Supporting Information in order to mitigate the limitations inherent in presenting such a large data set in (print) format. To support user efforts, this report involves explication of NAPRALERT data organization and the articulation of rational approaches to user-guided selection of evidence-based NP leads.
{"title":"Natural Products with Potential for the Treatment of Pain: Global Evidence from the NAPRALERT Database.","authors":"James G Graham, Jonathan Bisson, Guy H Harris, Zaijie Jim Wang, Donald P Waller, Guido F Pauli","doi":"10.1021/acs.jnatprod.4c00439","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00439","url":null,"abstract":"<p><p>Natural products (NPs) continue to inform the discovery and development of a diversity of drugs, both marketed and investigational. Pain, one of the most common of human experiences and profound challenges in medicine and biology, has emerged at the core of an urgent societal problem, in the United States and globally. The present study employs a retrospective analysis of an extensive set of published literature curated in the NAPRALERT database to identify NPs with experimental evidence of bioactivity supporting the selection and prioritization of NP leads with promise in pain management. The NAPRALERT pain data set currently documents >38,000 pain-relevant experiments reported in >1,750 distinct journals. The evidence presented here was annotated from >10,000 distinct scientific publications identifying NP extracts and isolates with experimental biological data indicating positive mitigation of pain, inflammation, and/or modulation of nociceptive signaling targets. Correlation of ethnomedical uses with experimental data represents a value-added approach to the selection and prioritization of leads. Dissemination of this unique NP/pain data set, with experimental data and information applicable to basic, translational, and clinical science stakeholders alike, furnishes practical evidence in support of a rational selection of NPs for directed pain research. A large portion of the NAPRALERT pain-relevant data set, along with a set of query tools designed to assist user-directed selection and prioritization of leads, are presented as Supporting Information in order to mitigate the limitations inherent in presenting such a large data set in (print) format. To support user efforts, this report involves explication of NAPRALERT data organization and the articulation of rational approaches to user-guided selection of evidence-based NP leads.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520342","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}
We have achieved the divergent total synthesis of nine isoflavone natural products 1-9 starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of 1-9 was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of 1-9 as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F (3) showed the best efficacy in ex vivo competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F (3) is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.
我们以市售的 2,4,6-三羟基苯乙酮为起始原料,实现了九种异黄酮天然产物 1-9 的发散全合成。1-9 的异黄酮骨架是通过关键的铃木-宫浦偶联反应构建的。对 1-9 作为治疗转甲状腺素(TTR)淀粉样变性病的潜在药物的研究表明,在体内外竞争性结合实验和硫黄素-T 荧光研究中,米力铂 F (3) 的疗效最好。因此,millexatin F (3) 有希望成为新型 TTR 淀粉样变性治疗药物的种子化合物。
{"title":"Divergent Total Synthesis of Isoflavone Natural Products and Their Potential as Therapeutic Agents for TTR Amyloidosis.","authors":"Nguyen Ngoc Thanh Luan, Takuya Okada, Takeshi Yokoyama, Mie Suzuki, Yuko Nabeshima, Mineyuki Mizuguchi, Naoki Toyooka","doi":"10.1021/acs.jnatprod.4c00812","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00812","url":null,"abstract":"<p><p>We have achieved the divergent total synthesis of nine isoflavone natural products <b>1</b>-<b>9</b> starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of <b>1</b>-<b>9</b> was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of <b>1</b>-<b>9</b> as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F (<b>3</b>) showed the best efficacy in <i>ex vivo</i> competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F (<b>3</b>) is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491140","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 : 2024-10-26DOI: 10.1021/acs.jnatprod.4c00751
Fadime Aydoğan, Pankaj Pandey, Frank R Fronczek, Daneel Ferreira, Ikhlas A Khan, Zulfiqar Ali, Amar G Chittiboyina
The phytochemical investigation of the MeOH extract of Astragalus condensatus roots led to the discovery of a new tetrahydropyran cycloartane-type triterpenoid, astracondensatol A (1), alongside six known cyclocephagenol derivatives (2, 3, 20, 32, 35, and 36). Elucidation of their structures involved 1D and 2D-NMR spectroscopy and mass data analysis. Upon comparing NMR spectroscopic data with prior literature, several carbon shift anomalies, particularly at C-24, prompted a reevaluation using quantum chemical calculations, resulting in the revision of the 24S to 24R absolute configuration for compound 2 and 38 other reported cyclocephagenol-type triterpenoids. X-ray crystallography data further supported the analysis in establishing the absolute configuration of compound 2. Ambiguous NOE correlations and publication bias could have played a significant role in miss-assigning the C-24 absolute configuration in tetrahydropyran cycloartane-type triterpenoids.
{"title":"Revisiting the Cyclocephagenols via <i>Astragalus condensatus</i>: Structural Insights and Configurational Revision.","authors":"Fadime Aydoğan, Pankaj Pandey, Frank R Fronczek, Daneel Ferreira, Ikhlas A Khan, Zulfiqar Ali, Amar G Chittiboyina","doi":"10.1021/acs.jnatprod.4c00751","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00751","url":null,"abstract":"<p><p>The phytochemical investigation of the MeOH extract of <i>Astragalus condensatus</i> roots led to the discovery of a new tetrahydropyran cycloartane-type triterpenoid, astracondensatol A (<b>1</b>), alongside six known cyclocephagenol derivatives (<b>2</b>, <b>3</b>, <b>20</b>, <b>32</b>, <b>35</b>, and <b>36</b>). Elucidation of their structures involved 1D and 2D-NMR spectroscopy and mass data analysis. Upon comparing NMR spectroscopic data with prior literature, several carbon shift anomalies, particularly at C-24, prompted a reevaluation using quantum chemical calculations, resulting in the revision of the 24<i>S</i> to 24<i>R</i> absolute configuration for compound <b>2</b> and 38 other reported cyclocephagenol-type triterpenoids. X-ray crystallography data further supported the analysis in establishing the absolute configuration of compound <b>2</b>. Ambiguous NOE correlations and publication bias could have played a significant role in miss-assigning the C-24 absolute configuration in tetrahydropyran cycloartane-type triterpenoids.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491142","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 : 2024-10-25Epub Date: 2024-10-11DOI: 10.1021/acs.jnatprod.4c00676
Mervic D Kagho, Katharina Schmidt, Christopher Lambert, Thomas Kaufmann, Lili Jia, Jan Faix, Klemens Rottner, Marc Stadler, Theresia Stradal, Philipp Klahn
In search of a more comprehensive structure-activity relationship (SAR) regarding the inhibitory effect of cytochalasin B (2) on actin polymerization, a virtual docking of 2 onto monomeric actin was conducted. This led to the identification of potentially important functional groups of 2 (i.e., the NH group of the isoindolone core (N-2) and the hydroxy groups at C-7 and C-20) involved in interactions with the residual amino acids of the binding pocket of actin. Chemical modifications of 2 at positions C-7, N-2, and C-20 led to derivatives 3-6, which were analyzed for their bioactivities. Compounds 3-5 exhibited reduced or no cytotoxicity in murine L929 fibroblasts compared to that of 2. Moreover, short- and long-term treatments of human osteosarcoma cells (U-2OS) with 3-6 affected the actin network to a variable extent, partially accompanied by the induction of multinucleation. Derivatives displaying acetylation at C-20 and N-2 were subjected to slow intracellular conversion to highly cytotoxic 2. Together, this study highlights the importance of the hydroxy group at C-7 and the NH function at N-2 for the potency of 2 on the inhibition of actin polymerization.
{"title":"Comprehensive Cell Biological Investigation of Cytochalasin B Derivatives with Distinct Activities on the Actin Network.","authors":"Mervic D Kagho, Katharina Schmidt, Christopher Lambert, Thomas Kaufmann, Lili Jia, Jan Faix, Klemens Rottner, Marc Stadler, Theresia Stradal, Philipp Klahn","doi":"10.1021/acs.jnatprod.4c00676","DOIUrl":"10.1021/acs.jnatprod.4c00676","url":null,"abstract":"<p><p>In search of a more comprehensive structure-activity relationship (SAR) regarding the inhibitory effect of cytochalasin B (<b>2</b>) on actin polymerization, a virtual docking of <b>2</b> onto monomeric actin was conducted. This led to the identification of potentially important functional groups of <b>2</b> (i.e., the NH group of the isoindolone core (N-2) and the hydroxy groups at C-7 and C-20) involved in interactions with the residual amino acids of the binding pocket of actin. Chemical modifications of <b>2</b> at positions C-7, N-2, and C-20 led to derivatives <b>3</b>-<b>6</b>, which were analyzed for their bioactivities. Compounds <b>3</b>-<b>5</b> exhibited reduced or no cytotoxicity in murine L929 fibroblasts compared to that of <b>2</b>. Moreover, short- and long-term treatments of human osteosarcoma cells (U-2OS) with <b>3</b>-<b>6</b> affected the actin network to a variable extent, partially accompanied by the induction of multinucleation. Derivatives displaying acetylation at C-20 and N-2 were subjected to slow intracellular conversion to highly cytotoxic <b>2</b>. Together, this study highlights the importance of the hydroxy group at C-7 and the NH function at N-2 for the potency of <b>2</b> on the inhibition of actin polymerization.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398715","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 : 2024-10-25Epub Date: 2024-10-09DOI: 10.1021/acs.jnatprod.4c00782
Shu-Shuai Chen, Yuan Gao, Li Chen, Xiao Tong, Pei-Qian Wu, Yi Huang, Shi-Jun He, Jian-Min Yue, Bin Zhou
Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus Penicillium bialowiezense ZBWPQ-27 that was isolated from a medicinal plant Euphorbia neriifolia, leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems (1-6 and 9-17), and two new carotane sesquiterpenoids (7 and 8). The structures including absolute configurations of the new compounds 1-8 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes (9-15) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound 11 displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC50 4.1 ± 0.2 μM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC50 4.6 ± 0.2 μM), with good SI values of 28 ± 2 and 25 ± 4, respectively.
{"title":"Immunosuppressive Breviane Spiroditerpenoids from <i>Penicillium bialowiezense</i> Isolated from a Medicinal Plant.","authors":"Shu-Shuai Chen, Yuan Gao, Li Chen, Xiao Tong, Pei-Qian Wu, Yi Huang, Shi-Jun He, Jian-Min Yue, Bin Zhou","doi":"10.1021/acs.jnatprod.4c00782","DOIUrl":"10.1021/acs.jnatprod.4c00782","url":null,"abstract":"<p><p>Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus <i>Penicillium bialowiezense</i> ZBWPQ-27 that was isolated from a medicinal plant <i>Euphorbia neriifolia</i>, leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems (<b>1</b>-<b>6</b> and <b>9</b>-<b>17</b>), and two new carotane sesquiterpenoids (<b>7</b> and <b>8</b>). The structures including absolute configurations of the new compounds <b>1</b>-<b>8</b> were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes (<b>9</b>-<b>15</b>) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound <b>11</b> displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC<sub>50</sub> 4.1 ± 0.2 μM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC<sub>50</sub> 4.6 ± 0.2 μM), with good SI values of 28 ± 2 and 25 ± 4, respectively.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386401","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 : 2024-10-25Epub Date: 2024-10-04DOI: 10.1021/acs.jnatprod.4c00973
Louisa Tham, Brodie W Bulcock, Samuele Sala, Gareth L Nealon, Gavin R Flematti, Stephen A Moggach, Matthew J Piggott
The marine alkaloid erebusinone is a secondary metabolite isolated from the Antarctic sponge Isodictya erinacea. Initial biological assays have shown that erebusinone increases amphipod mortality, probably by inhibition of the biosynthesis of molting hormone (ecdysone). Herein, we report the first total synthesis of the proposed structure of erebusinone and a structural revision.
{"title":"Total Synthesis and Structural Reassignment of the Molt-Inhibiting Marine Alkaloid Erebusinone.","authors":"Louisa Tham, Brodie W Bulcock, Samuele Sala, Gareth L Nealon, Gavin R Flematti, Stephen A Moggach, Matthew J Piggott","doi":"10.1021/acs.jnatprod.4c00973","DOIUrl":"10.1021/acs.jnatprod.4c00973","url":null,"abstract":"<p><p>The marine alkaloid erebusinone is a secondary metabolite isolated from the Antarctic sponge <i>Isodictya erinacea</i>. Initial biological assays have shown that erebusinone increases amphipod mortality, probably by inhibition of the biosynthesis of molting hormone (ecdysone). Herein, we report the first total synthesis of the proposed structure of erebusinone and a structural revision.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374703","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}
Fourteen previously undescribed sesterterpenoids (1-14) were isolated from Bipolaris maydis. Their structures with absolute configurations were elucidated by NMR, HRESIMS, DP4+ calculations, ECD calculations, single-crystal X-ray diffraction analyses, and the modified Mosher's method. Compounds 1-5 possess an uncommon 5/11 bicyclic ring system identified from B. maydis for the first time. Compounds 6-14 have a 5/8/5 tricyclic ring system, and these compounds both possess carbonyl groups in ring A. Compound 10 showed significant reversal of paclitaxel resistance in cancer cells.
{"title":"Maydisens, Sesterterpenoids with Anti-MDR Activity from <i>Bipolaris maydis</i>.","authors":"Yong Shen, Nanjin Ding, Lianghu Gu, Mengru Yu, Qin Li, Weiguang Sun, Chunmei Chen, Yonghui Zhang, Hucheng Zhu","doi":"10.1021/acs.jnatprod.4c00658","DOIUrl":"10.1021/acs.jnatprod.4c00658","url":null,"abstract":"<p><p>Fourteen previously undescribed sesterterpenoids (<b>1</b>-<b>14</b>) were isolated from <i>Bipolaris maydis</i>. Their structures with absolute configurations were elucidated by NMR, HRESIMS, DP4+ calculations, ECD calculations, single-crystal X-ray diffraction analyses, and the modified Mosher's method. Compounds <b>1</b>-<b>5</b> possess an uncommon 5/11 bicyclic ring system identified from <i>B. maydis</i> for the first time. Compounds <b>6</b>-<b>14</b> have a 5/8/5 tricyclic ring system, and these compounds both possess carbonyl groups in ring A. Compound <b>10</b> showed significant reversal of paclitaxel resistance in cancer cells.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363452","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}