C19-diterpenoid Alkaloids Research Articles

Aconitine in Synergistic, Additive and Antagonistic Approaches

Aconitine is a highly poisonous C19-diterpenoid alkaloid identified and isolated from the species of the genus Aconitum. Aconitine is indicated in the treatment of cardiovascular diseases (CVDs) and, due to its neurotoxic effects, is a very effective drug in pain release. A total of 101 relevant scientific papers were manually searched on the Web of Science, Scopus, Science Direct, Google Scholar, PubMed and Dovepress databases and in the books available in the library of the Department of Natural Sciences, the National University of Science and Technology POLITEHNICA Bucharest, Pitesti University Centre, Romania. In combination treatments, aconitine shows antiarrhythmic and anti-inflammatory activity, a synergistic antiproliferative effect and decreased reactive oxygen species (ROS) generation, an improved biodistribution and bioavailability. Additionally, the entrapment of aconitine in engineered nanoparticles represents a promising method for reducing the toxicity of this alkaloid. This review provides, for the first time, a comprehensive picture of the knowledge and research on the synergistic, additive and antagonistic effects of aconitine in combination treatments applied in vivo or in vitro. The summarized studies represent important clues in addressing the multitude of knowledge, which can find their utility in practical and clinical applications.

Seven new aconitine-type diterpenoid alkaloids from the roots of Aconitum apetalum.

Seven new aconitine-type C19-diterpenoid alkaloids, apetaldines K-Q (1-7), were isolated from the roots of Aconitum apetalum (Huth) B. Fedtsch. Their structures were established on the basis of extensive spectroscopic analyses (HRESIMS, 1D and 2D NMR). Among them, compounds 1 and 2 possess a unique 2-(E)-(2-methylbut-2-enamido)benzoate moiety at the C-18 position. Furthermore, cytotoxic activities of these diterpenoid alkaloids were also evaluated.

New insights into the chemotaxonomic implications of diterpenoid alkaloid composition in Aconitum sessiliflorum

Through phytochemical research, the composition of diterpenoid alkaloids in Aconitum sessiliflorum was analyzed, and sixteen compounds were identified. Among them, there are seven napelline type C20-diterpenoid alkaloids (1–4, 7–8, 15), three denudatine type C20-diterpenoid alkaloids (5–6, 16), and six aconitine type C19-diterpenoid alkaloids (9–14). On the basis of NMR spectroscopy, the structural analysis of the separated compounds was achieved by comparing with previous data. All sixteen compounds were isolated for the first time from the Aconitum sessiliflorum, of which five compounds (1, 6, 9, 13, 15) were isolated for the first time from series Brachypoda, where Aconitum sessiliflorum is classified. These diterpenoid alkaloids not only enrich the chemical diversity of Aconitum sessiliflorum, but also facilitate the analysis of their chemotaxonomic implications. Importantly, the diverse types and structural features of these diterpenoid alkaloids provide new insights into both the potential phylogenetic affiliations within the series Brachypoda and the varying degrees of evolutionary divergence among these related taxa.

Four new lycoctonine-type C19-diterpenoid alkaloids from the whole plants of Delphinium kamaonense

Four new lycoctonine-type C19-diterpenoid alkaloids kamaonensines H-K (1–4) have been isolated from the whole plants of Delphinium kamaonense, together with 12 known compounds (5–16). Interestingly, kamaonensines 1–3 contained a rare nitrone (immine N-oxide) moiety, respectively. Their structures were established by spectroscopic analyses. The active evaluation of compounds (1–16) by LPS induced RAW 264.7 macrophages showed that compounds 4 and 8 displayed strong anti-inflammatory activities. While compounds 11 and 12 also showed strong cytotoxicities by the RAW 264.7 cell viability assay.

Two Novel Diterpenoid Alkaloids from Aconitum Pendulum.

Two previously uncharacterized compounds, an aconitine-type C19-diterpenoid alkaloid (1) and a napelline-type diterpenoid alkaloid C20-diterpenoid alkaloid (2), as well as ten known compounds (3-12), were isolated from Aconitum pendulum. Their structures were elucidated based on spectroscopic data, including 1D and 2D NMR, IR, HR-ESI-MS, and single-crystal X-ray diffraction analysis. The anti-insecticidal activities of these compounds were evaluated by contact toxicity tests against two-spotted spider mites, and compounds 1, 2, and 9 showed moderate contact toxicity, with LC50 values of 0.86±0.09, 0.95±0.23, and 0.89±0.19 mg/mL, respectively. This study highlights the potential use of diterpenoid alkaloids as natural plant-derived pesticides for the management of plant pests.

Two new diterpenoid alkaloids from the roots of Aconitum nagarum and their cytotoxic activity

A chemical investigation on the roots of Aconitum nagarum afforded two undescribed C19-diterpenoid alkaloids nagarumines D and E (1 and 2). The structures of the new compounds were elucidated by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, as well as HR-ESI-MS. The two isolated alkaloids were tested in vitro for cytotoxic activity against five gastric tumor cell lines. Consequently, compound 2 exhibited some cytotoxicities against several human cancer cell lines with IC50 value less than 20.0 μM.

A concise and stereoselective synthesis of the BCDF tetracyclic ring system of C19-diterpenoid alkaloids.

A new synthetic route for the BCDF tetracyclic ring system of C19-diterpenoid alkaloids (C19-DTAs) has been developed. The key step is a Pd-catalyzed transannular alkenylation that installs a functionalized bridged F ring. The overall strategy is concise and stereoselective, and it provides a valuable new tool for the synthesis of C19-DTAs. The synthesis begins with a bridged [3.2.1] ring system, which is converted to a key intermediate through a series of highly regio- and stereoselective processes. The introduction of an allylic side chain with high precision is accomplished, culminating in a Pd-catalyzed transannular alkenylation that installs a functionalized bridged F ring to yield the BCDF tetracyclic analog of C19-DTAs.

Diterpenoid alkaloids from Delphinium trichophorum

The ethanol extract of the whole plant of Delphinium trichophorum Franch was subjected to a phytochemical study, leading to the isolation of ten unprecedented diterpenoid alkaloids, including nine delnudine-type C20-diterpenoid alkaloids named trichophodines A–I and one kusnezoline-type C20-diterpenoid alkaloid named trichophozine A. Additionally, seven known compounds were also identified. Their structures were elucidated on the basis of extensive spectroscopic analysis, including HSQC, HMBC, 1H–1H COSY, NOESY and X-ray crystallographic analysis. Most isolated compounds were screened for inhibitory activities against LPS-induced NO production in RAW 264.7 macrophage cells and acetylcholinesterase inhibitory effects. Guan-fu base V exhibited potent inhibitory activity against acetylcholinesterase, demonstrating an inhibitory rate of 53.81% at a concentration of 40 μM.

Trichodelphinine A alleviates pulmonary fibrosis by inhibiting collagen synthesis via NOX4-ARG1/TGF-β signaling pathway

BackgroundPulmonary fibrosis, a progressive and fatal lung disease with no effective treatment medication, is characterized by lung remodeling and fibroblastic foci caused by an oxidative imbalance with an overloading deposition of collagen. Trichodelphinine A, a hetisine-type C20-diterpenoid alkaloid, was found anti-fibrotic activity in vitro, but its effect and mechanism on pulmonary fibrosis still unknown. PurposeOur study aimed to investigate and validate the anti-fibrotic properties of trichodelphinine A in pulmonary fibrosis animals induced by bleomycin (BLM), and its mechanism whether via NOX4-ARG1/TGF-β signaling pathway. MethodsThe anti-fibrotic effects of trichodelphinine A were evaluated using BLM-induced rats through indicators of lung histopathology and collagen synthesis. Dynamic metabolomics evaluated the metabolic disorder and therapeutic effect of trichodelphinine A. The interaction between trichodelphinine A and NOX4 receptor was confirmed using CETSA and molecular dynamics experiments. Molecular biology experiments were conducted in NOX4 gene knockout mice to investigate the intervention effect of trichodelphinine A. ResultsTrichodelphinine A could suppress histopathologic changes, collagen deposition and proinflammatory cytokine release pulmonary fibrosis in bleomycin induced rats. Dynamic metabolomics studies revealed that trichodelphinine A could correct endogenous metabolic disorders of arachidonic acid, arginine and proline during fibrosis development, which revealed that the regulation of oxidative stress and amino acid metabolism targeting NOX4 and ARG1 may be the main pharmacological mechanisms of trichodelphinine A on pulmonary fibrosis. We further determined that trichodelphinine A inhibited over oxidative stress and collagen deposition by suppressing Nrf2-keap1 and ARG1-OAT signaling pathways, respectively. Molecular dynamics studies showed that trichodelphinine A was directly binds with NOX4, in which PHE354 and THR355 residues of NOX4 are critical binding sites for trichodelphinine A. Mechanistic validation in cells or mice with NOX4 knockout or silencing suggested that the anti-fibrotic effects of trichodelphinine A depended on inhibition of NOX4 to suppress ARG1/OAT activation and TGF-β/Smads signaling pathway. ConclusionCollectively, our findings indicate a powerful anti-fibrotic function of trichodelphinine A in pulmonary fibrosis via targeting NOX4. NOX4 mediates the activation of ARG1/OAT to regulate arginase-proline metabolism, and promotes TGF-β/Smads signaling pathway, thereby affecting the collagen synthesis in pulmonary fibrosis, which is a novel finding and indicates that inhibition of NOX4 is a novel therapeutic strategy for pulmonary fibrosis.

Brunonianines D-F, three new C19-diterpenoid alkaloids from the Delphinium brunonianum, with therapeutic effect on ovarian cancer in vitro and in vivo

The current standard treatment for ovarian cancer consists of surgery to reduce the size of the tumor, followed by treatment with chemotherapeutic drugs, which have major side effects. Therefore, finding a new natural product drug with fewer side effects is a strategy. Delphinium brunonianum (D. brunonianum) is a traditional Tibetan medicine, mainly from southern Tibet, China, whereas the chemical constituents in this plant remain elusive. The major metabolites in the dichloromethane fraction of D. brunonianum were analyzed and purified by HPLC and various column chromatography techniques. Nine diterpenoid alkaloids (1–9) and one amide alkaloid (10) were isolated from D. brunonianum, including three novel C19-type diterpenoid alkaloids (Brunonianines D-F) (1–3). Their structures were elucidated by 1D/2D NMR, HR-ESI-MS and single-crystal X-ray diffraction analyses. All compounds were evaluated for toxicity in four tumor cell lines. Most of the compounds exhibited potent inhibitory effects on Skov-3 cell lines, with IC50 values ranging from 2.57 to 8.05 μM. The western blotting experiment was used to further analyze the expression levels of molecules in the Bax/Bcl-2/Caspase-3 signaling pathway for compound 1. Molecular docking was performed to predict the binding modes of Brunonianine D with target proteins. In vivo experiments were also performed and evaluated in real time by monitoring the size of the Skov-3 tumor. Additionally, tumor H&E staining and the TUNEL assay used to evaluate anti-tumor effects.

Diterpenoid Alkaloids from Delphinium liangshanense.

Two new C19-diterpenoid alkaloids of the lycoctonine-type (liangshanine A and liangshanine B) and nineteen known compounds (3-21) were isolated from the whole plant of Delphinium liangshanense W. T. Wang, and all the compounds were identified by different spectroscopic analyses, such as IR, HR-ESI-MS and NMR. All the compounds were isolated from this plant for the first time and tested for the anti-proliferation effects on MH7 A and SF9 cells to figure their anti-rheumatoid arthritis and anti-insect activity, but none of them showed remarkable activity.

Asymmetric Synthesis of the Functionalized A/E-Ring Fragment of C18-Diterpenoid Alkaloids.

A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.

Diterpenoid Alkaloids from Delphinium ajacis and Their Anti-inflammatory Activity.

Three novel diterpenoid alkaloids, comprising two C19 -diterpenoid alkaloids (1 and 2) and one C20 -diterpenoid alkaloid (3), were isolated from Delphinium ajacis, alongside the six known compounds (4-9). Their structures were elucidated by spectroscopic methods (MS, UV, IR, 1D and 2D NMR) and chemical properties. Simultaneously, the anti-inflammatory properties of all compounds (1-9) was conducted, focusing on nitric oxide (NO) production in LPS-induced BV-2 cells. The results indicated compounds 1-3, 7, and 8 have potential anti-inflammatory activity.

Brunonianines A-C, C20-diterpenoid alkaloids with cyano group from Delphinium brunonianum Royle

Cyano tends to have better biological activity, but it is rarely reported in natural products, especially in the C20-diterpene alkaloids. Herein, three unprecedented C20-diterpenoid alkaloids, brunonianines A-C (1-3), possessing rare cyano functional group as well as an atisine backbone constructed from a phenethyl substituent and a tetrahydropyran ring, along with four C19-alkaloids (4–7) and one amide alkaloids (8), were isolated from the whole plant of Delphinium brunonianum Royle. Compounds 1–3 are also the first atisine type diterpenoid alkaloids with cyano group obtained from nature. The structures of the previously undescribed compounds were elucidated by HR-ESI-MS, 1D/2D NMR spectroscopic data and electronic circular dichroism calculations and single-crystal X-ray diffraction. Reasonable speculations have also been made regarding the biogenic synthetic pathways of compounds 1–3. In addition, the inhibitory activity of all compounds was also tested against four tumor lines: A549, Caco-2, H460 and Skov-3, where compound 2 (IC50 2.20 ± 0.21 μM) showed better inhibitory activity against Skov-3 cells than the hydroxycamptothecin. Using flow cytometry, cell staining, migration and invasion analysis, and Western blot, compound 2 was found to arrest cells in the G2/M phase and was able to effectively inhibit cell motility to achieve potent anti-tumor effects. In addition, compound 2 can effectively induce apoptosis by activating the Bax/Bcl-2/Caspase-3 signaling pathway.

Overview of the chemistry and biological activities of natural atisine-type diterpenoid alkaloids.

Atisine-type C20-diterpenoid alkaloids (DAs) are a very important class of diterpenoid alkaloids, which play an important role in the biosynthesis of DAs. To date, 87 atisine-type DAs and 11 bis-DAs containing an atisine unit have been reported from five genera in two families. The genus Spiraea in Rosaceae family could be regarded as the richest resource for atisine-type DAs, followed by the genera Delphinium and Aconitum in the Ranunculaceae family. Among the reported atisine-type DAs, several possess unprecedented skeletons. Natural atisine-type DAs have a wide range of biological activities, including antitumor, antiplatelet aggregation, biological control, and anti-inflammatory, analgesic, antiarrhythmic, and cholinesterase inhibitory effects, which are closely related to their structures. In particular, the antiparasitic effect of atisine-type DAs is more prominent than that of other types of DAs, which highlights their potential in antiparasite drug discovery. In summary, the high chemical and biological diversity of atisine-type DAs indicates their great potential as a vast resource for drug discovery.

Enantioselective route to an AE-ring intermediate in the total synthesis of talatisamine

Talatisamine [(–)-1] is a C19-diterpenoid alkaloid with an intricately fused ABCDEF-ring system. In 2020, we reported a total synthesis of racemic talatisamine [(±)-1], in which AE-ring fragment (±)-5-α/5-β was utilized as the pivotal early-stage intermediate. Herein, we disclose the development of an enantioselective route to (–)-5-β for the total synthesis of (–)-1. Enantioselective intermolecular Mannich, Lewis acid-mediated intramolecular Mannich, and reductive N-ethylation reactions were employed as the three key transformations.

Catalytic Asymmetric Total Synthesis of (-)-Garryine via an Enantioselective Heck Reaction.

The first asymmetric total synthesis of the hexacyclic veatchine-type C20-diterpenoid alkaloid (-)-garryine is presented. Key steps include a Pd-catalyzed enantioselective Heck reaction, a radical cyclization, and a photoinduced C-H activation/oxazolidine formation sequence. Of note, a highly enantioselective Heck reaction developed in this work provides efficient access to 6/6/6 tricyclic compounds, in particular, containing a C19-functionalitiy, which is useful for diverse transformations.

Kamaonensine A-G: Lycaconitine-type C19-diterpenoid alkaloids with anti-inflammatory activities from Delphinium kamaonense Huth

Delphinium kamaonense Huth is a sort of folkloric plant resource which is cultivated and planted with great ornamental and medicinal values. In this work, seven undescribed lycaconitine-type C19-diterpenoid alkaloids, especially a rare skeleton with –CH=N and N-oxide moieties, along with ten known compounds, were isolated from D. kamaonense, of which the structures were determined by various spectroscopic data, combined with calculated electronic circular dichroism (ECD) and single-crystal X-ray diffraction analysis. In vitro nitric oxide inhibitory activities assay of these compounds indicated that lycaconitine-type C19-diterpenoid alkaloids had significant anti-inflammatory inhibitory activities, with kamaonensine E being the most potent (0.9 ± 0.2 μM) stronger than positive (9.0 ± 1.3 μM). In the network pharmacology studies, binding three key targets mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14), and heat shock protein HSP 90-alpha (HSP90α), the anti-inflammatory mechanism might be related to MAPK signaling pathways. Furthermore, the molecular docking results revealed that the uncommon amides and methylenedioxy groups might be the most two promising pharmacophores for lycaconitine-type C19-diterpenoid alkaloids.

Diterpenoid and C20 diterpenoid alkaloid as a potent inhibitor of SARS-CoV-2 main protease (Mpro): from Piper barberi Gamble, an endemic and endangered species of Southern Western Ghats

The present study investigated the phytochemicals and in silico anti-nCoV properties of Piper barberi, an endangered and endemic species of Southern Western Ghats. Using conventional soxhlet extraction method, the leaf and stem were extracted separately with methanol (PBLM and PBSM). The bioactive compounds from the extracts were identified using HR-LCMS/MS-qTOF analysis. These compounds were subjected to various in silico analyses to identify potential drug candidates against nCoV. The HR LCMS/MS analysis of PBLM and PBSM revealed the presence of phenols, flavonoids, alkaloids, and terpenoids in it and this is the first report of the phytoconstituents present in the species P. barberi. All the identified bioactive compounds were subjected to predict ADMET. Out of 49 identified compounds, only 31 passed drug-likeness properties and toxicity tests. Molecular interaction studies were conducted using the AutoDockTools 4.2.6., which showed that only 13 compounds exhibited acceptable binding affinity with the nCoV target Mpro. Structural stability and binding free energy analyses of the five compounds with the higher binding affinity indicated that the bioactive compounds Hetisine and Ajaconine are stable with both hydrogen bonds and hydrophobic interactions. Hetisine shows stable binding among these two compounds with two hydrogen bond interactions with the crucial catalytic dyad residue (His41). Thus, this study concludes that these compounds might potentially be used as an alternative drug candidate for managing nCoV. However, further experimental validation, including in vitro and in vivo assays, is required to substantiate the results. Communicated by Ramaswamy H. Sarma

C19-diterpenoid alkaloids from Aconitum refractum var. circinatum

Two unprecedented aconitine-type C19-diterpenoid alkaloids, refractines A–B (1–2), along with 12 known compounds (3–14) were isolated from the roots of Aconitum refractum (Finet et Gagnep.) Hand. -Mazz. Their structures were elucidated based on extensive spectroscopic analyses, including 1D and 2D NMR, IR, and HR-ESI-MS data. All compounds were tested for inhibitory activities against NO production in LPS induced RAW 264.7 macrophages, compounds 10 and 14 had slight inhibited NO production with rate of 29.4% and 22.1% at the concentration of 30 μM, respectively.