Tetracyclic Diterpenes Research Articles

Identification, structural revision and biological evaluation of the phyllocladane-type diterpenoids from Callicarpa longifolia var. floccosa

Phyllocladane-type diterpenoids represent a rare group of tetracyclic diterpenes. Two diterpenoids (1 and 2) were extracted from Callicarpa longifolia var. floccosa, along with the Chemically synthesized derivatized compound 3. The crystal data for compound 1 were first reported in this study, and compound 2 was identified as a novel phyllocladane-type diterpenoid. In addition, calliterpenone monoacetate was previously erroneously reported as compound 2. We corrected the structure of calliterpenone monoacetate to 2a by X-ray diffraction, NMR calculations, and chemical synthesis, as well as the TDDFT-ECD method. At the same time, the antitumor activity of compounds 1 and 2 was studied.

Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine-1,5-Benzodiazepine Hybrids.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Functional Characterization of Three Diterpene Synthases Responsible for Tetracyclic Diterpene Biosynthesis in Scoparia dulcis

Scoparia dulcis produces unique biologically active diterpenoids such as scopadulcic acid B (SDB). They are biosynthesized from geranylgeranyl diphosphate (GGPP) via syn-copalyl diphosphate (syn-CPP) and scopadulanol as an important key intermediate. In this paper, we functionally characterized three diterpene synthases, SdCPS2, SdKSL1 and SdKSL2, from S. dulcis. The SdCPS2 catalyzed a cyclization reaction from GGPP to syn-CPP, and SdKSL1 did from syn-CPP to scopadulan-13α-ol. On the other hand, SdKSL2 was found to incorporate a non-sense mutation at 682. Therefore, we mutated the nucleotide residue from A to G in SdKSL2 to produce SdKSL2mut, and it was able to recover the catalytic function from syn-CPP to syn-aphidicol-16-ene, the precursor to scopadulin. From our results, SdCPS2 and SdKSL1 might be important key players for SDB biosynthesis in S. dulcis.

Secondary metabolites in Viguiera (Compositae, Heliantheae, Helianthinae) and segregated genera. A review of their biological activities with chemotaxonomic observations

Background: The first monograph of the genus Viguiera was published in 1918 by Blake, including about 141 species. Schilling & Panero based on studies of molecular sequences of nuclear Internal Transcribed Spacer and External Transcribed Spacer, as well as cpDNA, proposed to reclassify the genus, relocating its species in at least other nine genera. Question: Is it possible to identify distinctive patterns between the species of the new classification of Viguiera s. l. and the results of the chemical studies reported? Species considered: Sixty-seven species within the wide Viguiera circumscription with chemical studies and biological activities reported. Results: The species of the genus Viguiera synthesize terpenoids represented mainly by sesquiterpene lactones and diterpenes, with triterpenes, polyacetylenes, volatile terpenoids and flavonoids also present. The main types of secondary metabolites were present in the studied species, although some compounds were more frequent than others in some clades. Conclusion: Germacrolides, heliangolides, furanoheliangolides, tetracyclic diterpenes and flavonoids are the main constituents of Viguiera and segregated genera. Some interesting chemotaxonomic relationships are noted. Nevertheless, nondistinctive clear patterns were observed between clades and chemical groups. These results may be a consequence of the reported chemical studies of the species of Viguiera s. l., which have not agreed on objetives or methodologies.

Classification, Toxicity and Bioactivity of Natural Diterpenoid Alkaloids.

Diterpenoid alkaloids are natural compounds having complex structural features with many stereo-centres originating from the amination of natural tetracyclic diterpenes and produced primarily from plants in the Aconitum, Delphinium, Consolida genera. Corals, Xenia, Okinawan/Clavularia, Alcyonacea (soft corals) and marine sponges are rich sources of diterpenoids, despite the difficulty to access them and the lack of availability. Researchers have long been concerned with the potential beneficial or harmful effects of diterpenoid alkaloids due to their structural complexity, which accounts for their use as pharmaceuticals as well as their lousy reputation as toxic substances. Compounds belonging to this unique and fascinating family of natural products exhibit a broad spectrum of biological activities. Some of these compounds are on the list of clinical drugs, while others act as incredibly potent neurotoxins. Despite numerous attempts to prepare synthetic products, this review only introduces the natural diterpenoid alkaloids, describing ‘compounds’ structures and classifications and their toxicity and bioactivity. The purpose of the review is to highlight some existing relationships between the presence of substituents in the structure of such molecules and their recognised bioactivity.

Identification of Kaurane-Type Diterpenes as Inhibitors of Leishmania Pteridine Reductase I.

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC50) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme.

Approaches toward the Separation, Modification, Identification and Scale up Purification of Tetracyclic Diterpene Glycosides from Stevia rebaudiana (Bertoni) Bertoni.

Stevia rebaudiana (Bertoni) Bertoni is a plant species native to Brazil and Paraguay well-known by the sweet taste of their leaves. Since the recognition of rebaudioside A and other steviol glycosides as generally recognized as safe by the United States Food and Drug Administration in 2008 and grant of marketing approval by the European Union in 2011, the species has been widely cultivated and studied in several countries. Several efforts have been dedicated to the isolation and structure elucidation of minor components searching for novel non-caloric sugar substitutes with improved organoleptic properties. The present review provides an overview of the main chemical approaches found in the literature for identification and structural differentiation of diterpene glycosides from Stevia rebaudiana: High-performance Thin-Layer Chromatography, High-Performance Liquid Chromatography, Electrospray Ionization Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy. Modification of diterpene glycosides by chemical and enzymatic reactions together with some strategies to scale up of the purification process saving costs are also discussed. A list of natural diterpene glycosides, some examples of chemically modified and of enzymatically modified diterpene glycosides reported from 1931 to February 2021 were compiled using the scientific databases Google Scholar, ScienceDirect and PubMed.

Abstract 1854: Oridonin inhibits cell growth of esophageal carcinoma cells via induction of apoptosis

Abstract Esophageal Cancer estimated leading deaths are more than 400,000 every year in worldwide, while 80% due to esophageal squamous cell carcinoma. In worldwide, esophageal cancer leading death ranks in sixth among cancer leading causes of death, while the 5-year survival rate of esophageal cancer is 19%. Oridonin, a tetracyclic diterpenes compound, has been indicated the anti-tumor activity for digestive system tumors. To assess the anticancer activity of oridonin on esophageal cancer, we performed cell proliferation experiment of oridonin on esophageal squamous cell carcinoma cell line TE-8 using SRB assay. We found that IC50 of oridonin on TE-8 treated for 72h is 3.0μM, which is better than positive control Gemcitabine treatment on TE-8 for 72h (5.7 μM), as well as TE-8 cells shrunk and floated with increasing concentration on oridonin. At the same time, oridonin induced a dose-dependent inhibition of cell colony formation of esophageal cancer cell line. Colony numbers of TE-8 cell line treated with 1μM and 2μM oridonin are 111 and 54, respectively, which are significantly different (p<0.05). Accompanying with marked morphological changes, flow cytometer results showed that oridonin triggered sub-G0/G1 cell cycle arrest in a dose-dependent manner. After treatment by 10μM and 20μM oridonin for 24h, percentage of sub-G0/G1 cells were 25.5 and 55.3%, respectively, which are significantly different (p<0.05). The apoptosis results showed that oridonin treatment led to the accumulation of cells in early-(Annexin V+/PI-) and late-stage (Annexin V+/PI+) apoptosis in a dose-dependent manner. Citation Format: Xiaojun Zhang, Mengtao Xing, Yangcheng Ma, Xiao Wang, Jianying Zhang. Oridonin inhibits cell growth of esophageal carcinoma cells via induction of apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1854.

Structural diversity, bioactivities, and biosynthesis of natural diterpenoid alkaloids.

Covering: 2009 to 2018. Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, are a diverse class of compounds having complex structural features with many stereocenters. The important pharmacological activities and structural complexity of the diterpenoid alkaloids have long interested scientists due to their medicinal uses, infamous toxicity, and unique biosynthesis. Since 2009, 373 diterpenoid alkaloids, assigned to 46 skeletons, have been isolated and identified from plants mostly in the Ranunculaceae family. The names, classes, molecular weight, molecular formula, NMR data, and plant sources of these diterpene alkaloids are collated here. This review will be a detailed update of the naturally occurring diterpene alkaloids reported from the plant kingdom from 2009-2018, providing an in-depth discussion of their diversity, biological activities, pharmacokinetics, toxicity, application, evolution, and biosynthesis.

Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone B.

Total syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one-step regioselective and diastereoselective cycloenlargement in the form of a semipinacol-type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron-donating phenylthio group at this position.

Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone B

AbstractTotal syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one‐step regioselective and diastereoselective cycloenlargement in the form of a semipinacol‐type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron‐donating phenylthio group at this position.

Sucupira as a Potential Plant for Arthritis Treatment and Other Diseases.

Trees of the genus Pterodon, commonly known as “sucupira-branca” or “faveira,” are native to central Brazil. The Pterodon fruits are traditionally used in ethnomedicine as an infusion, in small doses, and at regular time intervals as an antirheumatic, anti-inflammatory, tonic, and depurative agent. The various compounds present in the Pterodon class are, generally, water-insoluble and derived from the fusion of high-molecular weight pentacarbonate units. Scientific research has shown that the major compounds isolated from Pterodon species are linear and/or tetracyclic diterpenes with vouacapane skeletons that partly underlie the pharmacological activities of the fruit-derived oil. Material from Pterodon species has several biological properties, such as analgesic, anti-inflammatory, and anticancer effects. Therefore, recent studies have sought to microencapsulate these extracts to protect them from potential chemical degradation and improve their water solubility, ensuring greater stability and quality of the end products. This review presents a succinct overview of the available scientific evidence of the biological activity and toxicity of Pterodon species in addition to other important aspects, including phytochemical and technological features.

ChemInform Abstract: The Enantioselective Construction of Tetracyclic Diterpene Skeletons with Friedel—Crafts Alkylation and Palladium‐Catalyzed Cycloalkenylation Reactions.

AbstractTricarbocyclic products (II) are obtained by an extension of the enantioselective Birch‐Cope sequence with Friedel‐Crafts alkylation reactions.

Phytochemicals and Biological Activities of Poisonous Genera of Ericaceae in China

The family Ericaceae is comprised of about 70 genera of which about 20 are found throughout China. Of these Ledum, Rhododendron, Enkianthus, Pieris, Craibiodendron, Gaultheria, Vaccinium, and Leucothoe are regarded as poisonous. Many species of these poisonous genera are used as Chinese herbal medicines for the treatment of, for example, inflammation, asthma, and coughs. Modem research has demonstrated that the toxic ingredients of these poisonous genera are chiefly tetracyclic diterpenes, which have adverse effects on the digestive, cardiovascular and nervous systems. Because various species of these poisonous genera also have medicinal functions, extensive studies of these plants have led to the identification of many kinds of compound. This paper compiles 306 compounds from the eight poisonous genera, reported in 141 references.

Tetracyclic Diterpenoids with Isomerized Isospongian Skeleton and Labdane Diterpenoids from the Fruits of Amomum kravanh

Four novel diterpenoids, including three tetracyclic diterpenes with isomerized isospongian skeletons, kravanhins A-C (1-3), and kravanhin D (4), and three new labdane diterpenes (5-7) were isolated from the fruits of Amomum kravanh. Compounds 1-4 had unprecedented isospongian diterpene skeletons with a trans-anti-cis fused tricyclic ring system. The structures of compounds 1-7 were established on the basis of extensive analysis of NMR spectra, CD, and X-ray crystallography. Compound 2 showed inhibitory activity on nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with an IC(50) value of 36.2 μM.

Conidiogenones H and I, Two New Diterpenes of Cyclopiane Class from a Marine‐Derived Endophytic Fungus Penicillium chrysogenum QEN‐24S

Two new tetracyclic diterpenes of the rarely reported cyclopiane class, conidiogenones H and I (1 and 2, resp.), along with five related congeners, conidiogenones B - D and F (3-5 and 6, resp.) and conidiogenol (7), were characterized from the culture extracts of Penicillium chrysogenum QEN-24S, an endophytic fungus derived from an unidentified marine red algal species of the genus Laurencia. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The inhibitory activity of theses diterpenes against four bacteria and one pathogen fungus was evaluated. Conidiogenone B (3) showed potent activity against Methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas fluorescens, P. aeruginosa, and Staphylococcus epidermidis (each with a MIC value of 8 μg/ml), while conidiogenol (7) showed obvious activity against P. fluorescens and S. epidermidis (each with a MIC value of 16 μg/ml). This is the first report on antimicrobial activity of cyclopiane diterpenes.

Enantioselective Total Synthesis of the Diterpenes Kempene‐2, Kempene‐1, and 3‐epi‐Kempene‐1 from the Defense Secretion of Higher Termites

Two rings in one sweep: A domino metathesis of the bicyclic dienyne 4 (TBS=tert-butyldimethylsilyl) obtained from a catalytic enantioselective Diels–Alder reaction as the key process enabled the efficient preparation of the tetracyclic diterpenes kempene-2 (1), kempene-1 (2), and 3-epi-kempene-1 (3).

グァラニーインディオの伝承薬の調査と<i>Scoparia dulcis</i>由来ジテルペン類に関する研究

In interviews on the traditional herbal medicines of Tupi-Guarany Indians at the herbal market of Asuncion and questionnaire from their users, it was clarified that various useful medicinal plants are available in Paraguay and most of them are generally used without drying. In the search for bioactive substances from those plants, a β-glucuronidase-inhibitory diterpene called scoparic acid A (SA) was isolated from Scoparia dulcis L. together with scoparic acid B, scoparic acid C, and the aphidicolin-like tetracyclic diterpenes scopadulcic acid A (SDA) and scopadulcic acid B (SDB). HPLC analysis of diterpenes in the individual plants of Paraguayan and Asian S. dulcis revealed the presence of three chemotypes based on major component, i.e., SA type, SDB type, and SDX type containing mainly scopadiol and scopadulciol (SDC). SA and SDB were elucidated to be mainly biosynthesized in the leaves via 2-C-methyl-D-erythritol- 4-phosphate pathway, and a leaf organ culture system containing methyl jasmonate 10 µM was found to enhance the production of diterpenes by activation of Ca-signal transduction systems such as calmodulin and protein kinase C. On the other hand, SDB and SDC were found to show multifaceted pharmacological effects such as inhibitory effects on gastric acid excretion, bone resorption, replication of herpes simplex virus type 1 (HSV-1), etc. In addition, SDC was suggested to be applicable to cancer gene therapy using ganciclovir or acyclovir and the HSV-1 thymidine kinase gene called the suicide gene.

ChemInform Abstract: The Total Synthesis of Tri- and Tetracyclic Diterpenes

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Ioniols I and II, Tetracyclic Diterpenes with Antibacterial Activity, from Sphaerococcus coronopifolius.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.