Twelve previously undescribed ophiobolin-type sesterterpenoids, undobolins A-L (1-12), were isolated from Aspergillus undulatus, and their structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction experiments. Compound 1 was the second example of 20-nor-ophiobolin reported, while compounds 2-6 were notable for oxygenation of C-2, and compound 6 showed significant inhibitory activity against ConA-induced T lymphocyte proliferation with an IC50 value of 2.3 μM, which suggests a promising new direction in the quest for immunosuppressive agents.
通过光谱分析、ECD 计算和单晶 X 射线衍射实验阐明了它们的结构。化合物 1 是第二个被报道的 20-去甲硫代异丁烯的例子,而化合物 2-6 的显著特点是 C-2 的含氧,化合物 6 对 ConA 诱导的 T 淋巴细胞增殖具有显著的抑制活性,IC50 值为 2.3 μM,这为寻找免疫抑制剂提供了新的方向。
{"title":"Undobolins A-L, Ophiobolin-Type Sesterterpenoids from <i>Aspergillus undulatus</i>.","authors":"Yuyi Zheng, Qin Li, Minglang Gu, Hong Liao, Yu Liang, Fei Liu, Xiao-Nian Li, Weiguang Sun, Chunmei Chen, Yonghui Zhang, Hucheng Zhu","doi":"10.1021/acs.jnatprod.4c00385","DOIUrl":"10.1021/acs.jnatprod.4c00385","url":null,"abstract":"<p><p>Twelve previously undescribed ophiobolin-type sesterterpenoids, undobolins A-L (<b>1</b>-<b>12</b>), were isolated from <i>Aspergillus undulatus</i>, and their structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction experiments. Compound <b>1</b> was the second example of 20-nor-ophiobolin reported, while compounds <b>2</b>-<b>6</b> were notable for oxygenation of C-2, and compound <b>6</b> showed significant inhibitory activity against ConA-induced T lymphocyte proliferation with an IC<sub>50</sub> value of 2.3 μM, which suggests a promising new direction in the quest for immunosuppressive agents.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755614","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}
Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.
{"title":"Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/β-Catenin in Colon Cancer Cells.","authors":"Yu Zou, Yuying He, Lijuan Tan, Xiaofei Xu, Changxing Qi, Yonghui Zhang","doi":"10.1021/acs.jnatprod.4c00084","DOIUrl":"10.1021/acs.jnatprod.4c00084","url":null,"abstract":"<p><p>Piperlongumine (<b>1</b>) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive <i>N</i>-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (<b>2</b>-<b>5</b>) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound <b>6</b>, structurally similar to compounds <b>2</b>-<b>5</b> but not releasing NO, served as a control. Among these derivatives, compound <b>5</b> exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound <b>5</b> inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound <b>5</b> as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750499","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 : 2024-08-23Epub Date: 2024-08-12DOI: 10.1021/acs.jnatprod.4c00675
Brodie W Bulcock, Rachel Chen, Ernest Lacey, Yit-Heng Chooi, Gavin R Flematti
Tertiary and allylic hydroxyl groups readily eliminate water during positive ion mode mass spectrometry and may show similar NMR spectra to their corresponding ethers. In a routine structure elucidation workflow, these factors can cause researchers to incorrectly assign diol moieties as ethers or vice versa, leading to inaccurate chemical structures. After facing this problem during our work on oxygenated sesquiterpenoids from a Fusarium sp. fungal strain, we became aware of this challenging issue. We examined the literature for oxygenated natural products bearing these functional groups, and with the aid of density functional calculations of NMR chemical shifts, we now report the structures of 15 natural products that should be revised. We further establish that derivatizing sub-micromolar amounts of alcohols to their sulfates can be used to distinguish these from their corresponding ethers using liquid chromatography negative ion mode mass spectrometry. Finally, we isolated lignoren/cyclonerodiol from the Fusarium sp. culture extract and supported its revised identity as cyclonerodiol using this sulfation approach. Our results suggest that ether-diol ambiguity could be a prevalent issue affecting the structure elucidation of oxygenated natural products and highlight the importance of using complementary techniques, such as sulfation with LC-(-)-ESI-MS or density functional calculations of NMR chemical shifts.
{"title":"Ether-Diol Ambiguity: An Inconspicuous Issue in the Structure Elucidation of Oxygenated Natural Products.","authors":"Brodie W Bulcock, Rachel Chen, Ernest Lacey, Yit-Heng Chooi, Gavin R Flematti","doi":"10.1021/acs.jnatprod.4c00675","DOIUrl":"10.1021/acs.jnatprod.4c00675","url":null,"abstract":"<p><p>Tertiary and allylic hydroxyl groups readily eliminate water during positive ion mode mass spectrometry and may show similar NMR spectra to their corresponding ethers. In a routine structure elucidation workflow, these factors can cause researchers to incorrectly assign diol moieties as ethers or vice versa, leading to inaccurate chemical structures. After facing this problem during our work on oxygenated sesquiterpenoids from a <i>Fusarium</i> sp. fungal strain, we became aware of this challenging issue. We examined the literature for oxygenated natural products bearing these functional groups, and with the aid of density functional calculations of NMR chemical shifts, we now report the structures of 15 natural products that should be revised. We further establish that derivatizing sub-micromolar amounts of alcohols to their sulfates can be used to distinguish these from their corresponding ethers using liquid chromatography negative ion mode mass spectrometry. Finally, we isolated lignoren/cyclonerodiol from the <i>Fusarium</i> sp. culture extract and supported its revised identity as cyclonerodiol using this sulfation approach. Our results suggest that ether-diol ambiguity could be a prevalent issue affecting the structure elucidation of oxygenated natural products and highlight the importance of using complementary techniques, such as sulfation with LC-(-)-ESI-MS or density functional calculations of NMR chemical shifts.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915472","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 : 2024-08-23Epub Date: 2024-07-22DOI: 10.1021/acs.jnatprod.4c00304
Quentin Dutertre, Philippe A Guy, Sylvain Sutour, Manuel C Peitsch, Nikolai V Ivanov, Gaetan Glauser, Stephan von Reuss
The Solanaceae plant family contains at least 98 genera and over 2700 species. The Duboisia genus stands out for its ability to produce pyridine and tropane alkaloids, which are relatively poorly characterized at the phytochemical level. In this study, we analyzed dried leaves of Duboisia spp. using supercritical CO2 extraction and ultra-high-pressure liquid chromatography coupled to high-resolution tandem mass spectrometry, followed by feature-based molecular networking. Thirty-one known tropane alkaloids were putatively annotated, and the identity of six (atropine, scopolamine, anisodamine, aposcopolamine, apoatropine, and noratropine) were identified using reference standards. Two new granatane alkaloids connected in the molecular network were highlighted from Duboisia myoporoides, and their α-granatane tropate and α-granatane isovalerate structures were unambiguously established by semisynthesis.
{"title":"Identification of Granatane Alkaloids from <i>Duboisia myoporoides</i> (Solanaceae) using Molecular Networking and Semisynthesis.","authors":"Quentin Dutertre, Philippe A Guy, Sylvain Sutour, Manuel C Peitsch, Nikolai V Ivanov, Gaetan Glauser, Stephan von Reuss","doi":"10.1021/acs.jnatprod.4c00304","DOIUrl":"10.1021/acs.jnatprod.4c00304","url":null,"abstract":"<p><p>The Solanaceae plant family contains at least 98 genera and over 2700 species. The <i>Duboisia</i> genus stands out for its ability to produce pyridine and tropane alkaloids, which are relatively poorly characterized at the phytochemical level. In this study, we analyzed dried leaves of <i>Duboisia spp.</i> using supercritical CO<sub>2</sub> extraction and ultra-high-pressure liquid chromatography coupled to high-resolution tandem mass spectrometry, followed by feature-based molecular networking. Thirty-one known tropane alkaloids were putatively annotated, and the identity of six (atropine, scopolamine, anisodamine, aposcopolamine, apoatropine, and noratropine) were identified using reference standards. Two new granatane alkaloids connected in the molecular network were highlighted from <i>Duboisia myoporoides</i>, and their α-granatane tropate and α-granatane isovalerate structures were unambiguously established by semisynthesis.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746771","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 : 2024-08-20DOI: 10.1021/acs.jnatprod.4c0077710.1021/acs.jnatprod.4c00777
Yong-Ying Han, Weiguang Yang, Ping Lan, Zeinab G. Khalil, Robert J. Capon and Martin G. Banwell*,
The revised structure, 2, assigned to the title natural product has been prepared by chemical synthesis using a reaction sequence involving six simple steps starting from 2,3-dimethoxybenzaldehyde and proceeding via intermediates 8, 12, and 14. A comparison of the NMR data acquired on synthetically derived compound 2 with those reported for the natural product reveals an excellent match. Preliminary biological screening of compound 2 along with analogues/precursors 7, 9, 10, 11, 13, 14, and 15 revealed that none exhibited antibacterial, antifungal or cytotoxic effects.
{"title":"Synthesis of the Corrected Structure Assigned to Clonorosin B, an Alkaloid Obtained from the Soil-derived Fungus Clonostachys rosea YRS-06","authors":"Yong-Ying Han, Weiguang Yang, Ping Lan, Zeinab G. Khalil, Robert J. Capon and Martin G. Banwell*, ","doi":"10.1021/acs.jnatprod.4c0077710.1021/acs.jnatprod.4c00777","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00777https://doi.org/10.1021/acs.jnatprod.4c00777","url":null,"abstract":"<p >The revised structure, <b>2</b>, assigned to the title natural product has been prepared by chemical synthesis using a reaction sequence involving six simple steps starting from 2,3-dimethoxybenzaldehyde and proceeding via intermediates <b>8</b>, <b>12</b>, and <b>14</b>. A comparison of the NMR data acquired on synthetically derived compound <b>2</b> with those reported for the natural product reveals an excellent match. Preliminary biological screening of compound <b>2</b> along with analogues/precursors <b>7</b>, <b>9</b>, <b>10</b>, <b>11</b>, <b>13</b>, <b>14</b>, and <b>15</b> revealed that none exhibited antibacterial, antifungal or cytotoxic effects.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326082","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 : 2024-08-19DOI: 10.1021/acs.jnatprod.4c00471
Yijing Song, Min Li, You Li, Tianyi Zhang, Jiawei Zhang, Dan Han, Fuzhi Lian, Xuqing Liu, Xuexian Fang
Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.
{"title":"Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.","authors":"Yijing Song, Min Li, You Li, Tianyi Zhang, Jiawei Zhang, Dan Han, Fuzhi Lian, Xuqing Liu, Xuexian Fang","doi":"10.1021/acs.jnatprod.4c00471","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00471","url":null,"abstract":"<p><p>Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO<sub>2</sub>, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002988","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 : 2024-08-16DOI: 10.1021/acs.jnatprod.4c0051610.1021/acs.jnatprod.4c00516
Marcelo R. de Amorim*, Sydney M. Schoellhorn, Camila de S. Barbosa, Giovana R. Mendes, Kamila de L. Macedo, Antonio G. Ferreira, Tiago Venâncio, Rafael V. C. Guido, Andrea N. L. Batista, João M. Batista Jr., Elizabeth Skellam* and Roberto G. S. Berlinck*,
Novel open-chain merocytochalasans, perochalasins A–C (1–3), containing an unusual N–O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived Peroneutypa sp. M16 fungus, along with cytochalasin Z27 (4), cytochalasin Z28 (5), [12]-cytochalasin (6), and phenochalasin B (7). The structures of compounds 1–3 were established by analysis of the spectroscopic data. Full genome sequencing of Peroneutypa sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B (7) into 1–3, based on isotope-labeled hydroxylamine (15NH2OH and ND2OD) feeding studies in vivo and in vitro. In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z27 (4) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive Plasmodium falciparum 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).
{"title":"Structure and Biosynthesis of Perochalasins A–C, Open-Chain Merocytochalasans Produced by the Marine-Derived Fungus Peroneutypa sp. M16","authors":"Marcelo R. de Amorim*, Sydney M. Schoellhorn, Camila de S. Barbosa, Giovana R. Mendes, Kamila de L. Macedo, Antonio G. Ferreira, Tiago Venâncio, Rafael V. C. Guido, Andrea N. L. Batista, João M. Batista Jr., Elizabeth Skellam* and Roberto G. S. Berlinck*, ","doi":"10.1021/acs.jnatprod.4c0051610.1021/acs.jnatprod.4c00516","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00516https://doi.org/10.1021/acs.jnatprod.4c00516","url":null,"abstract":"<p >Novel open-chain merocytochalasans, perochalasins A–C (<b>1</b>–<b>3</b>), containing an unusual N–O six-membered heterocyclic moiety, were isolated from cultures of the marine-derived <i>Peroneutypa</i> sp. M16 fungus, along with cytochalasin Z<sub>27</sub> (<b>4</b>), cytochalasin Z<sub>28</sub> (<b>5</b>), [12]-cytochalasin (<b>6</b>), and phenochalasin B (<b>7</b>). The structures of compounds <b>1</b>–<b>3</b> were established by analysis of the spectroscopic data. Full genome sequencing of <i>Peroneutypa</i> sp. M16 enabled the identification of a cytochalasan biosynthetic gene cluster and a proposal for the biosynthetic assembly of perochalasins. The proposal is supported by the nonenzymatic conversion of phenochalasin B (<b>7</b>) into <b>1</b>–<b>3</b>, based on isotope-labeled hydroxylamine (<sup>15</sup>NH<sub>2</sub>OH and ND<sub>2</sub>OD) feeding studies <i>in vivo</i> and <i>in vitro</i>. In contrast to other merocytochalasans, these are the first cytochalasans confirmed to arise via nucleophilic addition and at a distinct location from the reactive macrocycle olefin, potentially expanding further the range of merocytochalasans to be discovered or engineered. Cytochalasin Z<sub>27</sub> (<b>4</b>) exhibited antiplasmodial activities in the low micromolar range against the chloroquine-sensitive <i>Plasmodium falciparum</i> 3D7 strain as well as against resistant strains of the parasite (Dd2, TM90C6B, and 3D7r_MMV848).</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jnatprod.4c00516","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326060","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 : 2024-08-15DOI: 10.1021/acs.jnatprod.4c0073310.1021/acs.jnatprod.4c00733
Kensuke Irie, Ghulam Jeelani, Tomoyoshi Nozaki and Arihiro Iwasaki*,
Pemuchiamides A and B (1 and 2) were isolated from a marine Hormoscilla sp. cyanobacterium collected from Pemuchi Beach on Hateruma Island, Japan. Although 1 and 2 existed as a complex mixture of rotamers in chloroform-d, detailed analyses of their 2D NMR and tandem mass spectra revealed their planar structures, respectively. The absolute configurations of 1 and 2 were established via the degradation and derivatization reactions. Pemuchiamide A (1) exhibited potent growth-inhibitory activity against Trypanosoma brucei rhodesiense, the causative organism of African sleeping sickness, while 2 showed 10-fold weaker activity than 1. This result indicates that the presence of a hydroxy group at the C-3 position of the 4-aminobutanoic acid moiety negatively affects antitrypanosomal activity.
{"title":"Pemuchiamides A and B, Proline-Rich Linear Lipopeptides, Isolated from a Marine Hormoscilla sp. Cyanobacterium","authors":"Kensuke Irie, Ghulam Jeelani, Tomoyoshi Nozaki and Arihiro Iwasaki*, ","doi":"10.1021/acs.jnatprod.4c0073310.1021/acs.jnatprod.4c00733","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00733https://doi.org/10.1021/acs.jnatprod.4c00733","url":null,"abstract":"<p >Pemuchiamides A and B (<b>1</b> and <b>2</b>) were isolated from a marine <i>Hormoscilla</i> sp. cyanobacterium collected from Pemuchi Beach on Hateruma Island, Japan. Although <b>1</b> and <b>2</b> existed as a complex mixture of rotamers in chloroform-<i>d</i>, detailed analyses of their 2D NMR and tandem mass spectra revealed their planar structures, respectively. The absolute configurations of <b>1</b> and <b>2</b> were established via the degradation and derivatization reactions. Pemuchiamide A (<b>1</b>) exhibited potent growth-inhibitory activity against <i>Trypanosoma brucei rhodesiense</i>, the causative organism of African sleeping sickness, while <b>2</b> showed 10-fold weaker activity than <b>1</b>. This result indicates that the presence of a hydroxy group at the C-3 position of the 4-aminobutanoic acid moiety negatively affects antitrypanosomal activity.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325963","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 : 2024-08-14DOI: 10.1021/acs.jnatprod.4c0047710.1021/acs.jnatprod.4c00477
Sarath P. D. Senadeera, Dongdong Wang, Brice A. P. Wilson, Emily A. Smith, Antony Wamiru, Juliana A. Martinez Fiesco, Lin Du, Ping Zhang, Barry R. O’Keefe and John A. Beutler*,
A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (1), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N-methylated derivatives acroamines A1–A5 (2–6) were semisynthesized. Three additional brominated congeners A6-A8 (7–9) were also semisynthesized to investigate the structure–activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1–9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (1) and its brominated analogs (7–9) achieving moderate potency (IC50 2–50 μM) while none of the N-methylated analogs exhibited kinase inhibition.
{"title":"Acroamine A, a 2-Amino Adenine Alkaloid from the Marine Soft Coral Acrozoanthus australiae and Its Semisynthetic Derivatives That Inhibit cAMP-Dependent Protein Kinase A Catalytic Subunit Alpha","authors":"Sarath P. D. Senadeera, Dongdong Wang, Brice A. P. Wilson, Emily A. Smith, Antony Wamiru, Juliana A. Martinez Fiesco, Lin Du, Ping Zhang, Barry R. O’Keefe and John A. Beutler*, ","doi":"10.1021/acs.jnatprod.4c0047710.1021/acs.jnatprod.4c00477","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00477https://doi.org/10.1021/acs.jnatprod.4c00477","url":null,"abstract":"<p >A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral <i>Acrozoanthus australiae</i> as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (<b>1</b>), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five <i>N</i>-methylated derivatives acroamines A<sub>1</sub>–A<sub>5</sub> (<b>2</b>–<b>6</b>) were semisynthesized. Three additional brominated congeners A<sub>6</sub>-A<sub>8</sub> (<b>7</b>–<b>9</b>) were also semisynthesized to investigate the structure–activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds <b>1</b>–<b>9</b> were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (<b>1</b>) and its brominated analogs (<b>7</b>–<b>9</b>) achieving moderate potency (IC<sub>50</sub> 2–50 μM) while none of the <i>N</i>-methylated analogs exhibited kinase inhibition.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039300","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 : 2024-08-14DOI: 10.1021/acs.jnatprod.4c0033410.1021/acs.jnatprod.4c00334
Lin-Lin Gao, Yu-Qi Gao, Wu-Yang Liu, Marc Stadler, Yue-Tong Zhu, Jian-Zhao Qi, Wen-Bo Han* and Jin-Ming Gao*,
Eighteen nitrogen-containing compounds (1–18) were isolated from cultures of the lichen-associated Streptomyces flavidovirens collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A–C (2–4), two new furan pyrrolidones (8–9), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound 3, exhibited significantly better antineuroinflammatory activity than other isolated compounds (8–18). Compound 3 inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE2, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that 3 inhibited LPS-stimulated ROS generation. These findings suggested that compound 3 might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.
{"title":"Evaluation of Phenazine Derivatives from the Lichen-Associated Streptomyces flavidovirens as Potent Antineuroinflammatory Agents In Vitro and In Vivo","authors":"Lin-Lin Gao, Yu-Qi Gao, Wu-Yang Liu, Marc Stadler, Yue-Tong Zhu, Jian-Zhao Qi, Wen-Bo Han* and Jin-Ming Gao*, ","doi":"10.1021/acs.jnatprod.4c0033410.1021/acs.jnatprod.4c00334","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00334https://doi.org/10.1021/acs.jnatprod.4c00334","url":null,"abstract":"<p >Eighteen nitrogen-containing compounds (<b>1</b>–<b>18</b>) were isolated from cultures of the lichen-associated <i>Streptomyces flavidovirens</i> collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A–C (<b>2</b>–<b>4</b>), two new furan pyrrolidones (<b>8</b>–<b>9</b>), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound <b>3</b>, exhibited significantly better antineuroinflammatory activity than other isolated compounds (<b>8</b>–<b>18</b>). Compound <b>3</b> inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE<sub>2</sub>, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that <b>3</b> inhibited LPS-stimulated ROS generation. These findings suggested that compound <b>3</b> might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039272","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}