Lycocasine A, a Lycopodium Alkaloid from Lycopodiastrum casuarinoides and Its Acid-Sensing Ion Channel 1a Inhibitory Activity.

A novel Lycopodium alkaloid, lycocasine A (1), and seven known Lycopodium alkaloids (2-8), were isolated from Lycopodiastrum casuarinoides. Their structures were determined through NMR, HRESIMS, and X-ray diffraction analysis. Compound 1 features an unprecedented 5/6/6 tricyclic skeleton, highlighted by a 5-aza-tricyclic[6,3,1,02,6]dodecane motif. In bioactivity assays, compound 1 demonstrated weak inhibitory activity against acid-sensing ion channel 1a.

Lycopodium Alkaloids from Huperzia goebelii.

One new fawcettimine-type Lycopodium alkaloid, hupertimine F (1), together with five known (2-6) Lycopodium alkaloids were isolated from Huperzia goebelii. The structure of 1 was elucidated by 1D and 2D NMR spectra, HRESIMS, and X-ray diffraction. Structurally, 1 represents the fourth example of Lycopodium alkaloids characterized by a 5/5/5/5/6 pentacyclic ring system with a 1-aza-7-oxabicyclo[2.2.1]heptane moiety. These known compounds 2, 3, 5, and 6 were isolated from H. goebelii for the first time. Compounds 1-6 were evaluated for acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B inhibitory activities in vitro.

Huperzine alkaloids: forty years of total syntheses.

Covering: up to 2023Huperzine alkaloids are a group of natural products belonging to the Lycopodium alkaloids family. The representative member huperzine A has a unique structure and exhibits potent inhibitory activity against acetylcholine esterase (AChE). This subfamily of alkaloids provides a great opportunity for developing synthetic methodologies and asymmetric synthesis. The efforts towards the synthesis of huperzine A have cultivated dozens of total syntheses and a rich body of new chemistry. Impressive progress has also been made in the synthesis of other huperzine alkaloids. The total syntheses of huperzines B, U, O, Q and R, structure reassignment and total syntheses of huperzines K, M and N have been reported in the past decade. This review focuses on the synthetic organic chemistry and the biosynthesis and medicinal chemistry of huperzines are also covered briefly.

Casuattimines A-N, fourteen new Lycopodium alkaloids from Lycopodiastrum casuarinoides with Cav3.1 channel inhibitory activity.

Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Cav3.1 channel inhibitory activities presenting IC50 values of 10.75 ± 1.02 µM, 9.33 ± 0.79 µM, and 7.14 ± 0.86 µM, respectively. The dynamics of compound 4 against the Cav3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.

Lycopodium Alkaloids from Phlegmariurus carinatus with Cytotoxic and Neuroprotective Effects.

One new fawcettimine-type alkaloid, phlecarinadine A (1), and twelve known ones (2-13) were isolated from the whole plant of Phlegmariurus carinatus. Their chemical structures were unambiguously established by extensive spectroscopic analyses, including nuclear magnetic resonance (NMR) spectroscopic and high resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configuration of 1 was elucidated by the electronic circular dichroism (ECD) technique. These compounds were tested for their cytotoxic and neuroprotective activities. None of these compounds revealed cytotoxic activity against five tumor cells. Phlegmariurine B (2) exhibited potential neuroprotective effects against hemin-induced HT22 cell damage, with a 17.76 % increase in cell survival at 10 µM. In further study, 2 can ameliorate hemin-induced neuronal cell death via an anti-apoptotic pathway. These findings suggest that 2 might be a valuable lead compound with neuroprotective activity.

Plant carbonic anhydrase-like enzymes in neuroactive alkaloid biosynthesis.

Plants synthesize numerous alkaloids that mimic animal neurotransmitters1. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds2,3, yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids4, we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A5. Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target.

The apoptotic effect of the Lycopodium clavatum extracts on MCF-7 human breast cancer cells.

Breast cancer is a significant health problem worldwide, and the search for effective treatments is critical. Side effects of cancer treatments such as surgery, radiotherapy, and chemotherapy reduce the patient's standard of living. Recently, natural compounds from plants have gained attention as potential anticancer agents due to their safety, low toxicity, and potential efficacy. Lycopodium Clavatum (LC) is an herb abundant in tropical regions and Europe and is known for its various medicinal properties. In this study, we investigated the cytotoxic and apoptotic effects of LC Water Extract (LC-WE) and LC Ethanol Extract (LC-EE) plant extracts on MCF-7 human breast cancer cells. Our results showed that LC treatment led to a dose and time-dependent cytotoxic effect on MCF-7 cells, indicating its potential as an anticancer agent against human breast cancer. Additionally, we observed that LC treatment activated apoptosis-related proteins, including BAX, Caspase-3, and Caspase-9. These results suggest that LC may induce apoptosis as a mechanism underlying its cytotoxic effect on MCF-7 human breast cancer cells. Previous studies have shown the anti-cancer potential of LC against different types of cancer. However, the anti-cancer effect of LC on human breast cancer cells has not been investigated to date. Therefore, our study provides novel insights into the potential of LC as an anti-cancer agent against breast cancer. Overall, our results highlight the potential of LC as a promising natural compound for breast cancer treatment.

Lycopodium Alkaloids from Huperzia serrata and Their Anti-acetylcholinesterase Activities.

One new fawcettimine-type alkaloid (1), one new miscellaneous-type alkaloid (2), four new lycodine-type alkaloids (3-6), and eight known ones (7-14) were isolated from the whole plants of Huperzia serrata. Their structures and absolute configurations were elucidated based on spectroscopic data, X-ray diffraction, ECD calculation and Mosher's method. Compound 1 was a rare C18 N2 -type Lycopodium alkaloid, possessing serratinine skeleton with an amide side chain in C-5. The absolute configuration of the 18-OH of compounds 4-6 were first determined by Mosher's method. Moreover, compounds 1-14 were assayed anti-acetylcholinesterase effect in vitro, and compound 7 showed significant anti-acetylcholinesterase activity with an IC50 value of 16.18±1.64 µM.

A new abietane diterpenoid from Lycopodium complanatum.

A new abietane diterpenoid, 1ß, 11-epoxyabieta-12-hydroxy-8, 11, 13-triene-7-one (1), along with three known compounds (2-4), was isolated from Lycopodium complanatum. Their structures were confirmed by the analysis of 1D, 2D NMR and HRESIMS data, and comparison with previous spectral data. All compounds were tested for inhibitory activities against A549, HepG2 and MCF-7 tumor cell lines. [Figure: see text].

Cryptadine C, a new C27N3-type Lycopodium alkaloid from Lycopodium cryptomerinum.

A new C27N3-type Lycopodium alkaloid consisting of two decahydroquinolines and a piperidine, cryptadine C (1) was isolated from Lycopodium cryptomerinum. The structure and relative configuration of 1, which is related to those of cryptadines A and B, lycoperine A, and hupercumine A, was elucidated on the basis of spectroscopic data. Cryptadine C showed moderate inhibitory activity against acetylcholinesterase.

Synthetic Studies on Tetracyclic Diquinane Lycopodium Alkaloids Magellanine, Magellaninone and Paniculatine.

(-)-Magellanine, (+)-magellaninone, and (+)-paniculatine are three natural products isolated from the Lycopodium family that share a unique 6-5-5-6-fused tetracyclic diquinane core skeleton. Several members of this family have potent s anti-inflammatory and acetylcholinesterase-inhibitory properties and are under development for the treatment of Alzheimer's and other neurodegenerative diseases. Several research groups have undertaken the formal and total syntheses of this class of natural products. This review highlights over 20 reported total syntheses of these three alkaloids and the development of synthetic methods for the assembly of their core skeletons.

Phlegcarines A-C, three Lycopodium alkaloids from Phlegmariurus carinatus (Desv. ex Poir.) Ching.

Three undescribed Lycopodium alkaloids, phlegcarines A-C, along with nine known alkaloids, were isolated from the aerial parts of a gardening clubmoss Phlegmariurus carinatus (Desv. ex Poir.) Ching. Phlegcarine A is an undescribed Lycopodium alkaloid possessing an unprecedented 5/9/6/6 fused-tetracyclic ring system consisting of an oxa-cyclononanone, a piperidine, a methylcyclohaxane and an oxazolidine. Phlegcarine B is the first N-chloromethyl piperidinium Lycopodium alkaloid of (+)-lycoflexine. The semi-synthesis of phlegcarine B was investigated from (+)-fawcettimine. Phlegcarine C, an undescribed epimer of 12-epilycodoline, is a rare lycopodine-type alkaloid with ß-oriented H-4. Transformation of phlegcarine C and lycodoline to 12-epilycopodine N-oxide via keto-enol tautomerization was investigated using m-CPBA. The structural assignments were established through comprehensive spectroscopic techniques and chemical correlations. Phlegcarines A-C were assayed for their anti-acetylcholinesterase activity, but none of them exhibited biological activity more potent than that of huperzine A.

The Therapeutic Effects of Seven Lycopodium Compounds on Cell Models of Alzheimer's Disease.

BACKGROUND: As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. OBJECTIVE: To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. METHODS: We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. RESULTS: All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3ß-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAßPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAßPPß, thereby reduced Aß production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10µM. CONCLUSION: Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aß production and inhibiting AChE in AD.

Unified Total Synthesis of Tetracyclic Diquinane Lycopodium Alkaloids (+)-Paniculatine, (-)-Magellanine, and (+)-Magellaninone.

A unified route for the total synthesis of three tetracyclic diquinane Lycopodium alkaloids (+)-paniculatine, (-)-magellanine, and (+)-magellaninone has been accomplished in 13-14 overall steps based on late-stage diverse transformations from an advanced tetracyclic common intermediate. In the established synthesis, quick formation of the two five-membered rings was efficiently achieved by an intramolecular reductive coupling of ketone-carbonyl and ester-carbonyl and an organocatalytic intramolecular Michael addition of aldehyde-derived enamine to an internal enone functionality with satisfactory redox and step economies and excellent stereoselectivities, providing the requisite tricyclic carbo-framework possessing multiple dense stereogenic centers, and an intramolecular reductive amination finally furnished the essential piperidine ring.

Lycojapomines A-E: Lycopodium Alkaloids with Anti-Renal Fibrosis Potential from Lycopodium japonicum.

Five Lycopodium alkaloids featuring novel C17N2 (1 and 2), C29N3 (3 and 4), and C15N2 (5) skeletons were isolated from Lycopodium japonicum. Compound 1 is the first natural product containing a 3-aza[3.3.3]propellane motif. The structures of these compounds were elucidated by spectroscopic analysis, X-ray crystallography, and computational methods. Compounds 1 and 3-5 significantly inhibited TGF-ß1-induced fibronectin deposition in HK-2 cells at a nontoxic concentration of 20 µM.

Lycopodium Mitigates Oxidative Stress and Inflammation in the Colonic Mucosa of Acetic Acid-Induced Colitis in Rats.

Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are diseases of the gastrointestinal system involving genetic and environmental factors attributed to oxidative stress and inflammation. Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the important therapeutic strategies to keep the disease in remission. As there is no permanent cure for IBD except for chronic long-term treatment or surgery, it is therefore imperative to investigate plant-based agents that are receiving attention for their therapeutic benefits to overcome the debilitating clinical conditions of IBD. Lycopodium (LYCO), a plant of tropical and subtropical origin and known by numerous names such as ground pine, club moss, or devil's claw, has been popularly used for centuries in traditional medicine including Chinese and Indian medicines. In the present study, the effect of LYCO has been investigated in an acetic acid (AA)-induced colitis model in Wistar rats. LYCO was orally administered at the dose of 50 mg/kg/day either 3 days before or 30 min after the induction of IBD and continued for 7 days by intrarectal administration of AA. The changes in body weight and macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on days 0, 2, 4, and 7. The levels of myeloperoxidase (MPO), reduced glutathione (GSH), and malondialdehyde (MDA) were measured. AA caused a significant reduction in body weight and increased macroscopic and microscopic ulcer scores along with a significant decline in antioxidant enzymes, superoxide dismutase (SOD), and catalase and antioxidant substrate, glutathione (GSH). There was a concomitant increased formation of malondialdehyde (MDA), a marker of lipid peroxidation, and raised myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with LYCO significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. AA also caused the release of proinflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-23 (IL-23). Furthermore, AA also increased the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. LYCO treatment significantly reduced the release of calprotectin and proinflammatory cytokines. The results demonstrate that LYCO treatment has the potential to improve disease activity by inhibiting oxidative stress, lipid peroxidation, and inflammation along with histological preservation of colonic tissues.

Hupertimines A-E, Fawcettimine-Type Lycopodium Alkaloids from Huperzia serrata.

Five new fawcettimine-type Lycopodium alkaloids, hupertimines A-E (1-5), were discovered from the whole plant of Huperzia serrata, along with two known alkaloids, 8α-hydroxyphlegmariurine B (6) and 8ß-hydroxyphlegmariurine B (7). The structures of 1-7 were identified through HR-MS, IR, 1 H, 13 C, and 2D NMR, and single-crystal X-ray diffraction analysis. Structurally, compound 1 was the fourth example of Lycopodium alkaloid with an ether linkage between C-5 and C-13 and 2 was the third example of Lycopodium alkaloid with a 5/5/5/5/6 pentacyclic ring system and featuring a 1-aza-7-oxabicyclo[2.2.1]heptane unit. Compounds 1-7 were tested for their BACE1 inhibitory activity. In addition, the correct 1 H- and 13 C-NMR data for 7 were reported in current study.

Collective Total Syntheses of Five Lycopodium Alkaloids.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Lycopodium as a treatment for Urate Deposition (gout) in birds: case report

A 3-year-old male cockatiel (Nymphicus hollandicus) was diagnosed with joint arthritis due to hyperucemiasyndrome. The bird presented deposition of urate crystals on the synovial membrane with inflammation of joints and tendons (tufts), causing listlessness, anorexia and lameness, with difficulty in keeping perched or moving. Laboratory tests displayed an increase in uric acid and creatinine phosphokinase levels, and leukocytosis despite lymphopenia. Unsucessfully, the animal had been treated with allopathic medicine for 2 months, without a favorable response and still developing stressful reaction to handling.Methodology:High dilution therapy was attempted with 2 globules of Lycopodiumclavatum30 cH /bid and Arnica montana30 cH /bid /oral. The most expressive tufts were removed with daily cleaning of the affected area; a new diet was established and perches were removed, allowing the bird to remain on a flat surface until regression of symptoms. The medication was continued for 30 days. On the second appointment, although the caregiver reported episodes of probable pain, there was an improvement in behavior with normal appetite. Lyc30cH /sid was continued and Arn30cH /bid to qid, depending on pain episodes, for over 30 days. The tutor authorized the case report through a consent form. Results and discussion:Follow-up laboratory tests were performed everythree months for one year, reaching normal levels for uric acid (3.5-11 mg/dL) and CK (30-245mg/dL) on the third measurement. The bird presented no formation of new tufts along the second month of treatment. After 12 months, the animal ingests homeopathic globules spontaneously and presents stable clinical presentation (Lyc30cH / sid / 3 times a week) with no recurrence and without side effects nor stressful behavior. Conclusion: In view of these results, it is considered that homeopathic treatment is an option to be considered in the treatment of joint arthritis from hyperuricemia syndrome in birds.