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Plants contain a vast array of natural products yet to be discovered, particularly those minor bioactive constituents. Identification of these constituents requires a significant amount of plant material, presenting considerable technical challenges. Mugwort ( Artemisia argyi ) is a widely recognized insect repellent herb, particularly renowned for its extensive usage during the Dragon Boat Festival in China, but the specific constituent responsible for its repellent activity remains unknown. Here, we employed a gene-directed in vitro mining approach to characterize mugwort terpene synthases (TPSs) systematically in a yeast expression system. Based on the establishment of "Terpene synthase-standard library", we have successfully identified 54 terpene products, including a novel compound designated as cyclosantalol. Through activity screening, we have identified that (+)-intermedeol, which presents in trace amount in plants, exhibits significant repellent activity against mosquitoes and ticks. After establishing its safety and efficacy, we then achieved its biosynthetic production in a yeast chassis, with an initial yield of 2.34 g/L. The methodology employed in this study not only identified a highly effective, safe, and commercially viable insect repellent derived from mugwort but also holds promise for uncovering and producing other valuable plant natural products in future research endeavors.

Dhilirane-type meroterpenoids (DMs) featuring a 6/6/6/5/5 ring system represent a rare group of fungal meroterpenoids. To date, merely 11 DMs have been isolated or derived, leaving their chemical diversity predominantly unexplored. Herein, we leverage an understanding of biosynthesis to develop a workflow for discovery of DMs by genome mining, metabolite analysis, and tailoring enzyme catalysis. Twenty-three new DMs, including seven unprecedented scaffolds, were consequently identified. An α-ketoglutarate (α-KG)-dependent oxygenase DhiD was found to catalyze the stereodivergent ring contraction of dhilirolide D to form the dhilirane skeleton; while the cytochrome P450 DhiH reshaped the structural diversity by establishing diverse C-C bonds and oxidation. Crystallographic and mutagenesis experiments provide a molecular basis for the DhiD reaction and its stereodivergent products. Notably, DhiD exhibits substrate-controlled catalytic versatility in the chemical expansion of DMs through ring contraction, hydroxylation, dehydrogenation, epoxidation, isomerization, epimerization, and α-ketol cleavage. Bioassay results demonstrated that the obtained meroterpenoids exhibited anti-inflammatory and insecticidal activities. Our work provides insight into nature's arsenal for DM biosynthesis and the functional versatility of α-KG-dependent oxygenase and P450, which can be applied for target discovery and diversification of DM-type natural products.

Geraniol, an acyclic monoterpenoid of substantial value extracted from the essential oils of various aromatic plants, holds significant commercial and industrial importance in the realms of food, cosmetics, medicine, and bioenergy. Geraniol synthase, which is responsible for geraniol production, has been identified in only several plant species to date. Here, we present the first cloning and characterization of a geraniol synthase (PgfTPS) from Penicillium griseofulvum . This enzyme demonstrates pronounced specificity in catalyzing the conversion of geranyl diphosphate into geraniol. Moreover, through protein modeling and site-directed mutagenesis, we have identified key active-site residues crucial for the catalytic function of PgfTPS. Finally, we utilized engineered Saccharomyces cerevisiae as a host for PgfTPS expression to facilitate geraniol production. Our findings not only advance the development of efficient biocatalysts for geraniol generation but also establish a fundamental basis for further exploration into fungal monoterpene biosynthesis.

Geranyl esters (GEs) are valuable monoterpene esters derived from the esterification of geraniol and various carboxylic acids with a range of unique aromas and properties, making them valuable in perfumery, pharmaceutical, and cosmetic applications. Lipase-mediated esterification is considered to be a sustainable process but is challenged by the lack of a compatible catalytic method in conjunction with a customized microbial biosynthesis of geraniol. In this study, we developed an integrated process to convert glycerol and various carboxylates into GEs. The process includes microbial biosynthesis of geraniol using metabolically engineered Escherichia coli and enzymatic conversion of geraniol into GEs in a fermentation medium-organic biphasic system using an immobilized lipase. The enzymatic step for esterifying the target carboxylates with geraniol achieved >90% conversion under the optimized condition. Coupled with the geraniol from microbial fermentation, 0.59 g/L geranyl butyrate and 1.04 g/L geranyl hexanoate were produced subsequently, demonstrating the feasibility of converting renewable source into monoterpene esters through this integrated process, which bypassed feeding extra geraniol in the conventional lipase-mediated GE synthesis.

Ganoderma meroterpenoids are fungal derived hybrid natural product class containing a 1,2,4-trisubstituted benzene ring and a polycyclic terpenoid part. The representatives applanatumol E, H and I, lingzhilactone B, and meroapplanin B share the same bicyclic lactone moiety connected to the arene. Employing photo-Fries rearrangements as the key step enabled a general entry to these natural products. For the synthesis of the tetracyclic framework of lingzhiol, we made use of a powerful photoredox oxidative decarboxylation/Friedel-Crafts sequence.

Macrocyclic natural products, particularly those with no functionalities except unsaturation, are recognized for their therapeutic potential but are notoriously challenging to synthesize. In this study, we report the first total synthesis of an unconventional 18-membered, C 25 macrocyclic terpenoid, which has demonstrated substantial immunosuppressive activity. This synthesis was achieved through strategic modifications and innovative reaction engineering, utilizing α-terpineol and geraniol as starting materials, highlighting a novel approach in macrocyclic terpenoid synthesis.

We report the stereoselective total synthesis of rhodocoranes I and J in 10 steps and 16.4% overall yield from ( S )-limonene. The synthesis was accomplished through the convergent assembly of a highly substituted chiral cyclopentanone and a lithiated furanyl silyl ketene acetal. The requisite cyclopentanone framework was strategically constructed from the chiral pool, ( S )-limonene, through a sequence of steps that included a hydroboration/oxidation, ozonolysis, aldol condensation, reduction, and palladium-catalyzed diastereoselective allylic transposition. This study provides a general approach to the synthesis of the rhodocorane family, known for their antibacterial, antifungal, and cytotoxic properties.

Despite ongoing research on antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), their precise translocation mechanism remains elusive. This includes Buforin 2 (BF2), a well-known AMP, for which spontaneous translocation across the membrane has been proposed but a high barrier has been calculated. Here, we used computer simulations to investigate the effect of a nonequilibrium situation where the peptides are adsorbed on one side of the lipid bilayer, mimicking experimental conditions. We demonstrated that the asymmetric membrane adsorption of BF2 enhances its translocation across the lipid bilayer by lowering the energy barrier by tens of kJ mol -1 . We showed that asymmetric membrane adsorption also reduced the free energy barrier of lipid flip-flop but remained unlikely even at BF2 surface saturation. These results provide insight into the driving forces behind membrane translocation of cell-penetrating peptides in nonequilibrium conditions, mimicking experiments.

Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs ( G3-G10 ) and 40 simplifiers ( G11-G50 ) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava . Among these compounds, ( d )-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo , and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that ( d )-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. ( d )-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.

The delivery of oligonucleotides across biological barriers is a challenge of unsurpassed significance at the interface of materials science and medicine, with emerging clinical utility in prophylactic and therapeutic vaccinations, immunotherapies, genome editing, and cell rejuvenation. Here, we address the role of readily available branched lipids in the design, synthesis, and evaluation of isoprenoid charge-altering releasable transporters (CARTs), a pH-responsive oligomeric nanoparticle delivery system for RNA. Systematic variation of the lipid block reveals an emergent relationship between the lipid block and the neutralization kinetics of the polycationic block. Unexpectedly, iA21A11, a CART with the smallest lipid side chain, isoamyl-, was identified as the lead isoprenoid CART for the in vitro transfection of immortalized lymphoblastic cell lines. When administered intramuscularly in a murine model, iA21A11-mRNA complexes induce higher protein expression levels than our previous lead CART, ONA. Isoprenoid CARTs represent a new delivery platform for RNA vaccines and other polyanion-based therapeutics.

The addition of the O -linked N -acetylglucosamine ( O -GlcNAc) is a significant modification for active molecules, such as proteins, carbohydrates, and natural products. However, the synthesis of terpenoid glycoside derivatives decorated with GlcNAc remains a challenging task due to the absence of glycosyltransferases, key enzymes for catalyzing the transfer of GlcNAc to terpenoids. In this study, we demonstrated that the enzyme mutant UGT74AC1 T79Y/L48M/R28H/L109I/S15A/M76L/H47R efficiently transferred GlcNAc from uridine diphosphate (UDP)-GlcNAc to a variety of terpenoids. This powerful enzyme was employed to synthesize GlcNAc-decorated derivatives of terpenoids, including mogrol, steviol, andrographolide, protopanaxadiol, glycyrrhetinic acid, ursolic acid, and betulinic acid for the first time. To unravel the mechanism of UDP-GlcNAc recognition, we determined the X-ray crystal structure of the inactivated mutant UGT74AC1 His18A/Asp111A in complex with UDP-GlcNAc at a resolution of 1.66 Å. Through molecular dynamic simulation and activity analysis, we revealed the molecular mechanism and catalytically important amino acids directly involved in the recognition of UDP-GlcNAc. Overall, this study not only provided a potent biocatalyst capable of glycodiversifying natural products but also elucidated the structural basis for UDP-GlcNAc recognition by glycosyltransferases.

Magterpenes A-C ( 1 - 3 ), three unprecedented meroterpenoids featuring a unique 6/6/6/6/6 polycyclic skeleton, were isolated from the ethanol extract of Magnolia officinalis Rehd. et Wils. The compounds were obtained as racemic mixtures that were completely resolved through chiral columns. Their structures were elucidated by extensive analyses of one-dimensional (1D) and 2D nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, chemical calculations of 1 H/ 13 C NMR, and electronic circular dichroism calculations. The compounds were constructed via two Diels-Alder reactions in the proposed biosynthetic pathway. All isolates were evaluated for their nephroprotective and hepatoprotective activities. The results demonstrated that (+)- 1 and (-)- 1 possessed promising nephroprotective activities in a dose-dependent manner, while (-)- 2 and (+)- 3 exhibited moderate hepatoprotective activities.

Isoquinolinequinones represent an important family of natural alkaloids with profound biological activities. Heterologous expression of a rare bifunctional indole prenyltransferase/tryptophan indole-lyase enzyme from Streptomyces mirabilis P8-A2 in S. albidoflavus J1074 led to the activation of a putative isoquinolinequinone biosynthetic gene cluster and production of a novel isoquinolinequinone alkaloid, named maramycin ( 1 ). The structure of maramycin was determined by analysis of spectroscopic (1D/2D NMR) and MS spectrometric data. The prevalence of this bifunctional biosynthetic enzyme was explored and found to be a recent evolutionary event with only a few representatives in nature. Maramycin exhibited moderate cytotoxicity against human prostate cancer cell lines, LNCaP and C4-2B. The discovery of maramycin ( 1 ) enriched the chemical diversity of natural isoquinolinequinones and also provided new insights into crosstalk between the host biosynthetic genes and the heterologous biosynthetic genes in generating new chemical scaffolds.

The production of e-cigarette aerosols through vaping processes is known to cause the formation of various free radicals and reactive oxygen species (ROS). Despite the well-known oxidative potential and cytotoxicity of fresh vaping emissions, the effects of chemical aging on exhaled vaping aerosols by indoor atmospheric oxidants are yet to be elucidated. Terpenes are commonly found in e-liquids as flavor additives. In the presence of indoor ozone (O 3 ), e-cigarette aerosols that contain terpene flavorings can undergo chemical transformations, further producing ROS and reactive carbonyl species. Here, we simulated the aging process of the e-cigarette emissions in a 2 m 3 FEP film chamber with 100 ppbv of O 3 exposure for an hour. The aged vaping aerosols, along with fresh aerosols, were collected to detect the presence of ROS. The aged particles exhibited 2- to 11-fold greater oxidative potential, and further analysis showed that these particles formed a greater number of radicals in aqueous conditions. The aging process induced the formation of various alkyl hydroperoxides (ROOH), and through iodometric quantification, we saw that our aged vaping particles contained significantly greater amounts of these hydroperoxides than their fresh counterparts. Bronchial epithelial cells exposed to aged vaping aerosols exhibited an upregulation of the oxidative stress genes, HMOX-1 and GSTP1 , indicating the potential for inhalation toxicity. This work highlights the indirect danger of vaping in environments with high ground-level O 3 , which can chemically transform e-cigarette aerosols into new particles that can induce greater oxidative damage than fresh e-cigarette aerosols. Given that the toxicological characteristics of e-cigarettes are mainly associated with the inhalation of fresh aerosols in current studies, our work may provide a perspective that characterizes vaping exposure under secondhand or thirdhand conditions as a significant health risk.

Terpenes and pentene dimers are less studied volatile organic compounds (VOCs) but are associated with specific features of extra virgin olive oils (EVOOs). This study aimed to analyze mono- and sesquiterpenes and pentene dimers of Italian monovarietal EVOOs over 3 years (14 cultivars, 225 samples). A head space-solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) method recently validated was used for terpene and pentene dimer quantitation. The quantitative data collected were used for both the characterization and clustering of the cultivars. Sesquiterpenes were the molecules that most characterized the different cultivars, ranging from 3.908 to 38.215 mg/kg; different groups of cultivars were characterized by different groups of sesquiterpenes. Pentene dimers (1.336 and 3.860 mg/kg) and monoterpenes (0.430 and 1.794 mg/kg) showed much lower contents and variability among cultivars. The application of Kruskal-Wallis test-PCA-LDA-HCA to the experimental data allowed defining 4 clusters of cultivars and building a predictive model to classify the samples (94.3% correct classification). The model was further tested on 33 EVOOs, correctly classifying 91% of them.

Two novel meroterpenoids, alliisativins A and B ( 1 , 2 ) were discovered through a genome-based exploration of the biosynthetic gene clusters of the deep-sea-derived fungus Penicillium allii-sativi MCCC entry 3A00580. Extensive spectroscopic analysis, quantum calculations, chemical derivatization, and biogenetic considerations were utilized to establish their structures. Alliisativins A and B ( 1 , 2 ) possess a unique carbon skeleton featuring a drimane sesquiterpene with a highly oxidized polyketide. Noteworthily, alliisativin A ( 1 ) showed dual activity in promoting osteogenesis and inhibiting osteoclast, indicating an antiosteoporosis potential.

Penihemeroterpenoids A-C, the first meroterpenoids with an unprecedented 6/5/6/5/5/6/5 heptacyclic ring system, together with precursors penihemeroterpenoids D-F, were co-isolated from the fungus Penicillium herquei GZU-31-6. Among them, penihemeroterpenoids C-F exhibited lipid-lowering effects comparable to those of the positive control simvastatin by the activation of the AMPK/ACC/SREBP-1c signaling pathway, downregulated the mRNA levels of lipid synthesis genes FAS and PNPLA3, and increased the level of mRNA expression of the lipid export gene MTTP.

The skeletal transformations of diterpenoid forskolin were achieved by employing an oxidative rearrangement strategy. A library of 36 forskolin analogues with structural diversity was effectively generated. Computational analysis shows that 12 CTD compounds with unique scaffolds and ring systems were produced during the course of this work.

A global demand for tea tree oil (TTO) has resulted in increased adulteration in commercial products. In this study, we use a novel enantiomeric gas chromatography mass spectrometry method for chiral analysis of key terpenes ((±)-terpinen-4-ol, (±)-α-terpineol, and (±)-limonene) and quantification of components present at >0.01% to test different methods of identifying adulterated TTO. Data from authentic Australian ( n = 88) and oxidized ( n = 12) TTO samples of known provenance were consistent with recommended ranges in ISO 4730:2017 and previously published enantiomeric ratios, with p -cymene identified as the major marker of TTO oxidation. The 15 ISO 4730:2017 constituents comprised between 84.5 and 89.8% of the total ion chromatogram (TIC) peak area. An additional 53 peaks were detected in all samples (7.3-11.0% of TIC peak area), while an additional 43 peaks were detected in between 0 and 99% (0.15-2.0% of the TIC peak area). Analysis of nine commercial samples demonstrated that comparison to the ISO 4730:2017 standard does not always identify adulterated TTO samples. While statistical analysis of minor components in TTO did identify two commercial samples that differed from authentic TTO, the (+)-enantiomer percentages for limonene, terpinen-4-ol, and α-terpineol provided clearer evidence that these samples were adulterated. Thus, straightforward identification of unadulterated and unoxidized TTO could be based on analysis of appropriate enantiomeric ratios and quantitation of the p -cymene percentage.

Chinese chestnut ( Castanea mollissima BL.) is a well-known fruit tree that has been cultivated in East Asia for millennia. Leaves and buds of the plant can become seriously infested by the gall wasp Dryocosmus kuriphilus (GWDK), which results in gall formation and associated significant losses in fruit production. Herbivore-induced terpenes have been reported to play an important role in plant-herbivory interactions, and in this study, we show that upon herbivory by GWDK, four terpene-related compounds were significantly induced, while the concentrations of these four compounds in intact buds were relatively low. Among these compounds, ( E )-nerolidol and ( E , E )-α-farnesene have frequently been reported to be involved in plant herbivory defenses, which suggests direct and/or indirect functions in chestnut GWDK defenses. Candidate terpene synthase (TPS) genes that may account for ( E )-nerolidol and ( E , E )-α-farnesene terpene biosynthesis were characterized by transcriptomics and phylogenetic approaches, which revealed altered transcript levels for two TPSs: CmAFS , a TPS-g subfamily member, and CmNES/AFS, a TPS-b clade member. Both genes were dramatically upregulated in gene expression upon GWDK infestation. Furthermore, Agrobacterium tumefaciens -mediated transient overexpression in Nicotiana benthamiana showed that CmAFS catalyzed the formation of ( E , E )-α-farnesene, while CmNES / AFS showed dual ( E )-nerolidol and ( E , E )-α-farnesene synthase activity. Biochemical assays of the recombinant CmAFS and CmNES / AFS proteins confirmed their catalytic activity in vitro, and the enzymatic products were consistent with two of the major volatile compounds released upon GWDK-infested chestnut buds. Subcellular localization demonstrated that CmAFS and CmNES / AFS were both localized in the cytoplasm, the primary compartment for sesquiterpene synthesis. In summary, we show that two novel sesquiterpene synthase genes CmAFS and CmNES/AFS are inducible by herbivory and can account for the elevated accumulation of ( E , E )-α-farnesene and ( E )-nerolidol upon GWDK infestation and may be implicated in chestnut defense against GWDK herbivores.

Red algae or seaweeds produce highly distinctive halogenated terpenoid compounds, including the pentabromochlorinated monoterpene halomon that was once heralded as a promising anticancer agent. The first dedicated step in the biosynthesis of these natural product molecules is expected to be catalyzed by terpene synthase (TS) enzymes. Recent work has demonstrated an emerging class of type I TSs in red algal terpene biosynthesis. However, only one such enzyme from a notoriously haloterpenoid-producing red alga ( Laurencia pacifica ) has been functionally characterized and the product structure is not related to halogenated terpenoids. Herein, we report 10 new type I TSs from the red algae Portieria hornemannii , Plocamium pacificum , L. pacifica , and Laurencia subopposita that produce a diversity of halogenated mono- and sesquiterpenes. We used a combination of genome sequencing, terpenoid metabolomics, in vitro biochemistry, and bioinformatics to establish red algal TSs in all four species, including those associated with the selective production of key halogenated terpene precursors myrcene, trans -β-ocimene, and germacrene D-4-ol. These results expand on a small but growing number of characterized red algal TSs and offer insight into the biosynthesis of iconic halogenated algal compounds that are not without precedence elsewhere in biology.

New sesquiterpene backbones are accessible after incubation of caryolan-synthase (GcoA) and presilphiperfolan-8-β-ol synthase (BcBOT2) with a non-natural farnesyldiphosphate in which the central olefinic double bond is isomerized toward the methyl group. Two newly formed sesquiterpenoids are reported, a constitutional isomer of caryolan-1-ol ( 3 ), which we name iso -caryolan-1-ol ( 17 ), and the first terpenoid based on the isoclovane ring skeleton generated enzymatically thus far.

The class I sesquiterpene cyclase epi -isozizaene synthase from Streptomyces coelicolor (EIZS) catalyzes the transformation of linear farnesyl diphosphate (FPP) into the tricyclic hydrocarbon epi -isozizaene in the biosynthesis of albaflavenone antibiotics. The active site cavity of EIZS is largely framed by four aromatic residues - F95, F96, F198, and W203 - that form a product-shaped contour, serving as a template to chaperone conformations of the flexible substrate and multiple carbocation intermediates leading to epi -isozizaene. Remolding the active site contour by mutagenesis can redirect the cyclization cascade away from epi -isozizaene biosynthesis to generate alternative sesquiterpene products. Here, we present the biochemical and structural characterization of four EIZS mutants in which aromatic residues have been substituted with polar residues (F95S, F96H, F198S, and F198T) to generate alternative cyclization products. Most notably, F95S EIZS generates a mixture of monocyclic sesquiterpene precursors of bisabolane, a D2 diesel fuel substitute. X-ray crystal structures of the characterized mutants reveal subtle changes in the active site contour showing how each aromatic residue influences the chemistry of a different carbocation intermediate in the cyclization cascade. We advance that EIZS may serve as a robust platform for the development of designer cyclases for the generation of high-value sesquiterpene products ranging from pharmaceuticals to biofuels in synthetic biology approaches.

To overcome the high volatility, low aqueous solubility, and few definite action sites of monoterpenoid pesticides and improve their properties and effectiveness in the control of crop pathogenic fungi, herein, a series of natural turpentine-based amide derivatives exhibiting satisfactory antifungal activity were designed and synthesized. A systematic study was conducted on antifungal activity and the physiological and biochemical response of compounds 5o (EC 50 = 1.139 μg/mL) and 5j (EC 50 = 1.762 μg/mL) against Rhizoctonia solani . The effect of the target compound on the potential target-site succinate dehydrogenase was evaluated. The soluble concentrates of compounds 5o and 5j possessing good performance and control effects were prepared for practical application. To conduct a comprehensive analysis of the relationship between structural descriptors and activity, four representative title compounds were selected for theoretical calculation: 5o , 5j , 5k , and 5j . The binding mode of compound 5o and boscalid with succinate dehydrogenase was analyzed via molecular docking. This study provides a reference for the development of monoterpene pesticides with high efficiency, elucidated target sites, and the appropriate formula.

Terpenoids are an important class of natural products with diverse structures and bioactivities. Their hydrocarbon scaffolds are mainly derived from the terpenes produced by terpene cyclases (TCs). Otherwise, new hydrocarbon scaffolds can be achieved through oxidative rearrangement catalyzed by oxygenases such as P450s. Herein, we report the functional characterization of α/β- trans -bergamotene-producing TCs and their multifunctional P450 partners mined from different fungal species. In addition, novel sesquiterpenoids with hydrocarbon scaffolds different from bergamotenes were generated by combinatorial biosynthesis through mixing-and-matching these TC and P450 pairs. Our results provide a successful example of expanding the chemical diversity of terpenoids by combining genome mining and synthetic biology.

The preparation of complex molecules (e.g., biologically active secondary metabolites) remains an important pursuit in chemical synthesis. By virtue of their sophisticated architectures, complex natural products inspire total synthesis campaigns that can lead to completely new ways of building molecules. In the twentieth century, one such paradigm which emerged was the use of naturally occurring "chiral pool terpenes" as starting materials for total synthesis. These inexpensive and naturally abundant molecules provide an easily accessed source of enantioenriched material for the enantiospecific preparation of natural products. The most common applications of chiral pool terpenes are in syntheses where their structure can, entirely or largely, be superimposed directly onto a portion of the target structure. Less straightforward uses, where the structure of the starting chiral pool terpene is not immediately evident in the structure of the target, can be more challenging to implement. Nevertheless, these "nonintuitive" approaches illustrate the ultimate promise of chiral pool-based strategies: that any single chiral pool terpene could be applied to syntheses of an indefinite number of structurally diverse complex synthetic targets.By definition, such strategies require carefully orchestrated sequences of C-C bond forming and C-C cleaving reactions which result in remodeling of the terpene architecture. The combination of traditional rearrangement chemistry and transition-metal-catalyzed C-C cleavage methods, the latter of which were primarily developed in the early twenty-first century, provide a rich and powerful toolbox for implementing this remodeling approach. In this Account, we detail our efforts to use a variety of C-C cleavage tactics in the skeletal remodeling of carvone, a chiral pool terpene. This skeletal remodeling strategy enabled the reorganization of the carvone scaffold into synthetic intermediates with a variety of carboskeletons, which we, then, leveraged for the total syntheses of structurally disparate terpene natural products.We begin by describing our initial investigations into various, mechanistically distinct C-C cleavage processes involving cyclobutanols synthesized from carvone. These initial studies showcased how electrophile-mediated semipinacol rearrangements of these cyclobutanols can lead to [2.2.1]bicyclic intermediates, and how Rh- and Pd-catalyzed C-C cleavage can lead to a variety of densely functionalized cyclohexenes pertinent to natural product synthesis. We, then, present several total syntheses using these synthetic intermediates, beginning with the bridged, polycyclic sesquiterpenoid longiborneol, which was synthesized from a carvone-derived [2.2.1]bicycle following a key semipinacol rearrangement. Next, we discuss how several members of the macrocyclic phomactin family were synthesized from a cyclohexene derivative prepared through a Rh-catalyzed C-C cleavage reaction. Finally, we describe our synthesis of the marine diterpene xishacorene B, which was prepared using a key Pd-catalyzed C-C cleavage/cross-coupling that facilitated the assembly of the core [3.3.1]bicycle that is resident in the natural product structure.

Talaromyolides ( 1 - 6 ) are a group of unusual 6/6/6/6/6/6 hexacyclic meroterpenoids with (3 R )-6-hydroxymellein and 4,5-seco-drimane substructures, isolated from the marine fungus Talaromyces purpureogenus . We have identified the biosynthetic gene cluster tlxA-J by heterologous expression in Aspergillus , in vitro enzyme assays, and CRISPR-Cas9-based gene inactivation. Remarkably, the heterodimer of non-heme iron (NHI) enzymes, TlxJ-TlxI, catalyzes three steps of oxidation including a key reaction, hydroxylation at C-5 and C-9 of 12 , the intermediate with 3-ketohydroxydrimane scaffold, to facilitate a retro-aldol reaction, leading to the construction of the 4,5-secodrimane skeleton and characteristic ketal scaffold of 1 - 6 . The products of TlxJ-TlxI, 1 and 4 , were further hydroxylated at C-4'β by another NHI heterodimer, TlxA-TlxC, and acetylated by TlxB to yield the final products, 3 and 6 . The X-ray structural analysis coupled with site-directed mutagenesis provided insights into the heterodimer TlxJ-TlxI formation and its catalysis. This is the first report to show that two NHI proteins form a heterodimer for catalysis and utilizes a novel methodology to create functional oxygenase structures in secondary metabolite biosynthesis.

A brown rice cultivation of Aspergillus sp. CMB-MRF324 yielded six new meroterpenes, millmerranones A-F ( 1 - 6 ), and four known analogues, terreulactones A-D ( 7 - 10 ). Millmerranone A ( 1 ) possesses a unique carbon skeleton bearing a rare cyclic carbonate and undergoes an unprecedented base mediated rearrangement to seco -millmerranone A ( 1a ). We also report on an unexpected base rearrangement of 7 to 7a/b ; a plausible biosynthetic relationship linking 1 , 7 , and 9 ; and acetylcholinesterase inhibitory properties (IC 50 37 nM to >30 μM).

The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge-the inhibition of a human drug target-into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identified two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors appear to target an allosteric site, which confers selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-specific detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unanticipated structures and/or binding sites.

Rhodomentosones A and B ( 1 and 2 ), two pairs of novel enantiomeric phloroglucinol trimers featuring a unique 6/5/5/6/5/5/6-fused ring system were isolated from Rhodomyrtus tomentosa . Their structures with absolute configurations were elucidated by NMR spectroscopy, X-ray crystallography, and ECD calculation. The bioinspired syntheses of 1 and 2 were achieved in six steps featuring an organocatalytic asymmetric dehydroxylation/Michael addition/Kornblum-DeLaMare rearrangement/ketalization cascade reaction. Compounds 1 and 2 exhibited promising antiviral activities against respiratory syncytial virus (RSV).

Natural products are biosynthesized from a limited pool of starting materials via pathways that obey the same chemical logic as textbook organic reactions. Given the structure of a natural product, it is therefore often possible to predict its likely biosynthesis. Although biosynthesis mainly occurs in the highly specific chemical environments of enzymes, the field of biomimetic total synthesis attempts to replicate predisposed pathways using chemical reagents.We have followed several guidelines in our biomimetic approach to total synthesis. The overarching aim is to construct the same skeletal C-C and C-heteroatom bonds and in the same order as our biosynthetic hypothesis. In order to explore the innate reactivity of (bio)synthetic intermediates, the use of protecting groups is avoided or at least minimized. The key step, which is usually a cascade reaction, should be predisposed to selectively generate molecular complexity under substrate control (e.g., cycloadditions, radical cyclizations, carbocation rearrangements). In general, simple reagents and mild conditions are used; many of the total syntheses presented in this Account could be achieved using pre-1980s methodology. We have focused almost exclusively on the synthesis of meroterpenoids, that is, natural products of mixed terpene and aromatic polyketide origin, using commercially available terpenes and electron-rich aromatic compounds as starting materials. Finally, all of the syntheses in this Account involve a dearomatization step as a means to trigger a cascade reaction or to construct stereochemical complexity from a planar, aromatic intermediate.A biomimetic strategy can offer several advantages to a total synthesis project. Most obviously, successful biomimetic syntheses are usually concise and efficient, naturally adhering to the atom, step, and redox economies of synthesis. For example, in this Account, we describe a four-step synthesis of garcibracteatone and a three-step synthesis of nyingchinoid A. It is difficult to imagine shorter, non-biomimetic syntheses of these intricate molecules. Furthermore, biomimetic synthesis gives insight into biosynthesis by revealing the chemical relationships between biosynthetic intermediates. Access to these natural substrates allows collaboration with biochemists to help uncover the function of newly discovered enzymes and elucidate biosynthetic pathways, as demonstrated in our work on the napyradiomycin family. Third, by making biosynthetic connections between natural products, we can sometimes highlight incorrect structural assignments, and herein we discuss structure revisions of siphonodictyal B, rasumatranin D, and furoerioaustralasine. Last, biomimetic synthesis motivates the prediction of "undiscovered natural products" (i.e., missing links in biosynthesis), which inspired the isolation of prenylbruceol A and isobruceol.

Heterologous expression of a cryptic gene cluster in the fungus Aspergillus funiculosus CBS 116.56 led to the discovery of four new meroterpenoids, funiculolides A-D ( 1 - 4 ), derived from the aromatic polyketide 5-methylorsellinic acid (5-MOA). Intriguingly, funiculolide D ( 4 ), the apparent end product of the pathway, harbors an unusual spirocyclopentanone moiety, which is synthesized by the oxidative rearrangement catalyzed by the ferrous iron and α-ketoglutarate-dependent dioxygenase FncG.

Shikonin and S -enantiomer alkannin are important naphthoquinone derivatives present in many Boraginaceae species. We report that cytochrome P450 monooxygenases (CYPs) from a new CYP82AR subfamily catalyzed hydroxylations of deoxyshikonin at C-1' position of isoprenoid side chain. Two homologues were discovered from each species of the four Boraginaceae plants. One CYP preferred converting deoxyshikonin into shikonin, and the other stereoselectively hydroxylated deoxyshikonin into alkannin. The discovery might be a general feature of shikonin/alkannin-producing Boraginaceae plants.

The crisis of antibiotic resistance necessitates creative and innovative approaches, from chemical identification and analysis to the assessment of bioactivity. Plant natural products (NPs) represent a promising source of antibacterial lead compounds that could help fill the drug discovery pipeline in response to the growing antibiotic resistance crisis. The major strength of plant NPs lies in their rich and unique chemodiversity, their worldwide distribution and ease of access, their various antibacterial modes of action, and the proven clinical effectiveness of plant extracts from which they are isolated. While many studies have tried to summarize NPs with antibacterial activities, a comprehensive review with rigorous selection criteria has never been performed. In this work, the literature from 2012 to 2019 was systematically reviewed to highlight plant-derived compounds with antibacterial activity by focusing on their growth inhibitory activity. A total of 459 compounds are included in this Review, of which 50.8% are phenolic derivatives, 26.6% are terpenoids, 5.7% are alkaloids, and 17% are classified as other metabolites. A selection of 183 compounds is further discussed regarding their antibacterial activity, biosynthesis, structure-activity relationship, mechanism of action, and potential as antibiotics. Emerging trends in the field of antibacterial drug discovery from plants are also discussed. This Review brings to the forefront key findings on the antibacterial potential of plant NPs for consideration in future antibiotic discovery and development efforts.

Indoloterpenoids of the paxilline type belong to a large family of secondary metabolites that exhibit unique molecular architectures and a diverse set of biological activities. More than 100 congeners identified to date share a common structural motif that contains an indole moiety fused to a rearranged diterpenoid fragment. The representative physiological and cellular effects attributed to this family of natural products include neurological and insecticidal activities, modulation of lipid balance, and inhibition of mitosis. The uniting polycyclic motif combined with the diversity of individual structural features of paxilline indoloterpenoids and the broad scope of their biological activities have fascinated organic chemists for the past four decades and have led to the development of numerous syntheses. In this Account, we describe our contributions to this field and how they in turn shape new directions that are developing in our laboratory.We begin with the discussion of our strategy for the synthesis of the shared indoloterpenoid core. To address stereochemical challenges encountered in earlier reports, we planned to leverage a suitably substituted cyclopentanone in a polycyclization to form the desired trans -decalin motif. This polycyclization relied on a radical-polar crossover cascade initiated by hydrogen atom transfer. The original process exhibited poor diastereoselectivity, but we discovered an efficient solution to this problem that took advantage of intramolecular tethering effects, culminating in short synthesis of emindole SB. During these studies, we also identified indium-mediated alkenylation of silyl enol ethers with alkynes as a suitable method for the synthesis of highly substituted β,γ-unsaturated ketones that was critical to achieving brevity of our route. We subsequently developed a catalytic version of this transformation that allowed for a formal bimolecular ene reaction that exhibited unusual and potentially useful selectivity in construction of quaternary centers.To test the scope and limitations of our approach to paxilline indoloterpenoids and identify potential improvements, we developed a synthesis of the more complex congener nodulisporic acid C. The convergent assembly of this natural product was enabled by identification of new elements of stereocontrol in the radical-polar crossover polycyclization en route to the polycyclic terpenoid motif and development of a highly diastereoselective enyne cycloisomerization to access the indenopyran motif and a ketone arylation protocol to unite the two complex fragments.In subsequent studies, we expanded the radical-polar crossover cascade underlying our approach to paxilline indoloterpenoids to a bimolecular setting, which allowed for annulation of two unsaturated carbonyl components to produce functionalized cyclohexanes. This transformation is particularly well suited for installation of fully substituted carbons and can be complementary to the venerable Diels-Alder reaction. The utility of the new annulation was tested in the synthesis of forskolin, allowing for rapid construction of the complex polycyclic motif in this densely functionalized labdane diterpenoid.Over the past five years, our initial forays into the synthesis of paxilline indoloterpenoids have grown into a program that incorporates development of new synthetic methods and pursues artificial assembly of terpenoid natural products from several different families. We are encouraged by the increasing diversity of structural motifs made accessible by application of this chemistry and continue to discover new aspects of the underlying reactivity.

Biocatalytic transformations that leverage the selectivity and efficiency of enzymes represent powerful tools for the construction of complex natural products. Enabled by innovations in genome mining, bioinformatics, and enzyme engineering, synthetic chemists are now more than ever able to develop and employ enzymes to solve outstanding chemical problems, one of which is the reliable and facile generation of stereochemistry within natural product scaffolds. In recognition of this unmet need, our group has sought to advance novel chemoenzymatic strategies to both expand and reinvigorate the chiral pool. Broadly defined, the chiral pool comprises cheap, enantiopure feedstock chemicals that serve as popular foundations for asymmetric total synthesis. Among these building blocks, amino acids and enantiopure terpenes, whose core structures can be mapped onto several classes of structurally and pharmaceutically intriguing natural products, are of particular interest to the synthetic community.In this Account, we summarize recent efforts from our group in leveraging biocatalytic transformations to expand the chiral pool, as well as efforts toward the efficient application of these transformations in natural products total synthesis, the ultimate testing ground for any novel methodology. First, we describe several examples of enzymatic generation of noncanonical amino acids as means to simplify the synthesis of peptide natural products. By extracting amino acid hydroxylases from native biosynthetic pathways, we obtain efficient access to hydroxylated variants of proline, lysine, arginine, and their derivatives. The newly installed hydroxyl moiety then becomes a chemical handle that can facilitate additional complexity generation, thereby expanding the pool of amino acid-derived building blocks available for peptide synthesis. Next, we present our efforts in enzymatic C-H oxidations of diverse terpene scaffolds, in which traditional chemistry can be combined with strategic applications of biocatalysis to selectively and efficiently derivatize several commercial terpenoid skeletons. The synergistic logic of this approach enables a small handful of synthetic intermediates to provide access to a plethora of terpenoid natural product families. Taken together, these findings demonstrate the advantages of applying enzymes in total synthesis in conjunction with established methodologies, as well as toward the expansion of the chiral pool to enable facile incorporation of stereochemistry during synthetic campaigns.

Terpenes and their derivatives are important biomarkers of grape quality as they contribute to the flavor and aroma of grapes. However, the molecular basis of terpene biosynthesis throughout the grapevine phenological developmental cycle remains elusive. Our current study investigates the free and bound terpene biosynthesis of berries at different phenological stages from preveraison to harvest. Detailed gene expression (transcriptomics) analysis, terpenoid volatile production by gas chromatography-mass spectrometry (GC-MS), and in planta transient expression were employed. Our results show that concentrations of most individual terpenes at different stages are distinctive and increase from preveraison to the veraison stage followed by a decrease from veraison to maturity. The combined transcriptomic analysis and terpene profiling revealed that 22 genes belonging to the MEP pathway and multiple classes of transcription factor family members including bHLH and several hormone biosynthesis- or signaling-related genes likely participate in the regulation of terpenoid biosynthesis according to their specific expression patterns in berries. Quantitative real-time polymerase chain expression analysis of 8 key differentially expressed genes in MEP pathways and further 12 randomly selected genes was performed during 8 sampling stages and validated the RNA-seq-derived expression profiles. To further confirm the function of a subset of the differentially expressed genes, we investigated the effects of combined overexpression of 1-deoxy-d-xylulose-5-phosphate synthase ( VvDXS1-LOC100249323 ), 1-deoxy-d-xylulose-5-phosphate reductoisomerase ( VvDXR-LOC100248516 ), and terpene synthase ( VvTPS56-LOC100266449 ) on the production of terpenes by transient overexpression in Nicotiana benthamiana leaves. The overall developmental patterns of total terpenes and gene expression profiles will help guide the functional analyses of further candidate genes important for terpene biosynthesis of grape as well as identifying the master transcriptional and hormonal regulators of this pathway in the future.

From the venerable Robinson annulation to the irreplaceable Diels-Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.

In this work, 26 methylated acylphloroglucinol meroterpenoids with diverse skeletons, including 18 new ones (bellumones A-R, 1 - 18 ), were identified from the flowers of Hypericum bellum . Their structures including absolute configurations were elucidated by detailed spectroscopic data, calculated electronic circular dichroism (ECD), and X-ray diffraction (XRD). Through methylation at C-5, prenylation with different chain lengths of the acylphloroglucinol-derived core, along with different types of secondary cyclization, type A bicyclic polyprenylated acylphloroglucinols (BPAPs) ( 1 - 5 and 19 - 24 ) and dearomatized isoprenylated acylphloroglucinols (DIAPs) ( 6 - 18 and 25 - 26 ) were obtained. The significant results of anti-inflammatory, antioxidant, and anti-nonalcoholic steatohepatitis (anti-NASH) activities suggest its usefulness in daily health care.

Total synthesis of the Rhododendron meroterpenoids rubiginosins A and G, which both contain unusual 6-6-6-4 ring systems, has been achieved using a bioinspired cascade approach. Stepwise synthesis of these natural products, and the related 6-6-5-4 meroterpenoids fastinoid B and rhodonoid B, from naturally occurring chromene precursors is also reported.

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

The sesquiterpene cyclase epi -isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic precursor of the antibiotic albaflavenone. The hydrophobic active site is largely defined by aromatic residues that direct a multistep reaction sequence through multiple carbocation intermediates. The previous substitution of polar residues for a key aromatic residue, F96, converts EIZS into a high-fidelity sesquisabinene synthase: the F96S, F96M, and F96Q variants generate 78%, 91%, and 97% sesquisabinene A, respectively. Here, we report high-resolution X-ray crystal structures of two of these reprogrammed cyclases. The structures of the F96M EIZS-Mg 2+ 3 -risedronate and F96M EIZS-Mg 2+ 3 -inorganic pyrophosphate-benzyltriethylammonium cation complexes reveal structural changes in the F96 aromatic cluster that redirect the cyclization pathway leading from the bisabolyl carbocation intermediate in catalysis. The structure of the F96S EIZS-Mg 2+ 3 -neridronate complex reveals a partially occupied inhibitor and an enzyme active site caught in transition between open and closed states. Finally, three structures of wild-type EIZS complexed with the bisphosphonate inhibitors neridronate, pamidronate, and risedronate provide a foundation for understanding binding differences between wild-type and variant enzymes. These structures provide new insight regarding active site flexibility, particularly with regard to the potential for subtle expansion and contraction to accommodate ligands of varying sizes as well as bound water molecules. Additionally, these structures highlight the importance of conformational changes in the F96 aromatic cluster that could influence cation-π interactions with carbocation intermediates in catalysis.

Cognac spirit aromas result from the presence of a wide variety of volatile odorous compounds associated with the modalities of spirit distillation and aging. However, very few studies have been carried out on aging notes of Cognac spirits. An HPLC fractionation approach was used in order to evidence fractions of interest recalling the specific aromatic nuances of aged Cognac. Then, a GC-O/MS analysis of the selected fractions allowed one to detect odorous zones and identify several volatile compounds. Among them, various well-known volatile compounds representative of the terpenoid family were highlighted, such as geraniol, α-terpinene, nerol, α-terpineol, 1,8-cineole (eucalyptol) and, particularly, piperitone, santalol, and α-campholenal, which have not previously been cited in Cognac. These compounds were quantitated and their detection thresholds were determined. Geraniol, α-terpinene, α-terpineol, and 1,8-cineole concentrations increased while spirits were more aged, while nerol tends to decrease. A sensory contribution of terpenes was observed through perceptual synergic effects, along with β-damascenone and whisky lactone.

Terpenes are important contributors to wine aroma. Free and glycosidically bound terpenes are primarily formed in grapes. During fermentation, they undergo important transformation catalyzed by yeast, so that the terpene profile of grape is substantially different from that of the corresponding wine. The present paper assessed the ability of a Saccharomyces cerevisiae strain to transform 17 different terpenes. Biotransformation was performed by placing target compounds in incubation with resting cells. Volatile compounds produced were extracted by solid-phase extraction and analyzed by gas chromatography-mass spectrometry. Geranyl acetate, neryl acetate, citronellyl acetate, and menthyl acetate were formed from the corresponding terpene alcohols. β-Citronellol was the main product of geraniol transformation; geranial, an intermediate of this pathway, has also been detected. Limonene was hydroxylated by yeast to form carveol, trans -2,8-menthadien-1-ol, and cis -2,8-menthadien-1-ol. Moreover, yeast cells were found to be able to adsorb a significant portion of the terpenes present in the reaction batches, with the extent of this phenomenon being linked to terpene hydrophobicity.

To study the contribution of yeasts to the formation of terpene derivatives during winemaking, a dispersive liquid-liquid microextraction gas chromatography mass spectrometry method was developed for the quantitation of terpenes in white wines, synthetic wine, and a fermented synthetic medium. A mixture of acetone (disperser solvent) and dichloromethane (extraction solvent) was added to 5 mL of sample. The proposed method showed no matrix effect, good linearity in the enological range (from 10 to 200 μg/L), good recovery, and satisfactory inter- and intraday reproducibilities (below 20 and 15% of the relative standard deviation). This sample preparation technique is very interesting for high-throughput studies and economic and environmental reasons because it is fast and easy to operate with high enrichment and consumes a low volume of organic solvents. This method was applied to explore the capacities of 40 yeast strains to produce terpene compounds during fermentation of Chardonnay and Ugni Blanc musts as well as in a synthetic medium. Interestingly, most of the studied compounds were detected and quantified in the resulting wines. This study shows that yeast strains can intrinsically produce terpene derivatives under enological conditions and also highlights the differences between the de novo biosynthesis of terpenes and their precursor-linked production.

Garcinol is a natural product from the Garcinia Indica fruit and is well-known as an antioxidant, anti-inflammatory, and anticancer agent. However, the understanding of its mechanism of action is still incomplete. It has been reported to be a histone acetyltransferase (HAT) inhibitor. Here, we surprisingly found that garcinol is a potent histone deacetylase 11 (HDAC11) inhibitor (IC 50 ∼ 5 μM in vitro with the HPLC assay and IC 50 ∼ 10 μM in the cellular SHMT2 fatty acylation assay), which is comparable to previously reported HDAC11 inhibitors. Additionally, among all the HDACs tested, garcinol specifically inhibits HDAC11 over other HDACs. HDAC11 is the only class IV HDAC, and there are very few inhibitors available for it. Therefore, this study provides a new HDAC11 inhibitor lead from natural products and may help explain the various biological activities of garcinol.

Cannabinoids have surely been one of the most widely self-administered drugs other than caffeine. The U.S. FDA recently approved one cannabinoid-based drug whose active pharmaceutical ingredient (API) is cannabidiol (CBD). The long history of individual use of cannabis for a wide range of conditions has sparked great interest in other uses of CBD, in ethical drugs and botanical supplements as well as in foods and nonprescription wellness products. CBD may be sourced from cannabis plants but can also be prepared synthetically, the topic of this review.

Actinidine, a methylcyclopentane monoterpenoid pyridine alkaloid, has been found in many iridoid-rich plants and insect species. In a recent research on a well-known actinidine- and iridoid-producing ant species, Tapinoma melanocephalum (Fabricius) (Hymenoptera: Formicidae), no actinidine was detected in its hexane extracts by gas chromatography-mass spectrometry analysis using a common sample injection method, but a significant amount of actinidine was detected when a solid injection technique with a thermal separation probe was used. This result led us to hypothesize that heat can induce the production of actinidine in iridoid-rich organisms. To test our hypothesis, the occurrence of actinidine was investigated in four iridoid-rich organisms under different sample preparation temperatures, including two ant species, T. melanocephalum and Iridomyrmex anceps Roger (Hymenoptera: Formicidae), and two plant species, Actinidia polygama Maxim (Ericales: Actinidiaceae) and Nepeta cataria L. (Lamiales: Lamiaceae). Within a temperature range of 50, 100, 150, 200, and 250 °C, no actinidine was detected at 50 °C, but it appeared at temperatures above 100 °C for all four species. A positive relationship was observed between the heating temperature and actinidine production. The results indicate that actinidine could be generated at high temperatures. We also found that the presence of methylcyclopentane monoterpenoid iridoids (iridodials and nepetalactone) was needed for thermally induced actinidine production in all tested samples. These results suggest that the presence of actinidine in iridoid-rich plants and ants might be a consequence of using high temperatures during sample preparation.

Here, we reported that detailed investigation on trace targeted metabolites from nematode-trapping fungus Arthrobotrys oligospora mutant with deletion of P450 gene AOL_s00215g278 led to isolation of 9 new polyketide-terpenoid hybrid derivatives, including four new glycosides of the key precursor farnesyl hydrotoluquinol ( 1 ) and, surprisingly, four new sesquiterpenyl epoxy-cyclohexenoids (SECs) analogues. Among them, two major target metabolites 1 and 14 displayed moderate nematode inhibitory ability. Moreover, the mutant lacking AOL_s00215g278 could form far more nematode-capturing traps within 6 h in contact with nematodes and show rapid potent nematicidal activity with killing 93.7% preys, though deletion of the P450 gene resulted in dramatic decrease in fungal colony growth and failure to produce fungal conidia. The results unequivocally revealed that gene AOL_s00215g278 should be involved in not only the SEC biosynthetic pathway in the nematode-trapping fungus A. oligospora but also fungal conidiation and nematicidal activity.