Pub Date : 2024-08-13DOI: 10.1021/acs.jnatprod.4c0040610.1021/acs.jnatprod.4c00406
Lei Zhao, Heyao Ma, Yuhui Jiang, Yingying Li, Li Qiao, Yu Chen, Xiaowen Jiang, Lihui Wang*, Shu Wang* and Xinyu Fan*,
Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on human health. As a first-line drug for HCC, despite its excellent efficacy, lenvatinib (Len) is prone to developing drug resistance in HCC patients. The N6-methyladenosine (m6A) modification is not only related to the development of HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, our group first screened a small molecule m6A regulator, lobeline (Lob), from a library of 390 compounds (mostly natural products). In vitro experiments demonstrated that Lob could significantly enhance the sensitivity to Len of Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In Len-resistant cell-derived and patient-derived xenograft models, Lob could reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, respectively. Furthermore, MeRIP-m6A sequencing results indicated that the underlying molecular mechanism of Lob reversal of HCC drug resistance was related to UBE3B. Taken together, this study highlighted that Lob, a plant derived natural product, could reverse the resistance of HCC to Len by regulating the m6A levels. It is hoped that this will provide a pharmacological research basis for the clinical treatment of HCC patients.
{"title":"Identification of an m6A Natural Inhibitor, Lobeline, That Reverses Lenvatinib Resistance in Hepatocellular Tumors","authors":"Lei Zhao, Heyao Ma, Yuhui Jiang, Yingying Li, Li Qiao, Yu Chen, Xiaowen Jiang, Lihui Wang*, Shu Wang* and Xinyu Fan*, ","doi":"10.1021/acs.jnatprod.4c0040610.1021/acs.jnatprod.4c00406","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00406https://doi.org/10.1021/acs.jnatprod.4c00406","url":null,"abstract":"<p >Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on human health. As a first-line drug for HCC, despite its excellent efficacy, lenvatinib (Len) is prone to developing drug resistance in HCC patients. The N6-methyladenosine (m6A) modification is not only related to the development of HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, our group first screened a small molecule m6A regulator, lobeline (Lob), from a library of 390 compounds (mostly natural products). In vitro experiments demonstrated that Lob could significantly enhance the sensitivity to Len of Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In Len-resistant cell-derived and patient-derived xenograft models, Lob could reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, respectively. Furthermore, MeRIP-m6A sequencing results indicated that the underlying molecular mechanism of Lob reversal of HCC drug resistance was related to UBE3B. Taken together, this study highlighted that Lob, a plant derived natural product, could reverse the resistance of HCC to Len by regulating the m6A levels. It is hoped that this will provide a pharmacological research basis for the clinical treatment of HCC patients.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039231","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 : 2024-08-12DOI: 10.1021/acs.jnatprod.4c0067510.1021/acs.jnatprod.4c00675
Brodie W. Bulcock, Rachel Chen, Ernest Lacey, Yit-Heng Chooi and 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 and Gavin R. Flematti*, ","doi":"10.1021/acs.jnatprod.4c0067510.1021/acs.jnatprod.4c00675","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00675https://doi.org/10.1021/acs.jnatprod.4c00675","url":null,"abstract":"<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":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039441","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 : 2024-08-10DOI: 10.1021/acs.jnatprod.4c0053210.1021/acs.jnatprod.4c00532
Ludovica Lela, Maria Ponticelli, Vittorio Carlucci, Jan F. Stevens, Immacolata Faraone, Nikolay T. Tzvetkov* and Luigi Milella*,
Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, β-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine Tas2r expression. Xanthohumol and α-acids selectively increase Tas2r138 and Tas2r130–Tas2r138 expression, respectively, in STC-1 cells, while β-acids increased the expression of all bitter receptors studied, including Tas2r119, Tas2r105, Tas2r138, Tas2r120, and Tas2r130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased Tas2r138 expression, computational studies were performed on Tas2r138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.
{"title":"Insight into the Interaction of Humulus lupulus L. Specialized Metabolites and Gastrointestinal Bitter Taste Receptors: In Vitro Study in STC-1 Cells and Molecular Docking","authors":"Ludovica Lela, Maria Ponticelli, Vittorio Carlucci, Jan F. Stevens, Immacolata Faraone, Nikolay T. Tzvetkov* and Luigi Milella*, ","doi":"10.1021/acs.jnatprod.4c0053210.1021/acs.jnatprod.4c00532","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00532https://doi.org/10.1021/acs.jnatprod.4c00532","url":null,"abstract":"<p >Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, β-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine <i>Tas2r</i> expression. Xanthohumol and α-acids selectively increase <i>Tas2r</i>138 and <i>Tas2r</i>130–<i>Tas2r</i>138 expression, respectively, in STC-1 cells, while β-acids increased the expression of all bitter receptors studied, including <i>Tas2r</i>119, <i>Tas2r</i>105, <i>Tas2r</i>138, <i>Tas2r</i>120, and <i>Tas2r</i>130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased <i>Tas2r</i>138 expression, computational studies were performed on <i>Tas2r</i>138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039411","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}
Ten new drimane meroterpenoids talarines A–J (1–10), along with six known analogues (11–16), were isolated from desert soil-derived fungus Talaromyces pinophilus LD-7. Their 2D structures were elucidated by comprehensive interpretation of NMR and HRESIMS data. Electronic circular dichroism calculation was used to establish their absolute configurations. Compounds 2, 10, and 11 showed antiviral activities toward vesicular stomatitis virus with IC50 values of 18, 15, and 23 nM, respectively. The structure-bioactivity relationship indicated that chlorine substitution at C-5 contributed greatly to their antiviral activities. Finally, we identified a new halogenase outside the biosynthetic gene cluster, which was responsible for C-5 halogenation of the precursor isocoumarin 17 as a tailoring step in chlorinated meroterpenoids assembly.
{"title":"Antiviral Chlorinated Drimane Meroterpenoids from the Fungus Talaromyces pinophilus LD-7 and Their Biosynthetic Pathway","authors":"Meng Ren, Zhuang Li, Zixuan Wang, Wenjie Han, Fengxiao Wang, Yu Li, Wenrong Zhang, Xingjian Liu*, Jun Zhang* and Du-Qiang Luo*, ","doi":"10.1021/acs.jnatprod.4c0053910.1021/acs.jnatprod.4c00539","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00539https://doi.org/10.1021/acs.jnatprod.4c00539","url":null,"abstract":"<p >Ten new drimane meroterpenoids talarines A–J (<b>1</b>–<b>10</b>), along with six known analogues <b>(11–16)</b>, were isolated from desert soil-derived fungus <i>Talaromyces pinophilus</i> LD-7. Their 2D structures were elucidated by comprehensive interpretation of NMR and HRESIMS data. Electronic circular dichroism calculation was used to establish their absolute configurations. Compounds <b>2</b>, <b>10</b>, and <b>11</b> showed antiviral activities toward vesicular stomatitis virus with IC<sub>50</sub> values of 18, 15, and 23 nM, respectively. The structure-bioactivity relationship indicated that chlorine substitution at C-5 contributed greatly to their antiviral activities. Finally, we identified a new halogenase outside the biosynthetic gene cluster, which was responsible for C-5 halogenation of the precursor isocoumarin <b>17</b> as a tailoring step in chlorinated meroterpenoids assembly.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039432","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 : 2024-08-09DOI: 10.1021/acs.jnatprod.4c0057710.1021/acs.jnatprod.4c00577
Anita Barta, Agostina Salusso, Norbert Kúsz, Róbert Berkecz, Jan Schlauer, Dragica Purger, Judit Hohmann, Maria Cecilia Carpinella* and Andrea Vasas*,
Continuing our search for bioactive compounds in species from the Juncaceae family, Juncus articulatus was investigated. Ten previously undescribed phenanthrenes─articulins A–J (1–10)─and ten known compounds─juncuenin B, dehydrojuncuenin B, juncatrin B, ensifolins E, F, H, I, K, juncuenin D, and luzulin A (11–20)─along with other compounds, have been isolated and identified. The isolated compounds were evaluated for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-resistant Staphylococcus aureus (MRSA). Compounds 12 and 14 exhibited the most potent activity against planktonic and sessile MSSA and MRSA with minimum inhibitory concentration (MIC) values of 15.1 μM (12 for both bacterial strains) and 15.3 μM (14 for both bacterial strains). Compounds 15, 17, and 18 also exhibited activity against both strains, although to a lower extent, with MIC values ranging from 30.0 to 56.8 μM. The inhibition of biofilm formation of these compounds was observed at 15.1–114.3 μM. This study elucidates the phenanthrene composition of J. articulatus and the antibacterial effect of these compounds.
{"title":"Phenanthrenes from Juncus articulatus with Antibacterial and Biofilm Formation Inhibitory Activity","authors":"Anita Barta, Agostina Salusso, Norbert Kúsz, Róbert Berkecz, Jan Schlauer, Dragica Purger, Judit Hohmann, Maria Cecilia Carpinella* and Andrea Vasas*, ","doi":"10.1021/acs.jnatprod.4c0057710.1021/acs.jnatprod.4c00577","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00577https://doi.org/10.1021/acs.jnatprod.4c00577","url":null,"abstract":"<p >Continuing our search for bioactive compounds in species from the Juncaceae family, <i>Juncus articulatus</i> was investigated. Ten previously undescribed phenanthrenes─articulins A–J (<b>1</b>–<b>10</b>)─and ten known compounds─juncuenin B, dehydrojuncuenin B, juncatrin B, ensifolins E, F, H, I, K, juncuenin D, and luzulin A (<b>11</b>–<b>20</b>)─along with other compounds, have been isolated and identified. The isolated compounds were evaluated for antibacterial activity against <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA), and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Compounds <b>12</b> and <b>14</b> exhibited the most potent activity against planktonic and sessile MSSA and MRSA with minimum inhibitory concentration (MIC) values of 15.1 μM (<b>12</b> for both bacterial strains) and 15.3 μM (<b>14</b> for both bacterial strains). Compounds <b>15</b>, <b>17</b>, and <b>18</b> also exhibited activity against both strains, although to a lower extent, with MIC values ranging from 30.0 to 56.8 μM. The inhibition of biofilm formation of these compounds was observed at 15.1–114.3 μM. This study elucidates the phenanthrene composition of <i>J. articulatus</i> and the antibacterial effect of these compounds.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jnatprod.4c00577","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039566","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 : 2024-08-07DOI: 10.1021/acs.jnatprod.4c0055710.1021/acs.jnatprod.4c00557
Kittisak Thongpat, Natthawat Milehman, Worarat Rojanaverawong, Pannita Holasut, Sunhapas Soodvilai, Chutima S. Vaddhanaphuti and Kwanruthai Tadpetch*,
Total syntheses of two γ-butenolide natural products, asperjinone (1) and asperimide C (2) in both racemic and chiral forms have been accomplished utilizing Basavaiah’s one-pot Friedel–Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of 1 proposed by Williams et al. and the structure and absolute configuration of 2 reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of 1. Synthetic 1 exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 under LPS-induced renal inflammation condition and was superior to (S)-1, rac-2, 2, and a positive drug control, indomethacin. Moreover, compound 1 inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (1) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.
我们采用 Basavaiah 的一锅弗里德尔-卡夫斯/马来酸酐形成协议作为关键策略,完成了两种γ-丁烯内酯天然产物外消旋和手性形式的全合成:asperjinone (1) 和 asperimide C (2)。我们的合成验证了 Williams 等人提出的 1 的修正结构,以及 Li 小组报告的 2 的结构和绝对构型。在 LPS 诱导的肾脏炎症条件下,合成的 1 通过抑制促炎细胞因子 TNF-α、IL-1β 和 IL-6 的基因表达,在肾近端肾小管上皮细胞(RPTEC)中表现出显著的抗炎活性,优于 (S)-1、rac-2、2 和阳性药物对照吲哚美辛。此外,化合物 1 通过显著降低 iNOS 和 COX-2 基因的表达以及 NO 的总生成量,抑制了炎症的下游信号传导。asperjinone(1)的抗炎活性使其成为开发新型抗炎药物以应对炎症恶化的急性肾损伤的潜在候选药物。
{"title":"Total Synthesis and Anti-inflammatory Activity of Asperjinone and Asperimide C","authors":"Kittisak Thongpat, Natthawat Milehman, Worarat Rojanaverawong, Pannita Holasut, Sunhapas Soodvilai, Chutima S. Vaddhanaphuti and Kwanruthai Tadpetch*, ","doi":"10.1021/acs.jnatprod.4c0055710.1021/acs.jnatprod.4c00557","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00557https://doi.org/10.1021/acs.jnatprod.4c00557","url":null,"abstract":"<p >Total syntheses of two γ-butenolide natural products, asperjinone (<b>1</b>) and asperimide C (<b>2</b>) in both racemic and chiral forms have been accomplished utilizing Basavaiah’s one-pot Friedel–Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of <b>1</b> proposed by Williams et al. and the structure and absolute configuration of <b>2</b> reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of <b>1</b>. Synthetic <b>1</b> exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 under LPS-induced renal inflammation condition and was superior to (<i>S</i>)-<b>1</b>, <i>rac</i>-<b>2</b>, <b>2</b>, and a positive drug control, indomethacin. Moreover, compound <b>1</b> inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (<b>1</b>) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jnatprod.4c00557","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039404","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}
Metabolites with high chemical reactivity serve important roles in chemical defenses of organisms. Formaldehyde, as a simple and highly reactive small molecule, can be produced by microorganisms, plants, and animals. Its toxicity is well known, but information about its other biological functions remains scarce. Here, we report that the natural product SEK34b produced by Streptomyces species can react nonenzymatically with formaldehyde in water to yield the methylene-bridged dimer phaeochromycin F. This process can eliminate the toxic substance formaldehyde produced by Staphylococcus aureus. Furthermore, there is a substantial inhibitory impact of phaeochromycin F on S. aureus. We hypothesize that these constitute an integrated system of defense and attack of Streptomyces species against competitors. Our study indicates that formaldehyde can react with vancomycin and tigecycline under mild conditions to generate the derivatives bearing an imidazolidin-4-one moiety, thereby reducing the antibacterial activity of these antibiotics. These data provide a possible chemical interaction mechanism of bacteria involving the nonenzymatic reactions of formaldehyde with highly reactive natural products.
具有高化学反应活性的代谢物在生物体的化学防御中发挥着重要作用。甲醛是一种简单而高活性的小分子,可由微生物、植物和动物产生。甲醛的毒性众所周知,但有关它的其他生物功能的信息仍然很少。在此,我们报告了链霉菌产生的天然产物 SEK34b 能在水中与甲醛发生非酶反应,生成亚甲基桥联二聚体 phaeochromycin F。此外,辉绿霉素 F 对金黄色葡萄球菌也有很大的抑制作用。我们推测,这些都构成了链霉菌对竞争者的综合防御和攻击系统。我们的研究表明,甲醛可在温和条件下与万古霉素和替加环素发生反应,生成含有咪唑烷-4-酮分子的衍生物,从而降低这些抗生素的抗菌活性。这些数据提供了一种可能的细菌化学作用机制,涉及甲醛与高活性天然产物的非酶反应。
{"title":"Nonenzymatic Sequestering of Formaldehyde into the Antibiotic Methylene-Bridged Dimer Phaeochromycin F by <i>Streptomyces</i> sp. OUCMDZ-4982 as a Possible Multipronged Chemical Defense Mechanism.","authors":"Weihong Wang, Jiaxu Shang, Shupeng Yin, Kunyu Xia, Rui Ma, Weiming Zhu, Peng Fu","doi":"10.1021/acs.jnatprod.4c00702","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00702","url":null,"abstract":"<p><p>Metabolites with high chemical reactivity serve important roles in chemical defenses of organisms. Formaldehyde, as a simple and highly reactive small molecule, can be produced by microorganisms, plants, and animals. Its toxicity is well known, but information about its other biological functions remains scarce. Here, we report that the natural product SEK34b produced by <i>Streptomyces</i> species can react nonenzymatically with formaldehyde in water to yield the methylene-bridged dimer phaeochromycin F. This process can eliminate the toxic substance formaldehyde produced by <i>Staphylococcus aureus</i>. Furthermore, there is a substantial inhibitory impact of phaeochromycin F on <i>S. aureus</i>. We hypothesize that these constitute an integrated system of defense and attack of <i>Streptomyces</i> species against competitors. Our study indicates that formaldehyde can react with vancomycin and tigecycline under mild conditions to generate the derivatives bearing an imidazolidin-4-one moiety, thereby reducing the antibacterial activity of these antibiotics. These data provide a possible chemical interaction mechanism of bacteria involving the nonenzymatic reactions of formaldehyde with highly reactive natural products.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896016","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 : 2024-08-06DOI: 10.1021/acs.jnatprod.4c0037310.1021/acs.jnatprod.4c00373
Xuefeng Fu, Yang Jiao, Yao Feng, Fengwei Lin, Bing Zhang, Qing Mao, Jiahui Wang, Wen Jiang, Yanhua Mou*, Han Wang* and Shaojie Wang*,
Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 μM, 1.5-fold more potent than pristimerin (IC50 = 3.0 μM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.
{"title":"Scaffold Hopping of Pristimerin Provides Derivatives Containing a Privileged Quinoxaline Substructure as Potent Autophagy Inducers in Breast Cancer Cells","authors":"Xuefeng Fu, Yang Jiao, Yao Feng, Fengwei Lin, Bing Zhang, Qing Mao, Jiahui Wang, Wen Jiang, Yanhua Mou*, Han Wang* and Shaojie Wang*, ","doi":"10.1021/acs.jnatprod.4c0037310.1021/acs.jnatprod.4c00373","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00373https://doi.org/10.1021/acs.jnatprod.4c00373","url":null,"abstract":"<p >Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities <i>in vitro</i> using the MTT assay. The most potent cytotoxic compound (<b>21o</b>) significantly inhibited the proliferation of MCF-7 cells with an IC<sub>50</sub> value of 2.0 μM, 1.5-fold more potent than pristimerin (IC<sub>50</sub> = 3.0 μM). Compared with pristimerin, compound <b>21o</b> displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound <b>21o</b>. Compound <b>21o</b> induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound <b>21o</b> may serve as a lead compound for developing new therapies to treat breast cancer.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039336","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 : 2024-08-05DOI: 10.1021/acs.jnatprod.4c0056610.1021/acs.jnatprod.4c00566
María Belén Valdez, María Fernanda D′Jonsiles, Esteban Avigliano and Jorge A. Palermo*,
Unlike most common pentacyclic plant triterpenes, glutinol has a methyl group at position C-9 and a Δ5 double bond. At the same time, it lacks a methyl at C-10. These features significantly modify its chemical behavior compared to other triterpenes, particularly under oxidative conditions. Although the isolation of glutinol from various plant species has been documented, its chemistry remains largely unexplored. In this study, glutinol was isolated from the bark of Balfourodendron riedelianum as a starting material for top-down strategies of structural diversification, which included ring fusion, oxidation, aromatization, and ring cleavage reactions. Glutinol, together with a library of 22 derivatives, was evaluated for antifungal activity against three phytopathogenic Fusarium strains, F. solani, F. graminearum, and F. tucumaniae. Some of the derivatives displayed antifungal activity; in particular, compound 12, featuring a triazine ring, displayed the best fungicidal properties against F. solani and F. graminearum, while the ring B cleavage product 23 showed the best activity against F. tucumaniae. This study highlights the potential of glutinol as a scaffold for structural diversification, and these results may contribute to the design of novel fungicidal agents against phytopathogenic strains.
{"title":"Unlocking the Potential of Glutinol: Structural Diversification and Antifungal Activity against Phytopathogenic Fusarium Strains","authors":"María Belén Valdez, María Fernanda D′Jonsiles, Esteban Avigliano and Jorge A. Palermo*, ","doi":"10.1021/acs.jnatprod.4c0056610.1021/acs.jnatprod.4c00566","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00566https://doi.org/10.1021/acs.jnatprod.4c00566","url":null,"abstract":"<p >Unlike most common pentacyclic plant triterpenes, glutinol has a methyl group at position C-9 and a Δ<sub>5</sub> double bond. At the same time, it lacks a methyl at C-10. These features significantly modify its chemical behavior compared to other triterpenes, particularly under oxidative conditions. Although the isolation of glutinol from various plant species has been documented, its chemistry remains largely unexplored. In this study, glutinol was isolated from the bark of <i>Balfourodendron riedelianum</i> as a starting material for top-down strategies of structural diversification, which included ring fusion, oxidation, aromatization, and ring cleavage reactions. Glutinol, together with a library of 22 derivatives, was evaluated for antifungal activity against three phytopathogenic <i>Fusarium</i> strains, <i>F. solani</i>, <i>F. graminearum</i>, and <i>F. tucumaniae</i>. Some of the derivatives displayed antifungal activity; in particular, compound <b>12</b>, featuring a triazine ring, displayed the best fungicidal properties against <i>F. solani</i> and <i>F. graminearum</i>, while the ring B cleavage product <b>23</b> showed the best activity against <i>F. tucumaniae</i>. This study highlights the potential of glutinol as a scaffold for structural diversification, and these results may contribute to the design of novel fungicidal agents against phytopathogenic strains.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039182","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 : 2024-08-05DOI: 10.1021/acs.jnatprod.4c0043810.1021/acs.jnatprod.4c00438
Jae Sang Han, Eun-Sook Kim, Yong Beom Cho, Sun Young Kim, Mi Kyeong Lee, Bang Yeon Hwang* and Jin Woo Lee*,
Soil sustains human life by nourishing crops, storing food sources, and housing microbes, which may affect the nutrition and biosynthesis of secondary metabolites, some of which are used as drugs. To identify lead compounds for a new class of drugs, we collected soil-derived fungal strains from various environments, including urban areas. As various human pathogens are assumed to influence the biosynthetic pathways of metabolites in soil fungi, leading to the production of novel scaffolds, we focused our work on densely populated urban areas and tourist attractions. A soil-derived fungal extract library was screened against MDA-MB-231 cells to derive their cytotoxic activity. Notably, 10 μg/mL of the extract of Trichoderma guizhouense (DS9-1) was found to exhibit an inhibitory effect of 71%. Fractionation, isolation, and structure elucidation efforts led to the identification of nine new peptaibols, trichoguizaibols A–I (1–9), comprising 14 amino acid residues (14-AA peptaibols), and three new peptaibols, trichoguizaibols J–L (10–12), comprising 18 amino acid residues (18-AA peptaibols). The chemical structures of 1–12 were determined based on their 1D and 2D NMR spectra, HRESIMS, electronic circular dichroism data, and results of the advanced Marfey’s method. The 18-AA peptaibols were found to exhibit cytotoxicity against MDA-MB-231, SK-Hep1, SKOV3, DU145, and HCT116 cells greater than that of the 14-AA peptaibols. Among these compounds, 10–12 exhibited potent sub-micromolar IC50 values. These results are expected to shed light on a new direction for developing novel scaffolds as anticancer agents.
{"title":"Cytotoxic Peptaibols from Trichoderma guizhouense, a Fungus Isolated from an Urban Soil Sample","authors":"Jae Sang Han, Eun-Sook Kim, Yong Beom Cho, Sun Young Kim, Mi Kyeong Lee, Bang Yeon Hwang* and Jin Woo Lee*, ","doi":"10.1021/acs.jnatprod.4c0043810.1021/acs.jnatprod.4c00438","DOIUrl":"https://doi.org/10.1021/acs.jnatprod.4c00438https://doi.org/10.1021/acs.jnatprod.4c00438","url":null,"abstract":"<p >Soil sustains human life by nourishing crops, storing food sources, and housing microbes, which may affect the nutrition and biosynthesis of secondary metabolites, some of which are used as drugs. To identify lead compounds for a new class of drugs, we collected soil-derived fungal strains from various environments, including urban areas. As various human pathogens are assumed to influence the biosynthetic pathways of metabolites in soil fungi, leading to the production of novel scaffolds, we focused our work on densely populated urban areas and tourist attractions. A soil-derived fungal extract library was screened against MDA-MB-231 cells to derive their cytotoxic activity. Notably, 10 μg/mL of the extract of <i>Trichoderma guizhouense</i> (DS9-1) was found to exhibit an inhibitory effect of 71%. Fractionation, isolation, and structure elucidation efforts led to the identification of nine new peptaibols, trichoguizaibols A–I (<b>1</b>–<b>9</b>), comprising 14 amino acid residues (14-AA peptaibols), and three new peptaibols, trichoguizaibols J–L (<b>10</b>–<b>12</b>), comprising 18 amino acid residues (18-AA peptaibols). The chemical structures of <b>1</b>–<b>12</b> were determined based on their 1D and 2D NMR spectra, HRESIMS, electronic circular dichroism data, and results of the advanced Marfey’s method. The 18-AA peptaibols were found to exhibit cytotoxicity against MDA-MB-231, SK-Hep1, SKOV3, DU145, and HCT116 cells greater than that of the 14-AA peptaibols. Among these compounds, <b>10</b>–<b>12</b> exhibited potent sub-micromolar IC<sub>50</sub> values. These results are expected to shed light on a new direction for developing novel scaffolds as anticancer agents.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142039327","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}