Lei Li , Xin-Ying Zhu , Jun-Yu Zhu , Qing-Ya Cui , Yu-Wei Lin , Qing-Ren Lu , Shu-Qi Wu , Yi-Fan Fu , Qi-Lang Zhou , Tao Yuan , Zhang-Hua Sun , Dong Huang , Fang-Yu Yuan , Sheng Yin , Gui-Hua Tang
{"title":"hsqc引导下内生真菌青霉菌H-6抗脂肪吲哚二萜的发现和结构优化","authors":"Lei Li , Xin-Ying Zhu , Jun-Yu Zhu , Qing-Ya Cui , Yu-Wei Lin , Qing-Ren Lu , Shu-Qi Wu , Yi-Fan Fu , Qi-Lang Zhou , Tao Yuan , Zhang-Hua Sun , Dong Huang , Fang-Yu Yuan , Sheng Yin , Gui-Hua Tang","doi":"10.1016/j.ejmech.2025.117956","DOIUrl":null,"url":null,"abstract":"<div><div>Chemical investigation of <em>Penicillium janthinellum</em> H-6 using HSQC-guided small molecule accurate recognition technology (SMART) led to the isolation of nine new indole diterpenoids (IDTs), penijanidines D−L (<strong>1</strong>−<strong>9)</strong>, along with four known analogues (<strong>10</strong>−<strong>13</strong>). Architecturally, compound <strong>1</strong> represents an unusual imine-containing IDT, while compounds <strong>2</strong> and <strong>3</strong> are rare 1(2),2(18)-di-<em>seco</em>-IDT derivatives. Their structures including absolute configuration were determined by spectroscopic analysis and computational method. Meanwhile, structure optimization of the primary penijbirine (<strong>15</strong>) was conducted to obtain 22 new IDT derivatives (<strong>21</strong>−<strong>42</strong>). Systematic evaluation of the antiadipogenic effects of 42 IDTs, including 13 isolated ones (<strong>1</strong>−<strong>13</strong>), seven previously reported ones (<strong>14</strong>−<strong>20</strong>), and 22 semi-synthetic derivatives (<strong>21</strong>−<strong>42</strong>), in 3T3-L1 adipocytes identified the structurally optimized derivative <strong>38</strong> as the most potent molecular for triglyceride-lowering activity, exhibiting an EC<sub>50</sub> value of 0.25 ± 0.05 μM. Preliminary structure-activity relationship (SAR) analysis highlighted critical pharmacophoric features governing the lipid-lowering efficacy of these compounds. Mechanism studies revealed that <strong>38</strong> suppressed adipogenesis and lipogenesis via activating the AMPK signaling pathway, evidenced by significantly increased phosphorylation of AMPK (p-AMPK). Surface plasmon resonance (SPR) assays further confirmed that compound <strong>38</strong> directly bond to the AMPK protein with an affinity of <em>K</em><sub>D</sub> = 12.4 μM. This study not only expands the chemical diversity of bioactive IDTs but also identifies <strong>38</strong> as a novel AMPK-targeting lead compound for potential anti-obesity drug development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"297 ","pages":"Article 117956"},"PeriodicalIF":6.0000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"HSQC-guided discovery and structural optimization of antiadipogenic indole diterpenoids from endophytic fungus Penicillium janthinellum H-6\",\"authors\":\"Lei Li , Xin-Ying Zhu , Jun-Yu Zhu , Qing-Ya Cui , Yu-Wei Lin , Qing-Ren Lu , Shu-Qi Wu , Yi-Fan Fu , Qi-Lang Zhou , Tao Yuan , Zhang-Hua Sun , Dong Huang , Fang-Yu Yuan , Sheng Yin , Gui-Hua Tang\",\"doi\":\"10.1016/j.ejmech.2025.117956\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Chemical investigation of <em>Penicillium janthinellum</em> H-6 using HSQC-guided small molecule accurate recognition technology (SMART) led to the isolation of nine new indole diterpenoids (IDTs), penijanidines D−L (<strong>1</strong>−<strong>9)</strong>, along with four known analogues (<strong>10</strong>−<strong>13</strong>). Architecturally, compound <strong>1</strong> represents an unusual imine-containing IDT, while compounds <strong>2</strong> and <strong>3</strong> are rare 1(2),2(18)-di-<em>seco</em>-IDT derivatives. Their structures including absolute configuration were determined by spectroscopic analysis and computational method. Meanwhile, structure optimization of the primary penijbirine (<strong>15</strong>) was conducted to obtain 22 new IDT derivatives (<strong>21</strong>−<strong>42</strong>). Systematic evaluation of the antiadipogenic effects of 42 IDTs, including 13 isolated ones (<strong>1</strong>−<strong>13</strong>), seven previously reported ones (<strong>14</strong>−<strong>20</strong>), and 22 semi-synthetic derivatives (<strong>21</strong>−<strong>42</strong>), in 3T3-L1 adipocytes identified the structurally optimized derivative <strong>38</strong> as the most potent molecular for triglyceride-lowering activity, exhibiting an EC<sub>50</sub> value of 0.25 ± 0.05 μM. Preliminary structure-activity relationship (SAR) analysis highlighted critical pharmacophoric features governing the lipid-lowering efficacy of these compounds. Mechanism studies revealed that <strong>38</strong> suppressed adipogenesis and lipogenesis via activating the AMPK signaling pathway, evidenced by significantly increased phosphorylation of AMPK (p-AMPK). Surface plasmon resonance (SPR) assays further confirmed that compound <strong>38</strong> directly bond to the AMPK protein with an affinity of <em>K</em><sub>D</sub> = 12.4 μM. This study not only expands the chemical diversity of bioactive IDTs but also identifies <strong>38</strong> as a novel AMPK-targeting lead compound for potential anti-obesity drug development.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"297 \",\"pages\":\"Article 117956\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523425007214\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523425007214","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
HSQC-guided discovery and structural optimization of antiadipogenic indole diterpenoids from endophytic fungus Penicillium janthinellum H-6
Chemical investigation of Penicillium janthinellum H-6 using HSQC-guided small molecule accurate recognition technology (SMART) led to the isolation of nine new indole diterpenoids (IDTs), penijanidines D−L (1−9), along with four known analogues (10−13). Architecturally, compound 1 represents an unusual imine-containing IDT, while compounds 2 and 3 are rare 1(2),2(18)-di-seco-IDT derivatives. Their structures including absolute configuration were determined by spectroscopic analysis and computational method. Meanwhile, structure optimization of the primary penijbirine (15) was conducted to obtain 22 new IDT derivatives (21−42). Systematic evaluation of the antiadipogenic effects of 42 IDTs, including 13 isolated ones (1−13), seven previously reported ones (14−20), and 22 semi-synthetic derivatives (21−42), in 3T3-L1 adipocytes identified the structurally optimized derivative 38 as the most potent molecular for triglyceride-lowering activity, exhibiting an EC50 value of 0.25 ± 0.05 μM. Preliminary structure-activity relationship (SAR) analysis highlighted critical pharmacophoric features governing the lipid-lowering efficacy of these compounds. Mechanism studies revealed that 38 suppressed adipogenesis and lipogenesis via activating the AMPK signaling pathway, evidenced by significantly increased phosphorylation of AMPK (p-AMPK). Surface plasmon resonance (SPR) assays further confirmed that compound 38 directly bond to the AMPK protein with an affinity of KD = 12.4 μM. This study not only expands the chemical diversity of bioactive IDTs but also identifies 38 as a novel AMPK-targeting lead compound for potential anti-obesity drug development.
期刊介绍:
The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers.
A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.