Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.
{"title":"Recent advances in the total synthesis of galantamine, a natural medicine for Alzheimer's disease.","authors":"Bichu Cheng, Qi Wang, Yi An, Fener Chen","doi":"10.1039/d4np00001c","DOIUrl":"https://doi.org/10.1039/d4np00001c","url":null,"abstract":"<p><p>Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048210","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}
Jonathan R Chekan, Lisa S Mydy, Michael A Pasquale, Roland D Kersten
Covering 1965 to February 2024Plants are prolific peptide chemists and are known to make thousands of different peptidic molecules. These peptides vary dramatically in their size, chemistry, and bioactivity. Despite their differences, all plant peptides to date are biosynthesized as ribosomally synthesized and post-translationally modified peptides (RiPPs). Decades of research in plant RiPP biosynthesis have extended the definition and scope of RiPPs from microbial sources, establishing paradigms and discovering new families of biosynthetic enzymes. The discovery and elucidation of plant peptide pathways is challenging due to repurposing and evolution of housekeeping genes as both precursor peptides and biosynthetic enzymes and due to the low rates of gene clustering in plants. In this review, we highlight the chemistry, biosynthesis, and function of the known RiPP classes from plants and recommend a nomenclature for the recent addition of BURP-domain-derived RiPPs termed burpitides. Burpitides are an emerging family of cyclic plant RiPPs characterized by macrocyclic crosslinks between tyrosine or tryptophan side chains and other amino acid side chains or their peptide backbone that are formed by copper-dependent BURP-domain-containing proteins termed burpitide cyclases. Finally, we review the discovery of plant RiPPs through bioactivity-guided, structure-guided, and gene-guided approaches.
{"title":"Plant peptides - redefining an area of ribosomally synthesized and post-translationally modified peptides.","authors":"Jonathan R Chekan, Lisa S Mydy, Michael A Pasquale, Roland D Kersten","doi":"10.1039/d3np00042g","DOIUrl":"10.1039/d3np00042g","url":null,"abstract":"<p><p>Covering 1965 to February 2024Plants are prolific peptide chemists and are known to make thousands of different peptidic molecules. These peptides vary dramatically in their size, chemistry, and bioactivity. Despite their differences, all plant peptides to date are biosynthesized as ribosomally synthesized and post-translationally modified peptides (RiPPs). Decades of research in plant RiPP biosynthesis have extended the definition and scope of RiPPs from microbial sources, establishing paradigms and discovering new families of biosynthetic enzymes. The discovery and elucidation of plant peptide pathways is challenging due to repurposing and evolution of housekeeping genes as both precursor peptides and biosynthetic enzymes and due to the low rates of gene clustering in plants. In this review, we highlight the chemistry, biosynthesis, and function of the known RiPP classes from plants and recommend a nomenclature for the recent addition of BURP-domain-derived RiPPs termed burpitides. Burpitides are an emerging family of cyclic plant RiPPs characterized by macrocyclic crosslinks between tyrosine or tryptophan side chains and other amino acid side chains or their peptide backbone that are formed by copper-dependent BURP-domain-containing proteins termed burpitide cyclases. Finally, we review the discovery of plant RiPPs through bioactivity-guided, structure-guided, and gene-guided approaches.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970035","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}
Isabel P-M Pfeiffer, Maria-Paula Schröder, Silja Mordhorst
Covering: up to 2024Ribosomally synthesised and post-translationally modified peptides (RiPPs) comprise a substantial group of peptide natural products exhibiting noteworthy bioactivities ranging from antiinfective to anticancer and analgesic effects. Furthermore, RiPP biosynthetic pathways represent promising production routes for complex peptide drugs, and the RiPP technology is well-suited for peptide engineering to produce derivatives with specific functions. Thus, RiPP natural products possess features that render them potentially ideal candidates for drug discovery and development. Nonetheless, only a small number of RiPP-derived compounds have successfully reached the market thus far. This review initially outlines the therapeutic opportunities that RiPP-based compounds can offer, whilst subsequently discussing the limitations that require resolution in order to fully exploit the potential of RiPPs towards the development of innovative drugs.
{"title":"Opportunities and challenges of RiPP-based therapeutics.","authors":"Isabel P-M Pfeiffer, Maria-Paula Schröder, Silja Mordhorst","doi":"10.1039/d3np00057e","DOIUrl":"https://doi.org/10.1039/d3np00057e","url":null,"abstract":"<p><p>Covering: up to 2024Ribosomally synthesised and post-translationally modified peptides (RiPPs) comprise a substantial group of peptide natural products exhibiting noteworthy bioactivities ranging from antiinfective to anticancer and analgesic effects. Furthermore, RiPP biosynthetic pathways represent promising production routes for complex peptide drugs, and the RiPP technology is well-suited for peptide engineering to produce derivatives with specific functions. Thus, RiPP natural products possess features that render them potentially ideal candidates for drug discovery and development. Nonetheless, only a small number of RiPP-derived compounds have successfully reached the market thus far. This review initially outlines the therapeutic opportunities that RiPP-based compounds can offer, whilst subsequently discussing the limitations that require resolution in order to fully exploit the potential of RiPPs towards the development of innovative drugs.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139970034","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 will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C–C and C–O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, etc.) will be surveyed. Future directions of this particular area of research will also be assessed.
{"title":"Recent advances in oxidative phenol coupling for the total synthesis of natural products","authors":"Matthew C. Carson , Marisa C. Kozlowski","doi":"10.1039/d3np00009e","DOIUrl":"10.1039/d3np00009e","url":null,"abstract":"<div><p>Covering: 2008 to 2023</p></div><div><p>This review will describe oxidative phenol coupling as applied in the total synthesis of natural products. This review covers catalytic and electrochemical methods with a brief comparison to stoichiometric and enzymatic systems assessing their practicality, atom economy, and other measures. Natural products forged by C–C and C–O oxidative phenol couplings as well as from alkenyl phenol couplings will be addressed. Additionally, exploration into catalytic oxidative coupling of phenols and other related species (carbazoles, indoles, aryl ethers, <em>etc.</em>) will be surveyed. Future directions of this particular area of research will also be assessed.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9598950","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}
The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023.
{"title":"Recent asymmetric synthesis of natural products bearing an α-tertiary amine moiety via temporary chirality induction strategies","authors":"Hongjun Jeon , Jae Hyun Kim , Sanghee Kim","doi":"10.1039/d3np00032j","DOIUrl":"10.1039/d3np00032j","url":null,"abstract":"<div><p>Covering: 2013 to 2023</p></div><div><p>The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41230573","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}
Anthony R. Carroll , Brent R. Copp , Tanja Grkovic , Robert A. Keyzers , Michèle R. Prinsep
Covering: January to the end of December 2022
This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.
{"title":"Marine natural products†","authors":"Anthony R. Carroll , Brent R. Copp , Tanja Grkovic , Robert A. Keyzers , Michèle R. Prinsep","doi":"10.1039/d3np00061c","DOIUrl":"10.1039/d3np00061c","url":null,"abstract":"<div><p>Covering: January to the end of December 2022</p></div><div><p>This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139569197","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}
The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C–C and C–heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.
{"title":"Controllable skeletal reorganizations in natural product synthesis","authors":"Zeliang Zhang , Xiao Qian , Yucheng Gu , Jinghan Gui","doi":"10.1039/d3np00066d","DOIUrl":"10.1039/d3np00066d","url":null,"abstract":"<div><p>Covering: 2016 to 2023</p></div><div><p>The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C–C and C–heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139641220","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 dcalycinumine A from Daphniphyllum calycinum.
{"title":"Hot off the press","authors":"Robert A. Hill , Andrew Sutherland","doi":"10.1039/d4np90005g","DOIUrl":"10.1039/d4np90005g","url":null,"abstract":"<div><p>A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as dcalycinumine A from <em>Daphniphyllum calycinum</em>.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139690748","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}
Bioassay guided purification of the extracts of Combretum caffrum led to the discovery of six series of combretastatins A–D with cytotoxic activities ranging from sub nM to >50 μM ED50's against a wide variety of cancer cell lines. Of these, cis-stilbenes combretastatins A-4 and A-1 were the most potent, exhibiting in vivo efficacy against a wide variety of tumor types in murine models. These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites. They inhibited tumor growth by a novel antivascular and antineogenesis mechanism in which they stopped blood flows to the blood vessels causing necrosis. Over 20 clinical trials of the phosphate prodrugs of combretastatin A-4 (CA4P) and A-1 (CA1P) showed objective and stable responses against many tumor types, with increased survival times of many patients along with the confirmed cure of certain patients inflicted with anaplastic thyroid cancers. Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved in vitro and in vivo potency and an often-improved cellular spectrum. Unfortunately, these preclinical improvements did not translate clinically in any meaningful way. Objectively, CA4P remained the best compound and has garnered many Orphan drug designations by FDA. Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A–D, including bioassay guided discovery, total syntheses, and structure–activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented.
{"title":"Discovery, synthesis, activities, structure–activity relationships, and clinical development of combretastatins and analogs as anticancer drugs. A comprehensive review†‡","authors":"Sheo B. Singh","doi":"10.1039/d3np00053b","DOIUrl":"10.1039/d3np00053b","url":null,"abstract":"<div><p>Covering: 1982 to up to the end of 2022</p></div><div><p>Bioassay guided purification of the extracts of <em>Combretum caffrum</em> led to the discovery of six series of combretastatins A–D with cytotoxic activities ranging from sub nM to >50 μM ED<sub>50</sub>'s against a wide variety of cancer cell lines. Of these, <em>cis</em>-stilbenes combretastatins A-4 and A-1 were the most potent, exhibiting <em>in vivo</em> efficacy against a wide variety of tumor types in murine models. These antimitotic agents inhibited tubulin polymerization by reversibly binding to the colchicine binding sites. They inhibited tumor growth by a novel antivascular and antineogenesis mechanism in which they stopped blood flows to the blood vessels causing necrosis. Over 20 clinical trials of the phosphate prodrugs of combretastatin A-4 (CA4P) and A-1 (CA1P) showed objective and stable responses against many tumor types, with increased survival times of many patients along with the confirmed cure of certain patients inflicted with anaplastic thyroid cancers. Medicinal chemistry efforts led to the identification of three new leads (AVE8062, BNC105P, SCB01A) with improved <em>in vitro</em> and <em>in vivo</em> potency and an often-improved cellular spectrum. Unfortunately, these preclinical improvements did not translate clinically in any meaningful way. Objectively, CA4P remained the best compound and has garnered many Orphan drug designations by FDA. Clinical trials with tumor genetic mapping, particularly from previous responders, may help boost the success of these compounds in future studies. A comprehensive review of combretastatin series A–D, including bioassay guided discovery, total syntheses, and structure–activity relationship (SAR) studies, biological and mechanistic studies, and preclinical and clinical evaluations of the isolated combretastatins and analogs, along with the personal perspective of the author who originated this project, is presented.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138439851","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}
α,β-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,β-unsaturation in dhAAs has profound effects on the properties of these molecules. They display significant synthetic flexibility, readily undergoing reactions such as Michael additions, transition-metal-catalysed cross-couplings, and cycloadditions. These residues in peptides/proteins also exhibit great potential in bioorthogonal applications using click chemistry. Peptides containing contiguous dhAA residues have been extensively investigated in the field of foldamers, self-assembling supermolecules that mimic biomacromolecules such as proteins to fold into well-defined conformations. dhAA residues in these peptidyl materials tend to form a 2.05-helix. As a result, stretches of dhAA residues arrange in an extended conformation. In particular, peptidyl foldamers containing β-enamino acid units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by light-dependent E–Z isomerization. Among approximately 40 dhAAs found in the natural product inventory, dehydroalanine (Dha) and dehydrobutyrine (Dhb) are the most abundant. Dha is the simplest dehydro-α-amino acid, or α-dhAA, without any geometrical isomers, while its re-arranged isomer, 3-aminoacrylic acid (Aaa or ΔβAla), is the simplest dehydro-β-amino acid, or β-enamino acid, and displays E/Z isomerism. Dhb is the simplest α-dhAA that exhibits E/Z isomerism. The Z-isomer of Dhb (Z-Dhb) is sterically favourable and is present in the majority of naturally occurring peptides containing Dhb residues. Dha and Z-Dhb motifs are commonly found in ribosomally synthesized and post-translationally modified peptides (RiPPs). In the last decade, the formation of Dha and Dhb motifs in RiPPs has been extensively investigated, which will be briefly discussed in this review. The formation of other dhAA residues in natural products (NPs) is, however, less understood. In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.
{"title":"Dehydroamino acid residues in bioactive natural products","authors":"Shan Wang , Kewen Wu , Ya-Jie Tang , Hai Deng","doi":"10.1039/d3np00041a","DOIUrl":"10.1039/d3np00041a","url":null,"abstract":"<div><p>Covering: 2000 to up to 2023</p></div><div><p>α,β-Dehydroamino acids (dhAAs) are unsaturated nonproteinogenic amino acids found in a wide array of naturally occurring peptidyl metabolites, predominantly those from bacteria. Other organisms, such as fungi, higher plants and marine invertebrates, have also been found to produce dhAA-containing peptides. The α,β-unsaturation in dhAAs has profound effects on the properties of these molecules. They display significant synthetic flexibility, readily undergoing reactions such as Michael additions, transition-metal-catalysed cross-couplings, and cycloadditions. These residues in peptides/proteins also exhibit great potential in bioorthogonal applications using click chemistry. Peptides containing contiguous dhAA residues have been extensively investigated in the field of foldamers, self-assembling supermolecules that mimic biomacromolecules such as proteins to fold into well-defined conformations. dhAA residues in these peptidyl materials tend to form a 2.0<sub>5</sub>-helix. As a result, stretches of dhAA residues arrange in an extended conformation. In particular, peptidyl foldamers containing β-enamino acid units display interesting conformational, electronic, and supramolecular aggregation properties that can be modulated by light-dependent <em>E</em>–<em>Z</em> isomerization. Among approximately 40 dhAAs found in the natural product inventory, dehydroalanine (Dha) and dehydrobutyrine (Dhb) are the most abundant. Dha is the simplest dehydro-α-amino acid, or α-dhAA, without any geometrical isomers, while its re-arranged isomer, 3-aminoacrylic acid (Aaa or ΔβAla), is the simplest dehydro-β-amino acid, or β-enamino acid, and displays <em>E</em>/<em>Z</em> isomerism. Dhb is the simplest α-dhAA that exhibits <em>E</em>/<em>Z</em> isomerism. The <em>Z</em>-isomer of Dhb (<em>Z</em>-Dhb) is sterically favourable and is present in the majority of naturally occurring peptides containing Dhb residues. Dha and <em>Z</em>-Dhb motifs are commonly found in ribosomally synthesized and post-translationally modified peptides (RiPPs). In the last decade, the formation of Dha and Dhb motifs in RiPPs has been extensively investigated, which will be briefly discussed in this review. The formation of other dhAA residues in natural products (NPs) is, however, less understood. In this review, we will discuss recent advances in the biosynthesis of peptidyl NPs containing unusual dhAA residues and cryptic dhAA residues. The proposed biosynthetic pathways of these natural products will also be discussed.</p></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":null,"pages":null},"PeriodicalIF":11.9,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71519679","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}