The diverse interconversion of isomers among natural products (NPs) are shaped by both intrinsic structural characteristics and extrinsic environmental factors, representing a rich source of chemical complexity and biological diversity. Deciphering these intricate interconversion processes holds the potential to unlock a vast array of bioactive compounds, expanding our exploration of the chemical landscape. Identifying the specific conditions and molecular characteristics while accurately predicting ‘the ballet of nature’ will effectively achieve increased activity, lower toxicity, and superior pharmacokinetics. Such advancements will significantly broaden their applications in the development of valuable pharmaceuticals and products for medicine, agriculture, and industry. This review comprehensively outlines the origins and chemical classifications of paired interconvertible isomers in nature, including positional, tautomeric, geometric, optical, and conformational isomerism. Particular focus is given to the formation mechanisms of these interconversion processes.
{"title":"The ballet of nature: the interconvertible isomerisation of natural products","authors":"Ze-Jun Xu , Jing-Jing Han , Chun-Yang Zhang , Hong-Xiang Lou","doi":"10.1039/d5np00019j","DOIUrl":"10.1039/d5np00019j","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>The diverse interconversion of isomers among natural products (NPs) are shaped by both intrinsic structural characteristics and extrinsic environmental factors, representing a rich source of chemical complexity and biological diversity. Deciphering these intricate interconversion processes holds the potential to unlock a vast array of bioactive compounds, expanding our exploration of the chemical landscape. Identifying the specific conditions and molecular characteristics while accurately predicting ‘the ballet of nature’ will effectively achieve increased activity, lower toxicity, and superior pharmacokinetics. Such advancements will significantly broaden their applications in the development of valuable pharmaceuticals and products for medicine, agriculture, and industry. This review comprehensively outlines the origins and chemical classifications of paired interconvertible isomers in nature, including positional, tautomeric, geometric, optical, and conformational isomerism. Particular focus is given to the formation mechanisms of these interconversion processes.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 9","pages":"Pages 1548-1574"},"PeriodicalIF":10.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prenylated bacterial natural products (NPs), catalyzed by cluster-situated prenyltransferases (PTs), exhibit large structural diversity and broad biological activities and have received increasing attention for novel drug discovery and development. This review provides a comprehensive summary of the recent progress in the investigation of prenylated bacterial NPs. To highlight the structural and chemical space of prenylated bacterial NPs, we discuss their occurrence, structures, biosynthesis and bioactivities. Representative examples are summarized with illustrations of PT-catalyzed biosynthetic pathways of distinct NP classes, which present new opportunities for the discovery of novel prenylated bacterial NPs. The mechanistic study of PTs involved in bacterial NP biosynthesis has been outlined, and prenylated bacterial NPs hold great promise as novel biocatalysts for the synthesis of novel drug leads in modern medicine.
{"title":"Prenylated bacterial natural products: occurrence, chemical diversity, biosynthesis and bioactivity","authors":"Fan Zhang , Di Zhao , Yuzhu Wu , Lei Li","doi":"10.1039/d5np00011d","DOIUrl":"10.1039/d5np00011d","url":null,"abstract":"<div><div>Covering: 2000 to 2024</div></div><div><div>Prenylated bacterial natural products (NPs), catalyzed by cluster-situated prenyltransferases (PTs), exhibit large structural diversity and broad biological activities and have received increasing attention for novel drug discovery and development. This review provides a comprehensive summary of the recent progress in the investigation of prenylated bacterial NPs. To highlight the structural and chemical space of prenylated bacterial NPs, we discuss their occurrence, structures, biosynthesis and bioactivities. Representative examples are summarized with illustrations of PT-catalyzed biosynthetic pathways of distinct NP classes, which present new opportunities for the discovery of novel prenylated bacterial NPs. The mechanistic study of PTs involved in bacterial NP biosynthesis has been outlined, and prenylated bacterial NPs hold great promise as novel biocatalysts for the synthesis of novel drug leads in modern medicine.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1303-1343"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as hypbeaone A from Hypericum beanii.
{"title":"Hot off the Press","authors":"Robert A. Hill , Andrew Sutherland","doi":"10.1039/d5np90029h","DOIUrl":"10.1039/d5np90029h","url":null,"abstract":"<div><div>A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as hypbeaone A from <em>Hypericum beanii</em>.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1235-1239"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144751900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanqing Xue , Yijiao Xiong , Wei Huang , Jianing Liu , Wen Liu
Covering: 2013–2024
Benefiting significantly from recent advances in genome mining, ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have emerged as a source of chemical inspiration to drive the discovery of therapeutic agents and the development of new biological tools for addressing challenges to synthetic approaches. Despite being confined to twenty proteinogenic amino acid building blocks, the structural complexity and diversity of RiPPs that arise from enzymatic posttranslational modifications (PTMs) surpass expectations and are now believed to be comparable to those produced by non-ribosomal peptide synthetases. Here, we highlight the PTM enzymes characterized over the past decade that engage the –(NH–Cα–CO)n– repeating units in transformations, particularly those leading to structural rearrangements by peptide backbone remodeling. Unveiling the catalytic mechanisms of these unusual PTM enzymes deepens the understanding in RiPP biosynthesis and, eventually, will enhance our capability of rational design, development and production of functional peptide agents using synthetic biology strategies.
得益于基因组挖掘的最新进展，核糖体合成和翻译后修饰肽（RiPP）天然产物已经成为化学灵感的来源，推动了治疗药物的发现和新生物工具的开发，以应对合成方法的挑战。尽管局限于20个蛋白质原氨基酸构建块，但由酶促翻译后修饰（PTMs）产生的RiPPs的结构复杂性和多样性超出了预期，现在被认为与非核糖体肽合成酶产生的RiPPs相当。在这里，我们重点介绍了在过去十年中表征的PTM酶，这些酶在转化中参与-(nh - c - α- co)n-重复单元，特别是那些通过肽骨架重塑导致结构重排的酶。揭示这些不寻常的PTM酶的催化机制加深了对RiPP生物合成的理解，最终将提高我们利用合成生物学策略合理设计、开发和生产功能肽制剂的能力。
{"title":"Remodeling of ribosomally synthesized peptide backbones based on posttranslational modifications","authors":"Yanqing Xue , Yijiao Xiong , Wei Huang , Jianing Liu , Wen Liu","doi":"10.1039/d5np00018a","DOIUrl":"10.1039/d5np00018a","url":null,"abstract":"<div><div>Covering: 2013–2024</div></div><div><div>Benefiting significantly from recent advances in genome mining, ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products have emerged as a source of chemical inspiration to drive the discovery of therapeutic agents and the development of new biological tools for addressing challenges to synthetic approaches. Despite being confined to twenty proteinogenic amino acid building blocks, the structural complexity and diversity of RiPPs that arise from enzymatic posttranslational modifications (PTMs) surpass expectations and are now believed to be comparable to those produced by non-ribosomal peptide synthetases. Here, we highlight the PTM enzymes characterized over the past decade that engage the –(NH–C<sub>α</sub>–CO)<sub><em>n</em></sub>– repeating units in transformations, particularly those leading to structural rearrangements by peptide backbone remodeling. Unveiling the catalytic mechanisms of these unusual PTM enzymes deepens the understanding in RiPP biosynthesis and, eventually, will enhance our capability of rational design, development and production of functional peptide agents using synthetic biology strategies.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1276-1302"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark Ellerhorst , Vadim Nikitushkin , Walid K. Al-Jammal , Lucas Gregor , Ivan Vilotijević , Gerald Lackner
Covering: 2011 to 2025
The importance of redox cofactors like nicotinamide adenine dinucleotide or flavin adenine dinucleotide as cofactors for enzymatic reactions in living organisms is widely known. However, many microbial species also employ unusual redox cofactors such as the coenzyme F420 or the peptide-derived pyrroloquinoline quinone (PQQ). In this review, we introduce the reader to the recently discovered bacterial redox cofactor mycofactocin (MFT), a valine-tyrosine-derived small molecule of the class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with remarkable biosynthetic and functional similarities to PQQ. The cofactor plays an important role in the reoxidation of non-exchangeable nicotinamide redox cofactors of specialized oxidoreductases in mycobacteria and related actinobacteria. We highlight the bioinformatic discovery of the mycofactocin gene cluster and its auxiliary genes, present strategies for the chemical synthesis of the cofactor, and take a detailed look at the biosynthesis of the glycosylated molecule. Subsequently, the diverse mycofactocin-inducing conditions and associated oxidoreductase families are reviewed, and a potential electron transfer route from high-energy alcohols via mycofactocin to oxygen as a final electron acceptor is presented. The review concludes with a comparison of the physiological roles of PQQ and MFT, and an outlook for future research questions and potential biotechnological applications of mycofactocin.
{"title":"Recent insights into the biosynthesis and biological activities of the peptide-derived redox cofactor mycofactocin†","authors":"Mark Ellerhorst , Vadim Nikitushkin , Walid K. Al-Jammal , Lucas Gregor , Ivan Vilotijević , Gerald Lackner","doi":"10.1039/d5np00012b","DOIUrl":"10.1039/d5np00012b","url":null,"abstract":"<div><div>Covering: 2011 to 2025</div></div><div><div>The importance of redox cofactors like nicotinamide adenine dinucleotide or flavin adenine dinucleotide as cofactors for enzymatic reactions in living organisms is widely known. However, many microbial species also employ unusual redox cofactors such as the coenzyme F<sub>420</sub> or the peptide-derived pyrroloquinoline quinone (PQQ). In this review, we introduce the reader to the recently discovered bacterial redox cofactor mycofactocin (MFT), a valine-tyrosine-derived small molecule of the class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with remarkable biosynthetic and functional similarities to PQQ. The cofactor plays an important role in the reoxidation of non-exchangeable nicotinamide redox cofactors of specialized oxidoreductases in mycobacteria and related actinobacteria. We highlight the bioinformatic discovery of the mycofactocin gene cluster and its auxiliary genes, present strategies for the chemical synthesis of the cofactor, and take a detailed look at the biosynthesis of the glycosylated molecule. Subsequently, the diverse mycofactocin-inducing conditions and associated oxidoreductase families are reviewed, and a potential electron transfer route from high-energy alcohols <em>via</em> mycofactocin to oxygen as a final electron acceptor is presented. The review concludes with a comparison of the physiological roles of PQQ and MFT, and an outlook for future research questions and potential biotechnological applications of mycofactocin.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1344-1366"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reducing the prevalence of phytopathogens and their impact on crops is essential to reach sustainable agriculture goals. Synthetic pesticides have been commonly used to control crop disease but are now strongly linked to disease resistance, environmental pollution, depletion of soil biodiversity, and bioaccumulation, leading to adverse effects on human health. As a alternative, the prolific Trichoderma genus has been studied for its biocontrol properties, as well as its ability to promote plant growth and increase nutrient uptake. This is done through various mechanisms, one of which is the production of bioactive natural products with high chemical diversity. These include terpenoids, alkaloids, non-ribosomal peptides, polyketides and RiPPs. One of the most studied examples is 6-pentyl-2H-pyran-2-one, a volatile organic polyketide, which induces systemic acquired resistance, morphogenesis, and natural product biosynthesis in plants. Methods for culturing Trichoderma spp., isolating and characterising unique bioactive metabolites are discussed here, with an emphasis on dereplication strategies using metabolomics to optimise discovery. In addition, the role of genome mining for the study of natural product biosynthesis in Trichoderma, and more generally, filamentous fungi is discussed. Examples of bioinformatics tools available to date are listed here with applications in Trichoderma and other ascomycetes. New advances in genome engineering in Trichoderma are also detailed, providing insights into available strategies for the validation of biosynthetic gene clusters identified using genome mining. Finally, the use of a combination of omics approaches, namely metabologenomics, is presented as a growing field for natural product discovery in fungi.
{"title":"Advances in the discovery and study of Trichoderma natural products for biological control applications","authors":"Sophie Jin , Fabrizio Alberti","doi":"10.1039/d5np00017c","DOIUrl":"10.1039/d5np00017c","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Reducing the prevalence of phytopathogens and their impact on crops is essential to reach sustainable agriculture goals. Synthetic pesticides have been commonly used to control crop disease but are now strongly linked to disease resistance, environmental pollution, depletion of soil biodiversity, and bioaccumulation, leading to adverse effects on human health. As a alternative, the prolific <em>Trichoderma</em> genus has been studied for its biocontrol properties, as well as its ability to promote plant growth and increase nutrient uptake. This is done through various mechanisms, one of which is the production of bioactive natural products with high chemical diversity. These include terpenoids, alkaloids, non-ribosomal peptides, polyketides and RiPPs. One of the most studied examples is 6-pentyl-2<em>H</em>-pyran-2-one, a volatile organic polyketide, which induces systemic acquired resistance, morphogenesis, and natural product biosynthesis in plants. Methods for culturing <em>Trichoderma</em> spp., isolating and characterising unique bioactive metabolites are discussed here, with an emphasis on dereplication strategies using metabolomics to optimise discovery. In addition, the role of genome mining for the study of natural product biosynthesis in <em>Trichoderma</em>, and more generally, filamentous fungi is discussed. Examples of bioinformatics tools available to date are listed here with applications in <em>Trichoderma</em> and other ascomycetes. New advances in genome engineering in <em>Trichoderma</em> are also detailed, providing insights into available strategies for the validation of biosynthetic gene clusters identified using genome mining. Finally, the use of a combination of omics approaches, namely metabologenomics, is presented as a growing field for natural product discovery in fungi.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1367-1386"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manyun Chen , Dipesh Dhakal , Campbell W. Eckhardt , Hendrik Luesch , Yousong Ding
Covering: 2014 to 2024
Cyanobacteria are prolific producers of bioactive natural products, including promising drug leads for FDA-approved cancer therapeutics. Advances in genome sequencing and computational tools have revealed a wealth of cyanobacterial biosynthetic gene clusters (BGCs). However, progress in genome-driven discovery has been hindered by challenges in manipulating native hosts and the limited availability of efficient heterologous expression platforms. This highlight focuses on recent synthetic biology innovations on cyanobacterial systems that address these obstacles, facilitating the production of diverse cyanobacterial natural product families. We discuss key features of widely used cyanobacterial chassis, such as Synechocystis sp. PCC 6803, Synechococcus elongatus UTEX 2973, Anabaena sp. PCC 7120, and emerging hosts. Advances in BGC cloning, combinatorial biosynthesis, transcriptional and translational regulation, and host engineering are also highlighted. Together, these synthetic biology developments provide a powerful framework for expanding cyanobacterial natural product discovery and production.
{"title":"Synthetic biology strategies for cyanobacterial systems to heterologously produce cyanobacterial natural products","authors":"Manyun Chen , Dipesh Dhakal , Campbell W. Eckhardt , Hendrik Luesch , Yousong Ding","doi":"10.1039/d5np00009b","DOIUrl":"10.1039/d5np00009b","url":null,"abstract":"<div><div>Covering: 2014 to 2024</div></div><div><div>Cyanobacteria are prolific producers of bioactive natural products, including promising drug leads for FDA-approved cancer therapeutics. Advances in genome sequencing and computational tools have revealed a wealth of cyanobacterial biosynthetic gene clusters (BGCs). However, progress in genome-driven discovery has been hindered by challenges in manipulating native hosts and the limited availability of efficient heterologous expression platforms. This highlight focuses on recent synthetic biology innovations on cyanobacterial systems that address these obstacles, facilitating the production of diverse cyanobacterial natural product families. We discuss key features of widely used cyanobacterial chassis, such as <em>Synechocystis</em> sp. PCC 6803, <em>Synechococcus elongatus</em> UTEX 2973, <em>Anabaena</em> sp. PCC 7120, and emerging hosts. Advances in BGC cloning, combinatorial biosynthesis, transcriptional and translational regulation, and host engineering are also highlighted. Together, these synthetic biology developments provide a powerful framework for expanding cyanobacterial natural product discovery and production.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1240-1250"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natural product-based research encompasses the discovery, structure elucidation, biosynthesis, synthesis, and application of naturally occurring secondary metabolites. Securingine alkaloids, isolated from Flueggea suffruticosa, have emerged as valuable molecular frameworks for exploring various aspects of natural product research due to their distinct chemical structures, characterized by unique oxidation and rearrangement patterns. Herein, we provide a comprehensive account of our journey in developing novel synthetic strategies and tactics for accessing all known and even unknown securingines and investigating the potential application of securingine B as a novel class of natural product-based molecular photoswitches.
{"title":"Discovery, structure revision, synthesis, and application of all known and even unknown securingine alkaloids","authors":"Chungwoo Lee , Sunkyu Han","doi":"10.1039/d5np00025d","DOIUrl":"10.1039/d5np00025d","url":null,"abstract":"<div><div>Covering: up to 2025</div></div><div><div>Natural product-based research encompasses the discovery, structure elucidation, biosynthesis, synthesis, and application of naturally occurring secondary metabolites. Securingine alkaloids, isolated from <em>Flueggea suffruticosa</em>, have emerged as valuable molecular frameworks for exploring various aspects of natural product research due to their distinct chemical structures, characterized by unique oxidation and rearrangement patterns. Herein, we provide a comprehensive account of our journey in developing novel synthetic strategies and tactics for accessing all known and even unknown securingines and investigating the potential application of securingine B as a novel class of natural product-based molecular photoswitches.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1251-1264"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Resorcylic acid lactones (RALs) represent a significant category of polyketides characterized by a β-resorcylate unit embedded in a macrolactone ring. Since the discovery of radicicol in 1953, over 300 natural RALs have been identified, showcasing remarkable structural diversity and a wide range of pharmacological activities, including antitumor, antimalarial, antifungal, and immunomodulatory effects. RALs target multiple molecular pathways, such as heat shock protein 90 (HSP90), WNT-5A, pyruvate dehydrogenase kinase 2 (PDK2), mitogen-activated protein kinase (MAPK), and peroxiredoxin 1 (PRDX1). Despite their promising pharmacological profiles, the clinical development of RALs has progressed at a sluggish pace. This review comprehensively catalogs all natural RALs reported to date, explores their bioactivity mechanisms, and critically assesses preclinical and clinical progress. By addressing gaps in mechanistic understanding and translational research, this work highlights the challenges in drug-like properties and clinical applicability, offering valuable insights for future RAL research.
{"title":"The chemical and biological properties of natural resorcylic acid lactones†","authors":"Ying Gao , Wanpeng Li , Hanli Ruan","doi":"10.1039/d5np00033e","DOIUrl":"10.1039/d5np00033e","url":null,"abstract":"<div><div>Covering: 1953 to Feb 2025</div></div><div><div>Resorcylic acid lactones (RALs) represent a significant category of polyketides characterized by a β-resorcylate unit embedded in a macrolactone ring. Since the discovery of radicicol in 1953, over 300 natural RALs have been identified, showcasing remarkable structural diversity and a wide range of pharmacological activities, including antitumor, antimalarial, antifungal, and immunomodulatory effects. RALs target multiple molecular pathways, such as heat shock protein 90 (HSP90), WNT-5A, pyruvate dehydrogenase kinase 2 (PDK2), mitogen-activated protein kinase (MAPK), and peroxiredoxin 1 (PRDX1). Despite their promising pharmacological profiles, the clinical development of RALs has progressed at a sluggish pace. This review comprehensively catalogs all natural RALs reported to date, explores their bioactivity mechanisms, and critically assesses preclinical and clinical progress. By addressing gaps in mechanistic understanding and translational research, this work highlights the challenges in drug-like properties and clinical applicability, offering valuable insights for future RAL research.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1387-1410"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review described the total synthesis of naturally occurring cyclic peptides with unique structures covering 2020 to 2022, i.e., darobactin A, pyritide A2, decatransin, mannopeptimycin β, α- and β-amanitins, orfamide A, and MA026, paying particular attention to the construction of their unique structures via macrocyclization.
{"title":"Recent highlights of the total synthesis of cyclic peptide natural products","authors":"Takayuki Doi , Masaya Kumashiro , Kosuke Ohsawa","doi":"10.1039/d4np00056k","DOIUrl":"10.1039/d4np00056k","url":null,"abstract":"<div><div>Covering: 2020 to 2022</div></div><div><div>This review described the total synthesis of naturally occurring cyclic peptides with unique structures covering 2020 to 2022, <em>i.e.</em>, darobactin A, pyritide A2, decatransin, mannopeptimycin β, α- and β-amanitins, orfamide A, and MA026, paying particular attention to the construction of their unique structures <em>via</em> macrocyclization.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"42 8","pages":"Pages 1265-1275"},"PeriodicalIF":10.6,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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