Fragilides U-W: New 11,20-Epoxybriaranes from the Sea Whip Gorgonian Coral Junceella fragilis.

Three new 11,20-epoxybriaranes-fragilides U-W (1-3), as well as two known metabolites, junceellonoid D (4) and junceellin (5), were obtained from the octocoral Junceella fragilis. The structures of briaranes 1-3 were elucidated by spectroscopic methods and briaranes 3 and 5 displayed inhibition effects on inducible nitric oxide synthase (iNOS) release from RAW264.7.

Computer-Aided Chemotaxonomy and Bioprospecting Study of Diterpenes of the Lamiaceae Family.

Lamiaceae is one of the largest families of angiosperms and is classified into 12 subfamilies that are composed of 295 genera and 7775 species. It presents a variety of secondary metabolites such as diterpenes that are commonly found in their species, and some of them are known to be chemotaxonomic markers. The aim of this work was to construct a database of diterpenes and to use it to perform a chemotaxonomic analysis among the subfamilies of Lamiaceae, using molecular descriptors and self-organizing maps (SOMs). The 4115 different diterpenes corresponding to 6386 botanical occurrences, which are distributed in eight subfamilies, 66 genera, 639 different species and 4880 geographical locations, were added to SistematX. Molecular descriptors of diterpenes and their respective botanical occurrences were used to generate the SOMs. In all obtained maps, a match rate higher than 80% was observed, demonstrating a separation of the Lamiaceae subfamilies, corroborating with the morphological and molecular data proposed by Li et al. Therefore, through this chemotaxonomic study, we can predict the localization of a diterpene in a subfamily and assist in the search for secondary metabolites with specific structural characteristics, such as compounds with potential biological activity.

A Brief Review on New Naturally Occurring Cembranoid Diterpene Derivatives from the Soft Corals of the Genera Sarcophyton, Sinularia, and Lobophytum Since 2016.

This work reviews the new isolated cembranoid derivatives from species of the genera Sarcophyton, Sinularia, and Lobophytum as well as their biological properties, during 2016⁻2018. The compilation permitted to conclude that much more new cembranoid diterpenes were found in the soft corals of the genus Sarcophyton than in those belonging to the genera Lobophytum or Sinularia. Beyond the chemical composition, the biological properties were also reviewed, namely anti-microbial against several Gram-positive and Gram-negative bacteria and fungi, anti-inflammatory and anti-tumoral against several types of cancer cells. In spite of the biological activities detected in almost all samples, there is a remarkable diversity in the results which may be attributed to the chemical variability that needs to be deepened in order to develop new molecules with potential application in medicine.

Relationships between the Toxicities of Radix Aconiti Lateralis Preparata (Fuzi) and the Toxicokinetics of Its Main Diester-Diterpenoid Alkaloids.

The processed lateral root of Aconitum carmichaelii Deb (Aconiti Radix lateralis praeparata or Fuzi) is a potent traditional herbal medicine extensively used in treatment of cardiovascular diseases, rheumatism arthritis, and bronchitis in many Asian countries. Although Fuzi has promising therapeutic effects, its toxicities are frequently observed. Three main C19-diester-diterpenoid alkaloids (DDAs) are believed to be the principal toxins of the herb. Although toxicokinetic profiles of the toxic DDAs have already been examined in several studies, they have seldom been correlated with the toxicities of Fuzi. The current article aimed to investigate the relationship between the up-to-date toxicokinetic data of the toxic DDAs and the existing evidence of the toxic effects of Fuzi. Relationships between the cardiac toxicity and the plasma and heart concentration of DDAs in mice and rats were established. Based on our findings, clinical monitoring of the plasma concentrations of DDAs of Fuzi is recommended to prevent potential cardiac toxicities. Additionally, caution with respect to potential hepatic and renal toxicity induced by Fuzi should be exercised. In addition, further analyses focusing on the preclinical tissue distribution profile of DDAs and on the long-term toxicokinetic-toxicity correlation of DDAs are warranted for a better understanding of the toxic mechanisms and safer use of Fuzi.

Halimane diterpenoids: sources, structures, nomenclature and biological activities.

Covering: 1970 to 2017 Diterpenes with a halimane skeleton constitute a small group of natural products that can be biogenetically considered as being between labdane and clerodane diterpenoids. Some of these compounds show biological activities, such as antitumour, mosquito repellency, germination inhibition and antimicrobial, as well as being biomarkers for tuberculosis. To the best of our knowledge, there are no reviews on these compounds. In this review, halimane skeleton diterpenoids are classified according to their biogenetic origin, characterization and/or the enzymes involved in their biosynthesis. Herein, a review of their synthesis or synthetic approaches is communicated.

Anti-Cancer Activities of Diterpenoids Derived from Euphorbia fischeriana Steud.

Euphorbia fischeriana Steud is an essential oriental folk medicine used for healing cancer, edema and tuberculosis. Recently, its anticancer activitity has attracted more attention. A volume of research has indicated that diterpenoids are the major anticancer active constituents from this medicinal herb. In this review, we aimed to provide a summary of the promising anticancer diterpenoids from this plant; many diterpenoids mentioned in this article are newly discovered diterpenoids. According to the carbon skeleton and substituents, they can be classified into eight subtypes: ent-abietane, daphnane, tigliane, ingenane, ent-atisane, ent-rosane, ent-kaurane, and lathyrane. Futhermore, their key anticancer mechanisms and protein targets of these compounds will be discussed. These natural diterpenoids could provide a reservoir for drug discovery.

Rapid Screening and Identification of Diterpenoids in Tinospora sinensis Based on High-Performance Liquid Chromatography Coupled with Linear Ion Trap-Orbitrap Mass Spectrometry.

Diterpenoids are considered the major active compounds in Tinospora sinensis in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of diterpenoids in T. sinensis using high-performmance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. Two diterpenoid reference standards were first analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Then, based on the extracted ion chromatogram (EIC) data-mining method and characteristic fragmentation pathways analysis, diterpenoids in T. sinensis were rapidly screened and identified. After that, an important parameter, Clog P, was adopted to discriminate between the isomers of diterpenoids. As a result, 63 diterpenoids were characterized from the extract of T. sinensis, including 10 diterpenoids and 53 diterpenoid glycosides. Among them, 15 compounds were tentatively identified as new compounds. Finally, target isolation of one diterpenoid glycoside named tinosineside A was performed based on the obtained results, which further confirmed the deduced fragmentation patterns and identified diterpenoid profile in T. sinensis. The results demonstrated that the established method could be a rapid, effective analytical tool for screening and characterization of diterpenoids in the complex systems of natural medicines.

Bioinspired Asymmetric Synthesis of Hispidanin†A.

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-20,8ß-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.

Myrsinane, Premyrsinane, and Cyclomyrsinane Diterpenes from Euphorbia falcata as Potassium Ion Channel Inhibitors with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effects.

GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and ß-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata. The compounds were assayed on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cells. Blocking activity on GIRK channels was exerted by 13 compounds (61-83% at 10 µM), and, among them, five possessed low potency on the hERG channel (4-20% at 10 µM). These selective activities suggest that myrsinane-related diterpenes are potential lead compounds for the treatment of atrial fibrillation.

Using the knowns to discover the unknowns: MS-based dereplication uncovers structural diversity in 17-hydroxygeranyllinalool diterpene glycoside production in the Solanaceae.

Exploring the diversity of plant secondary metabolism requires efficient methods to obtain sufficient structural insights to discriminate previously known from unknown metabolites. De novo structure elucidation and confirmation of known metabolites (dereplication) remain a major bottleneck for mass spectrometry-based metabolomic workflows, and few systematic dereplication strategies have been developed for the analysis of entire compound classes across plant families, partly due to the complexity of plant metabolic profiles that complicates cross-species comparisons. 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs) are abundant defensive secondary metabolites whose malonyl and glycosyl decorations are induced by jasmonate signaling in the ecological model plant Nicotiana attenuata. The multiple labile glycosidic bonds of HGL-DTGs result in extensive in-source fragmentation (IS-CID) during ionization. To reconstruct these IS-CID clusters from profiling data and identify precursor ions, we applied a deconvolution algorithm and created an MS/MS library from positive-ion spectra of purified HGL-DTGs. From this library, 251 non-redundant fragments were annotated, and a workflow to characterize leaf, flower and fruit extracts of 35 solanaceous species was established. These analyses predicted 105 novel HGL-DTGs that were restricted to Nicotiana, Capsicum and Lycium species. Interestingly, malonylation is a highly conserved step in HGL-DTG metabolism, but is differentially affected by jasmonate signaling among Nicotiana species. This MS-based workflow is readily applicable for cross-species re-identification/annotation of other compound classes with sufficient fragmentation knowledge, and therefore has the potential to support hypotheses regarding secondary metabolism diversification.

Differentiation of Isodon japonica and Adulterants Based on Identification and Quantitation 14 Diterpenoids Using LC-MS-MS Library Search Approach and Hierarchical Cluster Analysis.

The aim of this study was to investigate the chemical differences between genunine Isodon japonica and its adulterants. A linear ion trap liquid chromatography with tandem mass spectrometry analytical method has been developed for the identification and quantification of 14 major diterpenoids in I. japonica. Data acquisition was multiple reaction monitoring transitions mode followed by an information-dependent acquisition using the enhanced product ion (EPI) scan in a single run. The target compounds were further identified and confirmed using an EPI spectral library. Overall validation of the assay was carried out including linearity, accuracy, precision, limits of detection and quantification. The results demonstrated that the method was selective, sensitive and reliable. The determination results of 21 batches of I. japonica and adulterants were then analyzed and differentiated by hierarchical clustering analysis.

Grayanane and leucothane diterpenoids from the leaves of Rhododendron micranthum.

Eleven grayanane diterpenoids, 1-epi-grayanotoxin IV, 1-epi-grayanotoxin II, 6-deoxy-1-epi-grayanotoxin XVII, 6-deoxygrayanotoxin XVII, 16-acetylgrayanotoxin II, 3-oxograyanotoxin IX, 14-deoxygrayanotoxin VIII, 14-acetylisograyanotoxin II, rhodomicranols C-E, and a leucothane diterpenoid, rhodomicranol F, together with eleven known diterpenoids were isolated from leaves of Rhododendron micranthum. Their structures were elucidated by spectroscopic analyses, with the absolute configurations of 1-epi-grayanotoxin IV and rhodomicranol C determined by single-crystal X-ray diffraction with Cu Kα radiation, and the structures of 14-acetylisograyanotoxin II and known grayanotoxins IX and X confirmed by single-crystal X-ray diffraction. All twenty-three diterpenoids were evaluated for their in vitro immunomodulatory activities, and none showed significant immunomodulatory activities in a dose-dependent manner. In addition, they are non-toxic to the murine lymphocytes in the general cytotoxicity assay.

Diterpenoids of terrestrial origin.

Covering: January to December 2013. Previous review, Nat. Prod. Rep., 2013, 30, 1346-1356. This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 179 references.

New casbane diterpenoids from a South China Sea soft coral, Sinularia sp.

Six new casbane diterpenoids, named as sinularcasbanes A-F (1-6), along with six known analogues 7-12, were isolated from a South China Sea soft coral, Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. All compounds were evaluated for their cytotoxicity against selected cancer cell lines and the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal macrophages.

Anti-inflammatory and cytotoxic cyathane diterpenoids from the medicinal fungus Cyathus africanus.

Five novel cyathane diterpenes, cyathins D-H (1-5), as well as three known diterpenes, neosarcodonin O (6), cyathatriol (7),and 11-O-acetylcyathatriol (8), were isolated from the solid culture of Cyathus africanus. The structures of the new compounds were elucidated by spectroscopic methods. The absolute configurations of compounds 2 and 8 were determined by single-crystal X-ray crystallographic analysis, whereas the absolute configuration of C-14 in 1 was determined via the circular dichroism data of the [Rh(2)(OCOCF(3))(4)] complex. Compounds 3, 5, 6, 8, and 9 showed potent inhibition against nitric oxide production in lipopolysaccaride-activated macrophages with an IC(50) value of 2.57, 1.45, 12.0, 10.73, and 9.45µM, respectively. Compounds 6 and 8 showed strong cytotoxicity against Hela and K562 cell lines with the IC(50) value less than 10µM.

A single residue change leads to a hydroxylated product from the class II diterpene cyclization catalyzed by abietadiene synthase.

Class II diterpene cyclases catalyze bicyclization of geranylgeranyl diphosphate. While this reaction typically is terminated via methyl deprotonation to yield copalyl diphosphate, in rare cases hydroxylated bicycles are produced instead. Abietadiene synthase is a bifunctional diterpene cyclase that usually produces a copalyl diphosphate intermediate. Here it is shown that substitution of aspartate for a conserved histidine in the class II active site of abietadiene synthase leads to selective production of 8α-hydroxy-CPP instead, demonstrating striking plasticity.

Guanacastane-type diterpenoids from Coprinus radians.

Thirteen diterpenoids, named radianspenes A-M (1-13), including three lactams radianspenes J (10), K (11) and L (12) and one dimer radianspene M (13), were isolated from fermentation products of the higher fungal strain Coprinus radians M65. All these compounds possessing guanacastane skeleton were evaluated for antitumor activity using MDA-MB-435 cell line. Radianspene C exhibited inhibitory activity with IC(50) of 0.91 µM.

The C19-diterpenoid alkaloids.

The diterpenoid alkaloids, with an intriguing chemistry and numerous varied bioactivities, constitute the largest and most complicated group of terpenoid alkaloids. Among them, the C19-diterpenoid alkaloids have attracted extensive and lasting attention from researchers. This chapter with 1075 references systematically summarizes the past 30 years of studies on the C19-diterpenoid alkaloids, covering the classification and distribution, biogenesis and biosynthesis, applications in the phytochemotaxonomy of Chinese Aconitum L., spectral properties (1H and 13C NMR, MS), X-ray crystallographic analysis, chemical reactions and chemical conversions (as a continuation of Volume 42 of this treatise), and pharmacological activity of this important group of alkaloids. This review on the C19-diterpenoid alkaloids, in combination with two previous reviews in this treatise (C20-diterpenoid alkaloids, Volume 59, and C18-diterpenoid alkaloids, Volume 67), will present readers with a complete and updated profile of the diterpenoid alkaloids. The only exception is the description of the total syntheses of the diterpenoid alkaloids, which will be summarized in a subsequent individual chapter.

Trigochilides A and B, two highly modified daphnane-type diterpenoids from Trigonostemon chinensis.

Trigochilides A (1) and B (2), two highly modified daphnane-type diterpenoids with 12-carbon-containing polyketide appendages at C-16 forming a macro-lactone with C-3, were isolated from the twigs and leaves of Trigonostemon chinensis. Their structures were elucidated by spectroscopic analysis. Trigochilides A (1) showed modest cytotoxicity against two tumor cell lines.