Diterpenoid Alkaloids Research Articles

Anti-rheumatic, and analgesic effects by the parent tuberous roots of Aconitum jaluense in adjuvant induced arthritis rats

The aim of this study was to test the anti-rheumatic effects of A. jaluense tubers in acute and chronic arthritis rats, and to assign its ingredients through UHPLC-TOF/MS. Subcutaneous injection of carrageenan for acute arthritis and complete Freund's adjuvant (CFA) for chronic arthritis was carried out in the hind paw of SD rats. The paw volume was measured by a plethysmometer thermal hyperalgesia was tested using a thermal plantar tester, and mechanical hyperalgesia was evaluated by ankle flexion evoked vocalizations. The expression of c-Fos in the brain hippocampus was measured with the avidin-biotin-peroxidase technique. The ingredients were assigned by UHPLC-TOF/MS, chromatography was performed by UHPLC system with DAD detector and BEH C18 column, and spectroscopy was conducted by ESI-MS system. The 80% ethanoic extract of A. jaluense tubers showed an acute anti-inflammatory effect by suppressing the edema volume in the hind paw of carrageenan-stimulated rats. In addition, A. jaluense tubers exerted an anti-rheumatic activity by reducing the secondary swelling volume from an immunological reaction in the left hind paw of CFA-induced chronic arthritis rats. Additionally, oral treatment with the 80% ethanoic extract -showed potent analgesic effects in the arthritis rats by recovering the paw withdrawal latency stimulated by the thermal hyperalgesia and by reducing the vocalization scores evoked by ankle flexion on both hind paws. Moreover, its treatment also indicated an anti-psychiatric effect by controlling the c-Fos protein expression of the brain hippocampus in CFA-stimulated arthritis rats. These results suggested that these therapeutic effects were exhibited by less toxic mono-esterified diterpenoid alkaloids (MDAs), and nontoxic non-esterified diterpenoid alkaloids (NDAs). A. jaluense tubers may act as viable therapeutic or preventive candidates for acute and chronic arthritis, particularly, for immune-inflammatory rheumatoid arthritis to suppress the pain and psychiatric condition.

Diterpenoid alkaloids from Delphinium forrestii var. viride and their anti-inflammation activity

Six undescribed diterpenoid alkaloids including five C19-diterpenoid alkaloids forrestlines A-E, and one C20-diterpenoid alkaloid forrestline F, together with nine known alkaloids have been isolated from the whole herbs of Delphinium forrestii var. vride. Their structures were elucidated by spectroscopic data, and their inhibitory activities on NO production stimulated by LPS in RAW264.7 macrophage cells were determined. Then, forrestline F, with the strongest inhibitory activity (IC50 of 9.57 ± 1.43 μM), was selected to study its possible anti-inflammatory mechanism. ELISA results showed that forrestline F suppressed inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosisfactor-α (TNF-α), and interleukin-6 (IL-6). Moreover, forrestline F could down-regulate LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blotting assay. It also inhibited expression of phosphorylation of MAPKs (including p-p38, p-ERK and p-JNK), and NF-κB p65, and decreased ROS accumulation by upregulating the expression of HO-1 expression via nuclear translocation of Nrf2. In conclusion, forrestline F showed anti-inflammatory effect by inhibiting NF-κB/MAPK and Nrf2/HO-1 signaling pathway. Therefore, forrestline F could be a promising molecule for the development of anti-inflammatory agents in the future.

Chemistry, biological activities and toxic effects of alkaloidal constituents of genus Delphinium - A mini review

The genus Delphinium is one of the essential members of the family Ranunculaceae. These species grow wild in North America, Europe, and Asia. They have demonstrated antioxidant, antimicrobial, and cytotoxic activities. Diterpenoid alkaloids are their main constituents and seem to be responsible for medicinal and toxic properties. The primary purpose of this paper is to review the therapeutic benefits of Delphinium species, chemical composition, and its medicinal uses, in addition to the reported toxic effects of these plants influencing different animals and humans.

Diterpenoid alkaloids from roots of Aconitum kongboense

The chemical constituents from the roots of Aconitum kongboense were studied. Twenty-five diterpenoid alkaloids were isolated from the 95% methanol extract of the roots of A. kongboense by silica gel, reverse-phase silica gel and basic alumina column chromatography. They included a new aconitine-type diterpenoid alkaloid, named as kongboensenine(1), and twenty-four known ones(2-25), i.e., acotarine F(2), acotarine G(3), 14-acetyltalatisamine(4), talatisamine(5), indaconitine(6), yunaconitine(7), chasmanine(8), 6-epi-foresticine(9), homochasmanine(10), 8-deacetyl-yunaconitine(11), chasmaconitine(12), ajaconine(13), franchetine(14), ezochasmanine(15), crassicautine(16), 14-O-deacylcrassicausine(17), genicunine A(18), falconeridine(19), sachaconitine(20), liljestrandisine(21), 8-methyl-14-acetyltalatisamine(22), kongboendine(23), 14-benzoylchasmanine(24) and pseudaconine(25). Their structures were elucidated by common spectroscopic methods including high-resolution electrospray ionization mass spectrometry(HR-ESI-MS) and nuclear magnetic resonance(NMR) techniques. Compounds 2-4, 10, 13, 15-19 and 21-22 were isolated from this plant for the first time. Experimental results showed that all compounds did not have a significant inhibitory activity against acetylcholinesterase(AChE).

Three New C19-Diterpenoid Alkaloids from Aconitum novoluridum.

Three new aconitine-type C19-diterpenoid alkaloid namely novolunines A (1), B (2), and C (3), along with fifteen known diterpenoid alkaloids were isolated from the roots of Aconitum novoluridum, whose phytochemical investigations have never been reported before. The structures of three new alkaloids were established on the basis of spectra data (high-resolution electrospray ionization (HR-ESI)-MS, IR, one dimensional (1D)- and 2D-NMR). Noteworthily, novolunines A (1) and B (2) are two diterpenoid alkaloids bearing conformational isomerism. In addition, the diterpenoid alkaloids 1-3 did not show any anti-acetylcholinesterase (AChE) or anti-inflammatory activities.

Total Syntheses of the C19 Diterpenoid Alkaloids (-)-Talatisamine, (-)-Liljestrandisine, and (-)-Liljestrandinine by a Fragment Coupling Approach.

The C19 diterpenoid alkaloids (C19 DTAs) are a large family of natural products, many of which modulate the activity of ion channels in vivo and are therefore of interest for the study of neurological and cardiovascular diseases. The complex architectures of these molecules continue to challenge the state-of-the art in chemical synthesis, particularly with respect to efficient assembly of their polcyclic ring systems. Here, we report the total syntheses of (−)-talatisamine, (−)-liljestrandisine, and (−)-liljestrandinine, three aconitine-type C19 DTAs, using a fragment coupling strategy. Key to this approach is a 1,2-addition/semipinacol rearrangement sequence which efficiently joins two complex fragments and sets an all-carbon quaternary center.

Isolation, identification, and activity evaluation of diterpenoid alkaloids from Aconitum sinomontanum

A phytochemical study led to the isolation of 25 diterpenoid alkaloids from Aconitum sinomontanum, of which six were described for the first time. Among them compounds 1–3 are anhydrolycoctonine derivatives, rare rearranged aconitine-type C19-diterpenoid alkaloids. To our best knowledge, less than ten of this type of alkaloids were isolated just from the genus Aconitum. The structures of these unreported compounds were elucidated by extensive analysis of NMR spectroscopic data and X-ray diffraction. The biological activities of compounds 1–3, 5–9, and 12–25 were evaluated. Among the tested compounds, compounds 2 and 17 showed potent inhibitory effect on the capsaicin (selective TRPV1 agonist) mediated activation of transient receptor potential vanilloid 1 (TRPV1) channels expressed in HEK-293 cells with inhibition rate of 31.78% and 30.94% at the concentration of 10 μM. Compounds 1–3, 5–9, 13, and 18–25 exhibited weak cytotoxic activity against human tumor cell lines NCI–H226 and MDA-MB-231 with inhibition rate over 10% at the concentration of 10 μM. Compound 16 showed most inhibitory effect on the expression of Nrf2 (NF–E2-related factor-2)-regulated gene with inhibition rate of 25% at the concentration of 20 μM.

Antinociceptive C19–diterpenoid alkaloids from the root of Aconitum episcopale

A chemical investigation on the roots of Aconitum episcopale afforded three undescribed aconitine–type C19–diterpenoid alkaloids, episcopalines A–C (1–3). The structures of the new compounds were elucidated by spectroscopic analysis (NMR, IR, UV, and MS). The isolated alkaloids were tested in vivo for their antinociceptive properties. As a result, episcopaline B (2) showed potent antinociceptive effect and its ID50 value (55.0 μmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen.

Aconitine poisoning due to confusion of aconite leaves with lovage

Due to a mix-up an older couple (69 years and 71years) ate a meal with herbs from their garden that contained leaves of monkshood (Aconitum napellus). The monkshood plants grew close to the herbs in their garden. Both patients developed the typical symptoms of aconitine poisoning with paresthesia, hypotension and bradycardia. Over the course of time both developed cardiac arrhythmia with ventricular extrasystoles and required monitoring on the intensive care unit (ICU). The husband was more severely affected and needed catecholamines for successful treatment of hypotension (70/40 mmHg) and bradycardia (45 bpm). The toxicological analysis of the patients' serum taken 3.5 h after ingestion led to the detection of 1.8 ng/ml and 2.0 ng/ml aconitine, respectively. The patients were discharged in good general condition after 1 and 2 days, respectively. Monkshood (Aconitum napellus) is one of the most toxic native plants that can also be found in gardens due to its popularity as an ornamental plant. All parts of the plant contain toxic diterpenoid alkaloids, such as aconitine. Aconitine causes persistent activation of the fast voltage-gated sodium channels resulting in severe cardiac and neurological toxicity. Treatment of aconitine-induced ventricular arrhythmias is challenging as they are often refractory to electrical cardioversion and antiarrhythmic drugs.

Asymmetric Total Syntheses of (+)-Davisinol and (+)-18-Benzoyldavisinol: A HAT-Initiated Transannular Redox Radical Approach.

The first and asymmetric total syntheses of two C11-oxygenated hetisine-type diterpenoid alkaloids, namely, (+)-davisinol and (+)-18-benzoyldavisinol, is described. The concise synthetic approach features a HAT-initiated transannular redox radical cyclization, an ODI-Diels-Alder cycloaddition, and an acylative kinetic resolution. By incorporating an efficient late-stage assembly of the azabicycle, our strategy would streamline the synthetic design of C20-diterpenoid alkaloids and pave the way for their modular syntheses.

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.

Antimicrobial Natural Products Produced by Soil-Derived Fungus Penicillium cremeogriseum W1-1

Ten compounds (1-10) were obtained from soil-derived Penicillium cremeogriseum W1-1 with the antimicrobial guided isolation procedure. Among them, 4 presented broad-spectrum antimicrobial activities and its preliminary mechanisms were evaluated. Compound 4 showed growth inhibition on drug-resistant pathogenic strains Escherichia coli and Candida albicans with post-contact effect (PCE), changed the morphology and membrane structure, killed cells with leakage, inhibited the growth of C. albicans by eradicating biofilms. Interestingly, the fraction containing 4 presented in vivo anti-pathogenic activities in mice, indicating this indole diterpenoid alkaloid could been used as potential antimicrobial agent.

Denudatine-type diterpenoid alkaloids from an aqueous extract of the lateral root of Aconitum carmichaelii

Five new denudatine-type diterpenoid alkaloids (1–5), along with the known analogue aconicarmine (6), were isolated from an aqueous decoction of the lateral roots of Aconitum carmichaelii (fu-zi). Their structures were determined by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Compound 5 is the first denudatine-type diterpenoid alcohol iminium alkaloid, which could be partially transformed into the aza acetal form in pyridine-d 5. Compound 5 inhibited mice writhing in an acetic acid-induced writhing assay.

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos.

Aconitine (AC), one of the bioactive diterpenoid alkaloids extracted from Aconitum plants, is widely used in traditional herbal medicine to treat various diseases. Emerging evidence indicates that AC has attracted great interest for its wide cardiotoxicity and neurotoxicity. However, the toxic effects of AC on embryonic development and its underlying mechanisms remain unclear. Here, a developmental toxicity assay of AC was performed on zebrafish embryos from 4 to 96 h post fertilization (hpf), and its underlying mechanisms were discussed. AC exposure impaired the cardiac, liver, and neurodevelopment. Especially, a high dose of AC (7.27 and 8.23 μM) exposure resulted in malformations at 72 and 96 hpf, including reduced body length, curved body shape, pericardial edema, yolk retention, swim bladder and brain developmental deficiency, and degeneration of dopaminergic neurons. High-concentration AC exposure caused a deficient cardiovascular system with cardiac dysfunctions, increased heart rates at 72 and 96 hpf, and reduced locomotor behavior at 120 hpf. AC treatment significantly increased the ROS level and triggered cell apoptosis in the heart and brain regions of embryos at 96 hpf in 7.27 and 8.23 μM AC treatment zebrafish. Oxidative stress was confirmed by reduced levels of T-SOD activity associated with accumulation of lipid peroxidation in larvae. The expression levels of oxidative stress-related genes (Nrf2, HO-1, Cat, and Sod-1) Erk1/2 and Bcl-2 were significantly downregulated at 96 hpf. The expression pattern of JNK and mitochondrial apoptosis-related genes (Bad, Bax, Cyto C, Casp-9, and Casp-3) was significantly upregulated. Taken together, all these parameters collectively provide the first evidence of AC-induced developmental toxicity in zebrafish embryo/larvae through ROS-medicated mitochondrial apoptosis involving Nrf2/HO-1 and JNK/Erk pathways.

Functional identification of the terpene synthase family involved in diterpenoid alkaloids biosynthesis in Aconitum carmichaelii

Aconitum carmichaelii is a high-value medicinal herb widely used across China, Japan, and other Asian countries. Aconitine-type diterpene alkaloids (DAs) are the characteristic compounds in Aconitum. Although six transcriptomes, based on short-read next generation sequencing technology, have been reported from the Aconitum species, the terpene synthase (TPS) corresponding to DAs biosynthesis remains unidentified. We apply a combination of Pacbio isoform sequencing and RNA sequencing to provide a comprehensive view of the A. carmichaelii transcriptome. Nineteen TPSs and five alternative splicing isoforms belonging to TPS-b, TPS-c, and TPS-e/f subfamilies were identified. In vitro enzyme reaction analysis functional identified two sesqui-TPSs and twelve diTPSs. Seven of the TPS-c subfamily genes reacted with GGPP to produce the intermediate ent-copalyl diphosphate. Five AcKSLs separately reacted with ent-CPP to produce ent-kaurene, ent-atiserene, and ent-13-epi-sandaracopimaradie: a new diterpene found in Aconitum. AcTPSs gene expression in conjunction DAs content analysis in different tissues validated that ent-CPP is the sole precursor to all DAs biosynthesis, with AcKSL1, AcKSL2s and AcKSL3-1 responsible for C20 atisine and napelline type DAs biosynthesis, respectively. These data clarified the molecular basis for the C20-DAs biosynthetic pathway in A. carmichaelii and pave the way for further exploration of C19-DAs biosynthesis in the Aconitum species.

Diterpenoid Alkaloids from the Aerial Parts of Aconitum flavum Hand.-Mazz

Sixteen diterpenoid alkaloids (DAs), including six aconitine-type alkaloids (5 and 9 − 13), seven 7,17-seco-aconitine-type alkaloids (1 − 4, 6 − 8), two napelline-type alkaloids (14 and 15) as well as one veatchine-type alkaloid (16), were isolated from the aerial parts of Aconitum flavum Hand.-Mazz. In which, flavumolines A − D (1 − 4) were four new ones, and flavumoline E (5) was reported as natural compound for the first time. Their chemical structures were elucidated by the analysis of extensive spectroscopic data. The inhibitory activities of these isolates on Cav3.1 low voltage-gated Ca2+ channel, NO production in LPS-activated RAW264.7cells, five human tumor cell lines, as well as acetylcholinesterase (AChE) were tested.

New napelline-type diterpenoid alkaloids from Aconiti kusnezoffii roots: Structure elucidation, plausible biogenetic pathway and biological activities

• Three new napelline-type diterpenoid alkaloids were isolated from Aconiti kusnezoffii roots. • The structures were successfully determined by spectroscopic methods. • Napelline B was isolated from Aconiti kusnezoffii roots for the first time. • Napellines B and C exhibited potential proliferation activities against RAW264.7 cells dose-dependently. Eleven alkaloids were isolated from the roots of Aconiti kusnezoffii . The structures of three new C 20 -diterpenoid alkaloids, named napellines C to E ( 1 – 3 ), were elucidated based on spectroscopic methods including HRESIMS, IR, and NMR, together with comparison of their spectroscopic data with those of known analogues in the literature. The plausible biogenetic pathway for napelline-type diterpenoid alkaloids is also proposed. In addition, napellines C to E ( 1 – 3 ), along with known napelline B , were evaluated in vitro for their proliferative activities against A549, HL-60, MCF-7, Bel-7402, BGC-823, and RAW264.7 cells. Among the compounds tested, napellines B and C at 50 μM ( vs. 5 μM, p < 0.01) exhibited the significant proliferating activities against RAW264.7 cells and their proliferative rates were −62.1 % and −59.6 %, respectively.

C19-diterpenoid alkaloids from the rhizomes of Aconitum pendulum

Six new C19-aconitine-type diterpenoid alkaloids, pendulumines A-F (1–6), together with six known ones (7–12), were isolated from the rhizomes of Aconitum pendulum. Their structures were elucidated using extensive spectroscopic data analysis, including 1D and 2D NMR, MS, and single-crystal X-ray diffraction analysis. The isolates were also tested for their analgesic activity based on the thermal avoidance response of the roundworm Pirstionchus pacificus, and 9 showed significant biological activity with an EC50 value of 0.08 ± 0.02 mg.mL−1.

Synthetic studies towards arcutinidine: An alternative strategy for construction of the complete carbon framework

A synthetic approach to the complete carbon framework of C 20 -diterpenoid alkaloid arcutinidine has been achieved. The key steps include a 1,4-conjugate addition and a palladium-catalyzed decarboxylative allylation to install the two vicinal all-carbon quaternary centers at C4 and C5; an oxidative dearomatization/IMDA cascade reaction to forge the C/D/F ring, and a ketyl-olefin cyclization to construct the B ring. • Alternative approach to the complete carbon framework of C 20 -diterpenoid alkaloid arcutinidine. • Synthetic strategy based on the bioinspired late-stage formation of the pyrrolidine ring through C-H amination. • A 1,4-conjugate addition and a palladium-catalyzed decarboxylative allylation to forge the two vicinal C4, C5 all-carbon quaternary centers. • atization/IMDA cascade reaction to forge the C/D/F ring in one-pot. • SmI 2 -mediated ketyl-olefin cyclization to construct the B ring.

Alkaloids of Delphinium grandiflorum and their implication to H2O2-induced cardiomyocytes injury

Three new diterpenoid alkaloids (1–3), and eight known alkaloids (4–11) were isolated from the aerial parts of Delphinium grandiflorum. Grandifline A (1) represents an unprecedented diterpenoid alkaloid ring system featuring a C-7NC17 hemiaminal moiety and a lactone fragment through the linkage of C-17OC19 unit. And we named this newly-discovered class of rearranged C19-diterpenoid alkaloid scaffold as grandiflodines (B-12). Grandifline B (2) is the first naturally-occurring 7,17-secolycoctonine diterpenoid alkaloid with a C-7OC17 unit forming a hemiacetal. Their structures were elucidated via spectroscopic data and single-crystal X-ray diffraction analysis. The protective effects of compounds 1–11 on H2O2-induced cardiomyocytes injury were assayed. And compounds 6 and 10 showed significant protective effects, with IC50 values of 1.881 ± 0.680 μM and 1.904 ± 0.750 μM, respectively. Further, compound 6 could reduce oxidative damage by inhibiting cell death via the AMPK/AKT/mTOR signaling pathway in H2O2-induced H9C2 cells.