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Canataxpropellane belongs to the medicinally important taxane diterpene family. The most prominent congener, Taxol, is one of the most commonly used anticancer agent in clinics today. Canataxpropellane exhibits a taxane skeleton with three additional transannular C–C bonds, resulting in a total of six contiguous quaternary carbons, of which four are located on a cyclobutane ring. Unfortunately, isolation of canataxpropellane from natural sources is inefficient. Here, we report a total synthesis of (–)-canataxpropellane in 26 steps and 0.5% overall yield from a known intermediate corresponding to 29 steps from commercial material. The core structure of the (–)-canataxpropellane (2) was assembled in two steps using a Diels–Alder/ortho-alkene-arene photocycloaddition sequence. Enantioselectivity was introduced by designing chiral siloxanes to serve as auxiliaries in the Diels–Alder reaction. [ABSTRACT FROM AUTHOR]

Abstract The Isodon plants (Lamiaceae) have been used in traditional Chinese medicine to alleviate sufferings from inflammations and cancers. This feature has been attributed to the presence of pharmacologically active ent -kaurane diterpenoids such as eriocalyxin B and oridonin. The Isodon eriocalyx (Dunn) Kudô species native to southwest China can accumulate a particularly high content of ent -kaurane diterpenoids (∼1.5% w/w of dried leaves). We previously identified diterpene synthases IeCPS1 and IeCPS2 as ent -copalyl diphosphate synthases (ent -CPS) potentially involved in Isodon ent -kaurane diterpenoids biosynthesis. In this study, analysis of RNA-seq transcriptome of the I. eriocalyx plant revealed three other diterpene synthase genes (IeCPS3 , IeKS1 , and IeKSL1). Their functional characterization through coupled in vitro enzyme assays has confirmed that IeCPS3 is an ent -CPS specifically producing ent -copalyl diphosphate (ent -CPP). IeKS1 accepted ent -CPP to produce exclusively ent -kaurene and may thus be defined as an ent -kaurene synthase (ent -KS). When IeKSL1 was combined with IeCPS2 or IeCPS3, no product was detected. Based on tissue-specific expression and metabolic localization studies, the IeCPS3 and IeKS1 transcripts were significantly accumulated in leaves where the ent -kaurane diterpenoid eriocalyxin B dominates, whereas weak expression of both were observed in germinating seeds in which gibberellin biosynthetic pathway is normally active. Our findings suggest that both IeCPS3 and IeKS1 possess dual roles in general (gibberellins) and specialized diterpenoid metabolism, such as that of the Isodon ent -kaurane diterpenoids. Graphical abstract Image 1 Highlights • Diterpene synthases IeCPS3, IeKS1 and IeKSL1 were identified in Isodon eriocalyx. • IeCPS3 is an ent -copalyl diphosphate synthase; IeKS1 is an ent -kaurene synthase. • IeCPS3 and IeKS1 are more abundant in leaves where eriocalyxin B accumulates. • IeKSL1 is unable to produce ent -kaurene, and quite distinct from IeKS1. [ABSTRACT FROM AUTHOR]

Based on a terpenoid overproduction platform in yeast for genome mining, a chimeric diterpene synthase from the endophytic fungus Colletotrichum gloeosporioides ES026 was characterized as the (5R,12R,14S)‐dolasta‐1(15),8‐diene synthase. The absolute configuration was independently verified through the use of enantioselectively deuterated terpene precursors, which unequivocally established the predicted C1‐III‐IV cyclization mode for this first characterized clade II‐D enzyme. Extensive isotopic labeling experiments and isolation of the intermediate (1R)‐δ‐araneosene supported the proposed cyclization mechanism. The missing link: Fungal chimeric diterpene synthases with prenyltransferase and terpene synthase domains fall into two clades (I+II) with six subclades (A–F). The present study reports the characterization of the first clade II‐D enzyme, the structures of its products, and the cyclization mechanism. The observed 12R configuration reveals a uniform stereochemistry at this carbon for all clade II enzyme products. [ABSTRACT FROM AUTHOR]

Abstract The surface extract of an accession of Psiadia punctulata (DC.) Vatke (Asteraceae) growing in Saudi Arabia was investigated for its phytochemical composition. A bio-guided investigation of the extract led to the isolation of thirteen ent -kaurane and trachylobane diterpenes and seventeen compounds previously described, including nine flavonoids and eight diterpenes. Three flavonoids and one ent -kaurane diterpene showed antimicrobial activity with MIC100 values ranging from 25 to 150 μg/ml. The extract showed antibacterial activity against Staphylococcus aureus (MIC 100 = 180 μg/ml) and antifungal activity against Candida albicans (MIC 0 = 130 μg/ml). The isolated 3′,4′,5,7-tetramethoxyflavone, at a concentration of 40 μg/ml, displayed the ability to reduce biofilm formation of S. aureus and C. albicans by 50% and 90% respectively. Graphical abstract Image 1 Highlights • The surface extract of Psiadia punctulata from Saudi Arabia was investigated. • Thirteen previously undescribed ent -kaurane and trachylobane diterpenes were isolated. • Nine known flavonoids and eight known diterpenes were also isolated. • The antimicrobial activity of the extracts, fractions and isolates was evaluated. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Quantitation of the five major and three minor diterpene acids in Copaifera reticulata oleoresin. • Solid phase extraction procedure for the quantitative separation of the diterpene acids from the oil. • Alternative strategy for the determination of diterpene acids using a quantitative HSQC approach. Abstract In this study, we present the quantitation of eight diterpene acids in the oleoresin of Copaifera reticulata Ducke by UHPLC-ELSD and quantitative HSQC (heteronuclear single quantum correlation spectroscopy). UHPLC was performed using reversed phase material and external calibration and showed RSD values of ≤ 3% (repeatability) and ≤ 4% (precision), and mean recovery rates of 91.2–104.8%. LOQs were determined with 10 and 20 μg/mL, and LODs with 4 and 8 μg/mL, respectively. For the qHSQC method, calibration curves of eight different NMR cross-peaks (furylic, endo- and exocyclic methine signals, exocyclic methylene and methyl signals) were established and normalized with dimethyl terephthalate, which served as internal standard. This approach allowed the direct quantification of four major and one minor diterpene, whereas simple calculation procedures led to the contents of the remaining minor compounds. Comparison with the results of the UHPLC assay showed good agreement for seven of the eight diterpene acids. In terms of precision, the qHSQC method was advantageous for the quantification of the three main compounds, whereas UHPLC-ELSD was superior in the determination of the minor components. In contrast to previous reports, kolavenic acid was identified as a major diterpene acid in the oleoresin of Copaifera reticulata , with amounts of 4.0 ± 0.3%. [ABSTRACT FROM AUTHOR]

Nine new macrocyclic diterpenoids ( 1 – 9 ), jatromultones A - I, along with eight known analogues ( 10 – 17 ) were isolated from the trunks of Jatropha multifida . The structures of the new compounds, including their absolute configurations, were elucidated by combination of spectroscopic analysis, single crystal X-ray diffraction, Rh 2 (OCOCF 3 ) 4 -induced CD method, and chemical correlations. All compounds were screened for the cytotoxicity against five cancer cell lines, including one drug-resistant cell line, and seven compounds exhibited significant activity with IC 50 values less than 10 μM. Compound 4 with IC 50 values ranging from 2.69 to 6.44 μM toward all cell lines was selected for further mechanistic study, which showed that 4 could arrest cell cycle at G2/M phase and induce apoptosis. The brief structure-activity relationships (SARs) of these macrocyclic diterpenoids were also discussed. [ABSTRACT FROM AUTHOR]

Abstract: We report on our accomplishment of the asymmetric synthesis of hispidanin A and its natural precursor, a labdane diterpenoid. In the first generation of synthesis, a semi‐synthesis strategy was employed to construct a labdane‐type diterpenoid, a natural precursor of hispidanin A, in which Barton's photolytic remote functionalization was employed as a key transformation. In addition, the totarane‐type dienophile counterpart was derived from commercially available (−)‐scalareol. In the second generation of synthesis, key elements included an iron‐catalyzed radical cascade to access the labdane‐type diene on the basis of hydrogen atom transfer, and an enantioselective cationic polyene cyclization furnished the totarane‐type dienophile. Reaction optimization and mechanistic analysis of the radical cascade reaction was conducted. Furthermore, the [4+2] cycloaddition reaction was achieved in excellent yield and selectivity under thermal conditions, which has been rationalized by using DFT transition‐state analysis and paved the way for final accomplishment of the total synthesis of hispidanin A. [ABSTRACT FROM AUTHOR]

Maoecrystal A (MC-A) is an ent-kaurane-type diterpene isolated from Rabdosia eriocalyx (Dunn) Hara. MC-A has been reported to show different types of pharmacological activities, including anticancer, anti-inflammatory and bacteriostatic functions. However, bioanalysis of MC-A has not been reported. The purpose of this study is to develop an UPLC-MS/MS method to quantify MC-A in plasma and determine its pharmacokinetic properties using an animal model. The separation was performed using a Waters HSS T3 column (50 mm × 2.1 mm, 1.8 μm, Waters Corp., Milford, MA, USA) with methanol and water containing 0.1% of formic acid as the mobile phases. The mass analysis was performed in a Waters Xevo TQ mass spectrometer using multiple reaction monitoring (MRM) in positive scan mode. Protein precipitation was used to extract the drug from rat plasma samples. The calibration curve is linear in the concentration range 0.49–2000.0 ng/mL. The extraction recovery and the matrix effect were 78.11 to 91.72% and 90.38 to 98.02%, respectively. The RSD of inter/intra-day precisions were <13.72% and the accuracy was >86.41%. Stability studies showed that MC-A was stable (RSD < 14.98%) at different conditions ( i . e ., short-term, long-term, bench, and three freeze-thaw cycles) in rat plasma. The method was successfully applied to a pharmacokinetic study using rats through oral and intravenous administration routes. The oral bioavailability of MC-A was only 2.9%. Further studies are needed to determine the absorption and metabolism in order to improve the oral bioavailability of MC-A. [ABSTRACT FROM AUTHOR]

A convenient approach to the construction of the 5-6-7 tricarbocyclic fused core structure of -cyanthiwigins via a Co-mediated Pauson-Khand reaction as a key step has been developed. The cyathane core intermediate obtained by this strategy was used in the concise synthesis of (±)-5-epi-cyanthiwigin I. The developed chemistry paves the way for the total synthesis of structurally diverse cyanthiwigins. [ABSTRACT FROM AUTHOR]

The first enantioselective total synthesis of (+)-taondiol, a pentacyclic marine meroterpenoid, has been achieved, which in addition to confirming the structure also established the absolute configuration of the natural product. The notable points in the synthetic route are synthesis of a highly functionalized tricyclic diterpenoid moiety starting from an enantiopure Wieland-Miescher ketone derivative in concise manner via Robinson-type annulation and an elegant hydrogen atom transfer olefin reduction followed by Lewis acid-catalyzed Friedel-Crafts reaction for one-pot C-C and C-O bond formations resulting in construction of the pentacyclic meroterpenoid skeleton. [ABSTRACT FROM AUTHOR]

Repeated administration of songorine to mice restored mnestic processes impaired by scopolamine treatment, which manifested in improvement of CPAR conditioning and normalization of behavioral activity throughtout the observation period. This thearpeutical effect surpassed that of pyracetam used as the reference drug. [ABSTRACT FROM AUTHOR]

Abstract: Two bacterial diterpene synthases from the actinomycete Allokutzneria albata were investigated, resulting in the identification of the structurally unprecedented compound spiroalbatene from the first and cembrene A from the second enzyme. Both enzymes were thoroughly investigated in terms of their mechanisms by isotope labeling experiments, site‐directed mutagenesis, and variation of the metal cofactors and pH value. For spiroalbatene synthase, the pH‐ and Mn2+‐dependent formation of the side product thunbergol was observed, which is biosynthetically linked to spiroalbatene. [ABSTRACT FROM AUTHOR]

The first total synthesis of a chromodorolide marine diterpenoid is described. The core of the diterpenoid is constructed by a bimolecular radical addition/cyclization/fragmentation cascade that unites two complex fragments and forms two C-C bonds and four contiguous stereogenic centers of (-)-chromodorolide B in a single step. This coupling step is initiated by visible-light photocatalytic fragmentation of a redox-active ester, which can be accomplished in the presence of an iridium or a less-precious electron-rich dicyanobenzene photocatalyst, and employs equimolar amounts of the two addends. Computational studies guided the development of this central step of the synthesis and provide insight into the origin of the observed stereoselectivity. [ABSTRACT FROM AUTHOR]

Abstract: Detailed literature inspections regarding the diterpenoids icetexone (1) and conacytone (3) reveal that the absolute configuration (AC) of these natural occurring compounds is not rigorously proven, despite they were originally isolated in 1976. This task is now completed by single‐crystal X‐ray diffraction Flack and Hooft parameters determination after processing data collected with Cu Kα graphite monochromated radiation. The AC of both compounds is further determined by vibrational circular dichroism measurements performed on icetexone acetate (2) and conacytone triacetate (4) since the solubility of 1 and 3 is limited. Comparison of the substituent chemical shifts (SCS) induced by acetylation of 1 and 3 to afford 2 and 4, respectively, reveals that in the case of icetexone, all six SCS values of the quinone ring are in excellent agreement with the expected values, while in the case of conacytone, three agree and three do not agree due to the presence of additional acetates near the quinone ring. Density functional theory calculations performed on 3‐hydroxythymoquinone (6) and its tautomer 4‐hydroxy‐1,2‐quinone 7, on 6‐hydroxythymoquinone (8) and its tautomer ortho‐quinone 9, and on icetexone (1) and the claimed natural occurring ortho‐quinone tautomer romulogarzone (5) indicate that 2‐hydroxy‐1,4‐quinones are more stable, by some 11‐14 kcal/mol, than their 4‐hydroxy‐1,2‐quinone tautomers, and therefore, romulogarzone (5) is inexistent. [ABSTRACT FROM AUTHOR]

The first total synthesis of parvifloron F, a bioactive highly oxidized abietane diterpene, was achieved. The abietane skeleton was constructed by Lewis acid promoted cyclization. Preliminary structure–activity relationship correlations were established for the synthetic intermediates against human tumor cell lines. Certain compounds showed unique selective antiproliferative activity against triple-negative breast cancer. The oxidation level of the abietane ring affected the selectivity. [ABSTRACT FROM AUTHOR]

The cytotoxic activity of the pimarane diterpene annonalide ( 1 ) and nine of its semisynthetic derivatives ( 2 – 10 ) was investigated against the human tumor cell lines HL-60 (leukemia), PC-3 (prostate adenocarcinoma), HepG2 (hepatocellular carcinoma), SF-295 (glioblastoma) and HCT-116 (colon cancer), and normal mouse fibroblast (L929) cells. The preparation of 2 – 10 involved derivatization of the side chain of 1 at C-13. Except for 2 , all derivatives are being reported for the first time. Most of the tested compounds presented IC 50 s below 4.0 μM, being considered potential antitumor agents. The structures of all new compounds were elucidated by spectroscopic analyses including 2D NMR and HRMS. Additionally, the interaction of annonalide ( 1 ) with ctDNA was evaluated using spectroscopic techniques, and the formation of a supramolecular complex with the macromolecule was confirmed. Competition assays with fluorescent probes (Hoechst and ethidium bromide) and theoretical studies confirmed that 1 interacts preferentially via DNA intercalation with stoichiometric ratio of 1:1 ( 1 :ctDNA). The ΔG value was calculated as −28.24 kJ mol −1 , and indicated that the interaction process occurs spontaneously. Docking studies revealed that van der Walls is the most important interaction in 1 -DNA and EB-DNA complexes, and that both ligands ( 1 and EB) interact with the same DNA residues (DA6, DA17 and DT19). [ABSTRACT FROM AUTHOR]

Tripterygium wilfordii, which has long been used as a medicinal plant, exhibits impressive and effective anti-inflammatory, immunosuppressive and anti-tumor activities. The main active ingredients are diterpenoids and triterpenoids, such as triptolide and celastrol, respectively. A major challenge to harnessing these natural products is that they are found in very low amounts in planta. Access has been further limited by the lack of knowledge regarding their underlying biosynthetic pathways, particularly for the abeo-abietane tri-epoxide lactone triptolide. Here suspension cell cultures of T. wilfordii were found to produce triptolide in an inducible fashion, with feeding studies indicating that miltiradiene is the relevant abietane olefin precursor. Subsequently, transcriptome data were used to identify eight putative (di)terpene synthases that were then characterized for their potential involvement in triptolide biosynthesis. This included not only biochemical studies which revealed the expected presence of class II diterpene cyclases that produce the intermediate copalyl diphosphate ( CPP), along with the more surprising finding of an atypical class I (di)terpene synthase that acts on CPP to produce the abietane olefin miltiradiene, but also their subcellular localization and, critically, genetic analysis. In particular, RNA interference targeting either both of the CPP synthases, TwTPS7v2 and TwTPS9v2, or the subsequently acting miltiradiene synthase, TwTPS27v2, led to decreased production of triptolide. Importantly, these results then both confirm that miltiradiene is the relevant precursor and the relevance of the identified diterpene synthases, enabling future studies of the biosynthesis of this important bioactive natural product. [ABSTRACT FROM AUTHOR]

The first total synthesis of the title diterpene was accomplished starting from the Wieland-Miescher ketone. A diastereoselective sulfa-Michael addition enabled the generation of the delicate β,γ-unsaturated ketone moiety, while the tetracyclic kempane skeleton was readily constructed through domino metathesis. [ABSTRACT FROM AUTHOR]

Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from D-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis. [ABSTRACT FROM AUTHOR]

1-Hydroxy-14-isopropyl-3β-methoxymethyl-7β,11β-dimethyl-3α-[((2-trimethylsilyl)ethoxy)methoxy]-1,2-secofusicocca-8,10(14)-dien-2-one, a highly functionalized 1,2-seco fusicoccane diterpene skeleton related to cotylenin A was synthesized in a convergent manner. The A ring segment, i. e ., (1′ R ,2 S , 2′ E ,5 S )-2-methoxymethyl-5-[1′-methyl-3’-(trimethylstannyl)prop-2-enyl]-2-[((2″-trimethylsilyl)ethoxy)methoxy]cyclopentanone, was synthesized in 20.1% yield over 18 steps from known ( S )-5-isopropenyl-2-methylcyclopent-1-enecarbaldehyde. This was coupled with the C ring segment, i. e ., ( R )-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, which was prepared according to our previous report. The Stille coupling reaction between alkenylstannane and sterically hindered triflate proceeded successfully in the presence of PEPPSI-SIPr (85%), and the total yield of the target molecule was 17.1% over the longest linear sequences (19 steps) from ( S )-5-isopropenyl-2-methylcyclopent-1-enecarbaldehyde. [ABSTRACT FROM AUTHOR]

Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs. [ABSTRACT FROM AUTHOR]

An improved synthesis of an eneimide, which is a useful precursor to pleuromutilin-based antibiotics, is reported. This synthesis proceeds in six steps and 17% overall yield (27% based on recovery of a key hydrindenone intermediate) and requires two fewer chromatography steps and five fewer days of reaction time than the previously reported route. The use of expensive, acutely toxic, and precious metal reagents or catalysts has been minimized. [ABSTRACT FROM AUTHOR]

Total syntheses of the reported structures of the rhamnofolane diterpene natural products curcusones I and J in racemic form were achieved. The synthetic strategy features a novel tandem gold-catalyzed furan formation and furan-allene [4+3] cycloaddition to build the 5,7-fused ring system with an oxa-bridge in one step, and a stereoselective exo-Diels-Alder reaction to form the 6-membered ring. The newly developed tandem gold catalysis is quite general and can be scaled up. Our syntheses suggest that structural revisions of curcusones I and J are needed. [ABSTRACT FROM AUTHOR]

Phytocassanes and momilactones are the major diterpenoid phytoalexins inductively produced in rice as bioactive substances. Regardless of extensive studies on the biosynthetic pathways of these phytoalexins, bioconversion of diterpene hydrocarbons is not shownin planta. To elucidate the entire biosynthetic pathways of these phytoalexins, uniformly13C-labeledent-cassadiene andsyn-pimaradiene were enzymatically synthesized with structural verification by GC–MS and13C-NMR. Application of the13C-labeled substrates on rice leaves led to the detection of13C-labeled metabolites using LC-MS/MS. Further application of this method in the mossHypnum plumaeformeand the nearest out-group ofOryzaspeciesLeersia perrieri, respectively, resulted in successful bioconversion of these labeled substrates into phytoalexins in these plants. These results demonstrate that genuine biosynthetic pathways from these diterpene hydrocarbons to the end product phytoalexins occur in these plants and that enzymatically synthesized [U-13C20] diterpene substrates are a powerful tool for chasing endogenous metabolites without dilution with naturally abundant unlabeled compounds. Uniformly labeled13C-diterpene: A powerful tool for tracing endogenous metabolites without dilution with naturally abundant unlabeled compounds [ABSTRACT FROM PUBLISHER]

Atisane-type diterpenoids are the principal constituent of tetracyclic C20-diterpenoids, widely isolated from the plant kingdom with varying degrees of structural complexity and pharmacological activity. The tetracarbocyclic system with the unique bicyclo[2.2.2]octane skeleton of this natural product family has generated interest within the synthetic community. Divergent total synthesis is an effective tactic to synthesize several atisane-type diterpenoids using structural interconversion from a common intermediate. This account summarizes the divergent total synthesis of atisane-type diterpenoids. [ABSTRACT FROM AUTHOR]

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids: cheloviolenes A and B and dendrillolide C. [ABSTRACT FROM AUTHOR]

Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels-Alder cycloaddition at room temperature. The synthesis relies on iron-catalyzed coupling to construct a Z-configured trisubstituted alkene, an iron-catalyzed radical cascade to generate a labdane-type diene, and both Yamamoto cationic polyene cyclization and palladium-catalyzed Stille coupling to generate a totarane-type dienophile. [ABSTRACT FROM AUTHOR]

The first enantiospecific synthesis of hispidanin A ( 4), a dimeric diterpenoid from the rhizomes of Isodon hispida, was achieved with a longest linear sequence of 12 steps in 6.5 % overall yield. A key component is the use of the abundant and naturally occurring diterpenoids (+)-sclareolide and (+)-sclareol as starting materials, which enables the gram-scale preparation of the key intermediates totarane ( 1) and s- trans-12E,14-labdadien-20,8β-olide ( 2). Subsequently a thermal or an erbium-catalyzed intermolecular Diels-Alder reaction of totarane ( 1) with labdadienolide ( 2) provide convergent and rapid access to the natural product hispidanin A ( 4). The synthetic studies have offered significant impetus for the efficient construction of these architecturally complex natural products. [ABSTRACT FROM AUTHOR]

The naturally occurring diterpenoids beyerenoic ( 1 ) and kaurenoic acids ( 2 ) extracted from Perymenium buphthalmoides DC., were treated with NaOH and reacted with ZnCl 2 to afford two μ 4 -Oxo tetrazinc clusters ( μ 4 -oxo)-hexakis( μ 2 -beyerenate)-tetra-zinc(II) ( 5 ) and ( μ 4 -oxo)-hexakis( μ 2 -kaurenate)-tetra-zinc(II) ( 6 ). Both species were unequivocally characterized and their structures in the solid state determined by single crystal X-ray diffraction techniques. [ABSTRACT FROM AUTHOR]

Described is a method for the formal γ-arylation of cyclohexenones allowing synthesis of a remote all-carbon quaternary center. The process involves the palladium-catalyzed α-arylation of a α-substituted cyclic vinylogous ester followed by the Stork-Danheiser transposition. The synthetic utility of this protocol is featured in the total syntheses of (±)-12-hydroxy-13-methylpodocarpa-8,11,13-trien-3-one, (±)-3β,12-dihydroxy-13-methylpodocarpane-8,11,13-triene, and (±)-O-methyl nimbinone. [ABSTRACT FROM AUTHOR]

Forskolin is a unique structurally complex labdane-type diterpenoid used in the treatment of glaucoma and heart failure based on its activity as a cyclic AMP booster. Commercial production of forskolin relies exclusively on extraction from its only known natural source, the plant Coleus forskohlii, in which forskolin accumulates in the root cork. Here, we report the discovery of five cytochrome P450s and two acetyltransferases which catalyze a cascade of reactions converting the forskolin precursor 13R-manoyl oxide into forskolin and a diverse array of additional labdane- type diterpenoids. A minimal set of three P450s in combination with a single acetyl transferase was identified that catalyzes the conversion of 13R-manoyl oxide into forskolin as demonstrated by transient expression in Nicotiana benthamiana. The entire pathway for forskolin production from glucose encompassing expression of nine genes was stably integrated into Saccharomyces cerevisiae and afforded forskolin titers of 40 mg/L. [ABSTRACT FROM AUTHOR]

An efficient and straightforward semisynthesis of the antiprotozoal abietane diterpenoid (-)-sugikurojin A, starting from the readily available methyl ester of callitrisic acid (4-epi-dehydroabietic acid) isolated from sandarac resin, is reported. This optimized semisynthetic route provides a convenient source of the antiprotozoal compound, in four steps from methyl callitrisate in 50% overall yield, for further biological studies. [ABSTRACT FROM AUTHOR]

A series of pleuromutilin derivatives bearing piperazine ring have been reported. The in vitro antibacterial activities of the synthetic derivatives against MRSA (ATCC 43300), Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212), Enterococcus faecium (ATCC35667) and Escherichia coli (ATCC25922) were evaluated by the broth dilution method. Most of the synthesized derivatives displayed potent activities. Compounds 11c , 12a and 12c were found to be the most active antibacterial derivatives against MRSA (minimum inhibitory concentration = 0.015 μg/mL). The binding of compounds 11c , 12a and 12c to the 50s ribosome were investigated by molecular modeling. Compound 11c possessed lower binding free energy compared with compounds 12a and 12c . Compound 11c was further evaluated in MRSA systemic infection model and displayed superior in vivo efficacy to that of tiamulin. [ABSTRACT FROM AUTHOR]

We used a systems genetics approach to elucidate the molecular mechanisms of the responses of maize to grey leaf spot ( GLS) disease caused by Cercospora zeina, a threat to maize production globally. Expression analysis of earleaf samples in a subtropical maize recombinant inbred line population ( CML444 × SC Malawi) subjected in the field to C. zeina infection allowed detection of 20 206 expression quantitative trait loci ( eQTLs). Four trans- eQTL hotspots coincided with GLS disease QTLs mapped in the same field experiment. Co-expression network analysis identified three expression modules correlated with GLS disease scores. The module ( GY-s) most highly correlated with susceptibility ( r = 0.71; 179 genes) was enriched for the glyoxylate pathway, lipid metabolism, diterpenoid biosynthesis and responses to pathogen molecules such as chitin. The GY-s module was enriched for genes with trans- eQTLs in hotspots on chromosomes 9 and 10, which also coincided with phenotypic QTLs for susceptibility to GLS. This transcriptional network has significant overlap with the GLS susceptibility response of maize line B73, and may reflect pathogen manipulation for nutrient acquisition and/or unsuccessful defence responses, such as kauralexin production by the diterpenoid biosynthesis pathway. The co-expression module that correlated best with resistance ( TQ-r; 1498 genes) was enriched for genes with trans- eQTLs in hotspots coinciding with GLS resistance QTLs on chromosome 9. Jasmonate responses were implicated in resistance to GLS through co-expression of COI1 and enrichment of genes with the Gene Ontology term 'cullin- RING ubiquitin ligase complex' in the TQ-r module. Consistent with this, JAZ repressor expression was highly correlated with the severity of GLS disease in the GY-s susceptibility network. [ABSTRACT FROM AUTHOR]

Four new ent-abietane diterpenoids, along with four known ones were isolated from the aerial parts of Isodon serra, a traditional Chinese folk medicine. The new diterpenoids were named as serrin K (1), xerophilusin XVII (2), and enanderianins Q and R (3 and 4), while the known ones were identified as rubescansin J (5), (3α,14β)-3,18-[(1-methylethane-1,1-diyl)dioxy]-ent-abieta-7,15(17)-diene-14,16-diol (6), xerophilusin XIV (7), and enanderianin P (8), respectively. Their structures were elucidated by extensive spectroscopic analysis and comparison with the literature. Compound 1 showed remarkable inhibitory activity towards NO production in LPS-stimulated RAW264.7 cells (IC50 = 1.8 μM) and weak cytotoxicity towards five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480). [ABSTRACT FROM AUTHOR]

Key message: Transcriptional activation of genes belonging to the plastidial MEP-derived isoprenoid pathway by elicitation with methyl jasmonate and coronatine enhanced the content of bioactive abietane diterpenes in Salvia sclarea hairy roots. Abstract: We have shown that aethiopinone, an abietane diterpene synthesized in Salvia sclarea roots is cytotoxic and induces apoptosis in human melanoma cells. To develop a production platform for this compound and other abietane diterpenes, hairy root technology was combined with the elicitation of methyl jasmonate (MeJA) or the phytotoxin coronatine (Cor). Both MeJA and Cor induced a significant accumulation of aethiopinone, but prolonged exposure to MeJA irremediably caused inhibition of hairy root growth, which was unaffected by Cor treatment. Considering together the fold increase in aethiopinone content and the final hairy root biomass, the best combination was a Cor treatment for 28 days, which allowed to obtain up to 105.34 ± 2.30 mg L of this compound to be obtained, corresponding to a 24-fold increase above the basal content in untreated hairy roots. MeJA or Cor elicitation also enhanced the synthesis of other bioactive abietane-quinone diterpenes. The elicitor-dependent steering effect was due to a coordinated transcriptional activation of several biosynthetic genes belonging to the plastidial MEP-derived isoprenoid pathway. High correlations between aethiopinone content and MeJA or Cor-elicited level of gene transcripts were found for DXS2 (r = 0.99), DXR ( r = 0.99), and GGPPS ( r = 0.98), encoding enzymes acting upstream of GGPP, the common precursor of diterpenes and other plastidial-derived terpenes, as well as CPPS ( r = 0.99), encoding the enzyme involved in the first cyclization steps leading to copalyl-diphosphate, the precursor of abietane-like diterpenes. These results point to these genes as possible targets of metabolic engineering approaches to establish a more efficient production platform for such promising anti-proliferative plant-derived compounds. [ABSTRACT FROM AUTHOR]

A biomimetic synthesis of briareolate ester B (3) from briareolate ester L (1) via the intermediate briareolate ester G (2) has been achieved through a unique transannular oxa-6π electrocyclization induced by UVA light. UVC irradiation of 3 triggered a rapid retro-6π electrocyclization to establish an unprecedented photochromic switch. In the ground state, reaction of 1 led to the formation of a polycyclic γ-spiroketal γ-lactone 5, architecturally related to the ether-bridged cembranoids of the cladiellin class. [ABSTRACT FROM AUTHOR]

Tripterygium wilfordii (Celastraceae) is a medicinal plant with anti-inflammatory and immunosuppressive properties. Identification of a vast array of unusual sesquiterpenoids, diterpenoids and triterpenoids in T. wilfordii has spurred investigations of their pharmacological properties. The tri-epoxide lactone triptolide was the first of many diterpenoids identified, attracting interest due to the spectrum of bioactivities. To probe the genetic underpinning of diterpenoid diversity, an expansion of the class II diterpene synthase (diTPS) family was recently identified in a leaf transcriptome. Following detection of triptolide and simple diterpene scaffolds in the root, we sequenced and mined the root transcriptome. This allowed identification of the root-specific complement of TPSs and an expansion in the class I diTPS family. Functional characterization of the class II diTPSs established their activities in the formation of four C-20 diphosphate intermediates, precursors of both generalized and specialized metabolism and a novel scaffold for Celastraceae. Functional pairs of the class I and II enzymes resulted in formation of three scaffolds, accounting for some of the terpenoid diversity found in T. wilfordii. The absence of activity-forming abietane-type diterpenes encouraged further testing of TPSs outside the canonical class I diTPS family. TwTPS27, close relative of mono-TPSs, was found to couple with TwTPS9, converting normal-copalyl diphosphate to miltiradiene. The phylogenetic distance to established diTPSs indicates neo-functionalization of TwTPS27 into a diTPS, a function not previously observed in the TPS-b subfamily. This example of evolutionary convergence expands the functionality of TPSs in the TPS-b family and may contribute miltiradiene to the diterpenoids of T. wilfordii. [ABSTRACT FROM AUTHOR]

The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P. amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene. [ABSTRACT FROM AUTHOR]

The small pro-inflammatory 10 kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E ( 1 ), crinipellin F ( 2 ), crinipellin G ( 3 ) and crinipellin H ( 4 ) were isolated from fermentations of a Crinipellis species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1 , 2 , and 3 inhibited the LPS/IFN-γ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC 50 values of 15 μM, 1.5 μM, and 3.15 μM respectively, whereas compound 4 was devoid of any biological activity. Moreover, compounds 1 , 2 and 3 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFN-γ stimulated MonoMac6 cells. [ABSTRACT FROM AUTHOR]

Paxilline indole diterpenes have been a subject of scientific inquiry for over 30 years due to their diverse biological activities and unique structural features. These efforts resulted in a multitude of synthetic approaches and a dozen completed synthesis. Here, we discuss our contributions to this area that culminated in an 11-step synthesis of (±)-emindole SB. [ABSTRACT FROM AUTHOR]

A divergent synthesis of 10 icetexane natural products based on a proposed biogenetic cationic ring expansion of a reduced carnosic acid derivative is described. Of these icetexanes, (+)-salvicanol, (−)-cyclocoulterone, (−)-coulterone, (−)-obtusinone D, and (−)-obtusinone E have been synthesized for the first time. In addition, the hypothesis for the non-enzymatic biogenesis of benzo[1,3]dioxole natural products has been experimentally investigated. Additional experimental evidence for the abiotic formation of the methylenedioxy unit is provided, as photolysis of the quinone (+)-komaroviquinone resulted in the formation of the [1,3]dioxole-containing natural product (−)-cyclocoulterone and (+)-komarovispirone. [ABSTRACT FROM AUTHOR]

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects. [ABSTRACT FROM AUTHOR]

This review overviewed several successful synthetic approaches to total synthesis of Pallavicinia diterpenoids, in which these instructive examples were discussed to provide the reader with the published synthetic strategies that have been successfully applied in their total syntheses. It is hoped that well-polished synthetic works will in the future enlighten numerous brilliant ideas and lay the foundation for other efficient synthetic approaches, affording sufficient quantities for further biological evaluation. [ABSTRACT FROM AUTHOR]

A unified approach to four different (atisine, ajaconine, denudatine, and hetidine) diterpenoid alkaloid skeletons was developed and applied to the total synthesis of the natural products dihydroajaconine ( 2, atisine type) and gymnandine ( 4, denudatine type). The synthesis features a biogenetically inspired strategy that relies on C−H oxidation, aza-pinacol coupling, and aza-Prins cyclization as key steps. [ABSTRACT FROM AUTHOR]

A synthetic approach to the isocopalane diterpenes ent-spongian-16-one, ent-isoagatholactone, and anisodorin 5 is presented. ent-Spongian-16-one was prepared by using a tricyclic diterpene building block as the starting material. Furthermore, ent-spongian-16-one was easily converted into ent-isoagatholactone and anisodorin 5 through organic transformations. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two novel 13,14- seco -abietane diterpenes were obtained. • Nukiangendine A (1) bears a novel structure with a 6/6/6/5 ring system. • Nukiangendine A (1) exhibited potent anti-HCV effect. Abstract From Abies nukiangensis , two novel 13,14- seco -abietane diterpenes, nukiangendines A (1) and B (2) were isolated. Their relative structures were determined by extensive NMR and HRMS spectroscopic analysis. The absolute configuration of 1 was established by ECD calculations. Compound 1 showed significant anti-hepatitis C virus (HCV) effects. [ABSTRACT FROM AUTHOR]

Darwinolide, a recently identified marine natural product from the Antarctic sponge Dendrilla membranosa, was previously shown to exhibit promising activity against the biofilm phase of methicillin‐resistant Staphylococcus aureus. Its challenging tetracyclic rearranged spongian diterpenoid structure links a trimethylcyclohexyl subunit to a seven‐membered core with two fused tetrahydrofuran units. Herein, we describe the first synthesis of (+)‐darwinolide, which features a convergent aldol fragment coupling, an Ireland–Claisen rearrangement, and an organocatalytic desymmetrization as the key steps. Our results provide a foundation for the development of novel antibiofilm‐specific antibiotics. Prime cuts: The first total synthesis of (+)‐darwinolide, an antibiofilm‐specific antibiotic from the Antarctic sponge Dendrilla membranosa, is reported and features a convergent aldol fragment coupling, an Ireland–Claisen rearrangement, and an organocatalytic desymmetrization as the key steps. [ABSTRACT FROM AUTHOR]

We present a full account of the development of a strategy that culminated in the first total syntheses of the unique oxetane-containing natural product (+)-dictyoxetane and the macrocyclic diterpene (+)-dolabellane V. Our retrosynthetic planning was guided by both classical and nonconventional strategies to construct the oxetane, which is embedded in an unprecedented 2,7-dioxatricyclo[4.2.1.03,8]nonane ring system. Highlights of the successful approach include highly diastereoselective carbonyl addition reactions to assemble the full carbon skeleton, a Grob fragmentation to construct the 11-membered macrocycle of (+)-dolabellane V, and a bioinspired 4- exo-tet, 5- exo-trig cyclization sequence to form the complex dioxatricyclic framework of (+)-dictyoxetane. Furthermore, an unprecedented strain-releasing type I dyotropic rearrangement of an epoxide-oxetane substrate was developed. [ABSTRACT FROM AUTHOR]