Serratene Triterpenoids Research Articles

Two new serratene triterpenes from club moss cultivars

Two new serratene triterpenes, 14α,21β-dihydroxyserrat-3β-yl acetate and 3α,21β-dihydroxyserrat-14-en-23-oic acid, together with eight known compounds were isolated from two club moss cultivars, Phlegmariurus carinatus (Desv.) Ching and Phlegmariurus nummulariifolius (Blume) Ching. 14α,21β-Ddihydroxyserrat-3β-yl acetate (1) was isolated from P. carinatus, and 3α,21β-dihydroxyserrat-14-en-23-oic acid (2), an undescribed carboxylic group at C-23 position of the serratene triterpenoids, was isolated from P. nummulariifolius. The structures of these new compounds were elucidated by using HR-ESIMS, UV, IR, 1D (1H and 13C NMR spectra), 2D NMR spectra, experimental ECD spectrometry and the single-crystal X-ray analysis. Biological evaluation of 14α,21β-dihydroxyserrat-3β-yl acetate (1) and lycoclavanol (8) revealed moderate cytotoxic activity on three tumor cell lines (HepG2, A549 and HuCCA-1) whereas 3α,21β-dihydroxyserrat-14-en-23-oic acid (2) showed strong inhibitory effect on HuCCA-1 cells with the IC50 of 4.72 µM.

Serratene triterpenoids from Lycopodium cernuum L. as α-glucosidase inhibitors: Identification, structure–activity relationship and molecular docking studies

Phytochemical investigation of Lycopodium cernuum L. afforded seven undescribed serratene triterpenoids named 3β, 21β-dihydroxyserra-14-en-24-oic acid-3β-(5′-hydroxybenzoate) (1), 3β, 21β, 24-trihydroxyserrat-14-en-3β-(5′-hydroxyl benzoate) (2), 3β, 14α, 15α, 21β-tetrahydroxyserratane-24-methyl ester (3), 3β, 14α, 21β-trihydroxyserratane-15α-(4′-methoxy-5′-hydroxybenzoate)-24-methyl ester (4), 3β, 14α, 21β-trihydroxyserratane-15α-(4′-methoxy-5′-hydroxybenzoate) (5), 3β-hydroxy-21β-acetate-16-oxoserrat-14-en-24-oic acid (6), 3β, 21β-dihydroxy-16α, 29-epoxyserrat-14-en-24-methyl ester (7), together with eleven known compounds (8–18), whose chemical structures were elucidated through spectroscopic analysis of HRESIMS, 1D NMR, 2D NMR and comparison between the literature. All compounds were evaluated for their α-glucosidase inhibitory activity for the first time. The results showed that compounds 1, 2, 4, 5, 6, 10, 13, 15, and 16 were among the most potent α-glucosidase inhibitors, with IC50 values ranging from 23.22 ± 0.64 to 50.65 ± 0.82 μM. Structure–activity relationship (SAR) studies indicated that the combined properties of the 5-hydroxybenzoate moiety at C-3, β-OH at C-21, COOH- at C-24, and Δ14,15 groups enabled an increase in the α-glucosidase inhibitory effect. In addition, molecular docking studies showed that the potential inhibitors mainly interact with key amino acid residues in the active site of α-glucosidase through hydrogen bonds and hydrophobic forces.

The traditional uses, secondary metabolites, and pharmacology of Lycopodium species

Lycopodium is a genus of the family Pteridophytes, which is widely distributed in temperate and tropical climates and tropical mountains. Plants of genus Lycopodium are ancient medicinal plants which have been used in different traditional medicinal system to treat many diseases, mainly focus on central nervous system and inflammation-related diseases. Rigorous pharmacological and clinical studies conducted in recent decades have demonstrated their special efficacy in the treatment of Alzheimer's disease (AD). Furthermore, secondary metabolites and extracts from these plants have been proven to possess neuroprotective, anti-tumor, anti-inflammatory, anti-microbial, and antiviral effects, which supports most of traditional medicinal uses of Lycopodium plants. To date, a total of 508 secondary metabolites have been reported from the 46 species belonging to genus Lycopodium. Among those metabolites, Lycopodium alkaloids and serratene triterpenoids represent two major classes of bioactive ingredients. Notably, huperzine A, a Lycopodium alkaloid originally isolated from L. serratum, was licensed in China as a drug for the treatment of AD and in the United States as a dietary supplement. Besides, serratane-type triterpenoids may be potential candidates for the development of anticancer drugs. This review covers the literatures available from 1947 to 2020 and mainly discusses knowledge on ethnopharmacology, secondary metabolites, pharmacological activities, clinical trials, toxicology, and quality control of Lycopodium species. In addition, the present review also draws attention to the gaps that still exist in the scientific studies on Lycopodium plants, which would accelerate the contemporary development of this traditional medicinal plant.

Serratane triterpenoids from Lycopodium complanatum and their anti-cancer and anti-inflammatory activities

Phytochemical investigation of the ethyl acetate fraction of Lycopodium complanatum led to eight new serratane triterpenoids (lycomplanatums A-H, 1–8), along with five known analogues (9–13). Their structures were elucidated by extensive spectroscopic methods, including 1D/2D NMR, HRESIMS, and DFT GIAO 13C NMR calculation. Among them, compounds 2 and 13 showed moderate antiproliferative effects against seven human cancer cell lines, especially for MCF-7 with IC50 values of 13.8–44.7 μM. Additionally, the compounds were screened for anti-inflammatory effects based on their inhibitory activities of nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 2 and 13 diminished NO production more potently than others in a concentration-dependent manner.

Serratane triterpenoids isolated from Lycopodium clavatum by bioactivity-guided fractionation attenuate the production of inflammatory mediators.

Lycopodium clavatum has been used in traditional medicine for the treatment of kidney disorders, rheumatic arthritis, cystitis, and gastritis. We isolated a new serratane triterpenoid (2), and five known triterpenoids (1, 3-6) from the ethyl acetate fraction of L. clavatum by bioactivity-guided fractionation based on their suppression of inflammatory cytokines. Two different cell lines, RAW 264.7 and HT-29 were used to determine the anti-inflammatory activity of the isolated compounds. Among them, compounds 1, 2, 4, and 5 significantly inhibited the production of lipopolysaccharide (LPS)-induced NO in macrophages. Compounds 1, 2, 4, and 5 reduced inducible nitric oxide (iNOS) expression in RAW 264.7 cells and compounds 1 and 6 downregulated COX-2, which correlated with the reduced expression of PGE2. Compounds 1, 2, 4, and 5 downregulated pro-inflammatory cytokines, such as interleukin-1β (IL-1β) in macrophages, and additionally suppressed the levels of IL-8 in HT-29 cells. To determine the signaling pathways involved in the suppression of NO production by these compounds, we investigated ERK1/2 and nuclear factor-kappa B (NF-κB) expression by western blot analysis. We observed that these compounds downregulated the expression of LPS-induced NF-κB and pERK 1/2 in RAW 264.7 cells. Our results demonstrate that serratane triterpenoids isolated from L. clavatum may be used as potential candidates for treating inflammatory bowel disease (IBD) due to their anti-inflammatory effects.

Anti-cholinesterase activities of constituents isolated from Lycopodiastrum casuarinoides

Phytochemical investigation of the ethyl acetate extract of Lycopodiastrum casuarinoides (Spring) Holub (Lycopodiaceae) led to the isolation of nine compounds, including two new serratene triterpenoids, serrat-14-en-3α,21α-diol (1), 26-nor-8-oxo-21-one-α-onocerin (6), one new abietane diterpenoid, lycocasuarinone A (7), one new sesquiterpene acid, 7, 9-diene-1,4-epoxy-2-hydroxy-10-carboxylic acid (8) and one new chromone derivative, 5,7-dihydroxy-2-methyl esterchromone (9), together with four known serratene triterpenoids (2–5). Abietane diterpenoid (7) and sesquiterpene acid (8) from Lycopodiastrum casuarinoides are reported for the first time. Their structures and stereochemistry were unambiguously elucidated by spectroscopic analysis and comparison with known ones. All the compounds were tested for acetylcholinesterase (AChE) and butyrocholinesterase (BuChE) inhibitory activities. Bioactivity assays revealed that compound 6 exhibited the most potent AChE inhibitory effect.

Cytotoxic polyhydroxy serratene triterpenoids from Lycopodium complanatum

Phytochemical investigation of the 70% aqueous EtOH extract of Lycopodium complanatum led to six new polyhydroxy serratene triterpenoids (serrat A-F, 1–6), along with a known analogue (7). Their structures and configurations were elucidated by data analysis of HRESIMS, 1D and 2D NMR, in combination with comparisons of reported experimental spectroscopic data. All the isolates were evaluated cytotoxic activities against HepG2 cells, MCF-7 cells and series human lung cancer cell lines A549, Calu-6, NCI-H441, NCI-H226 and NCI-H1975. The results indicated that certain compounds inhibited proliferation of human cancer cells. Moreover, all compounds possessed selective cytotoxic activities on MCF-7 cells. Further, possible biosynthesis pathways of these compounds were proposed.

Pumilol, a Diterpenoid with a Rare Strobane Skeleton from Pinus pumila (Pinaceae)

Pumilol (1), a strobane diterpenoid, reported herein for the first time, was isolated from the bark of Pinus pumila (Pall.) Regel (Siberian Dwarf Pine or Japanese Stone Pine), along with 17 known compounds including serratane triterpenoids, not previously reported from this species, and four ferulate derivatives. The absolute configuration of pumilolwas established using HR-ESI-MS, NMR, the DP4+ probabilities and by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Labda-8(17),13-dien-15-oic acid (4), bornyl (E)-4-hydroxycinnamate (14) and bornyl (E)-ferulate (15) showed activity against S.aureus and/or E.faecalis with MIC90 values 12.5-50μm.

Triterpenoids and steroids from the bark of Pinus merkusii (Pinaceae)

Serratene triterpenoids are considered chemotaxonomy compounds from the Pinaceae family, within the Pinus genus. However, no studies have been conducted on the constituents of serratene triterpenoids of Pinus merkusii. P. merkusii is the only pine species native to Southeast Asia, including Indonesia. This study aimed to investigate the use of triterpenoids and steroids from the bark of P. merkusii as chemotaxonomic biomarkers. Five lipophilic extractives, including three triterpenoids (3β-methoxyserratt-14-en-21-one (C1), 3α,21β- dimethoxy-D14-serratene (C3), serrate-14-en-3β,21β-diol (C5)), and two steroids (stigmast-4-en-3-one (C2) and β-sitosterol (C4)), were isolated from the n-hexane extract of the bark of P. merkusii using column chromatography and thin–layer chromatography. The structures of the triterpenoids and steroids were characterized on the basis of their spectroscopic data. The discovery of serratene triterpenoids and steroids in P. merkusii bark characterizes this species as being in chemical accordance with other species of the Pinus genus and Pinaceae family.

Neolignans and serratane triterpenoids with inhibitory effects on xanthine oxidase from Palhinhaea cernua

Three new neolignans, lycocernuasides B-D (1–3), three new serratane triterpenoids, lycernuic ketones D (8) and E (9), and lycernuic A (10), together with six known compounds, were isolated from the 75% aqueous EtOH extract of Palhinhaea cernua. Their structures and absolute configurations were established primarily by NMR, HRESIMS and circular dichroism (CD). All compounds were evaluated the inhibitory activities of xanthine oxidase. Compounds 1–3 displayed moderate inhibitory effects on xanthine oxidase with IC50 values of 30.36μM, 42.65μM and 35.33μM, respectively.

Lycojaponicuminol A–F: Cytotoxic serratene triterpenoids from Lycopodium japonicum

Six new serratene triterpenoids (1–6), together with nine known triterpenoid compounds were isolated from the extract of club moss Lycopodium japonicum. The structures of isolated compounds were established by spectroscopic methods. The cytotoxic activities of all compounds were evaluated against three human cancer cell lines in vitro by MTT assay. Compounds 2, 6–8 and 11 exhibited moderate activities against all three cell lines with IC50 values of 2.28–11.81μg/mL.

Low-Volatile Lipophilic Compounds in Needles, Defoliated Twigs, and Outer Bark of Pinus thunbergii

Despite a long history of the use of Pinus thunbergii for technical, medicinal, agricultural, and other purposes, the composition of low-volatile metabolites in the used parts of the plant has been poorly investigated. We report here on the distribution of lipophilic extractive compounds in different parts of the shoot system (needles, defoliated twigs, outer bark) of P. thunbergii studied by GC/MS. The highest and lowest contents of lipophilic substances were found in defoliated twigs and in outer bark correspondingly. Acid compounds in the extract of needles comprised mainly labdane type diterpenoids (trans-communic acid), while in the extracts of defoliated twigs and outer bark the acids were represented predominantly by abietane type compounds (neoabietic, dehydroabietic, abietic, levopimaric and palustric acids). The major neutral components of the extract of needles were 10-nonacosanol, labdanoids (18-hydroxy-1 3-epi-manoyl oxide, trans-communol), and beta-sitosterol. In the case of the extract of defoliated twigs, labdanoids (18-hydroxy-13-epi-manoyl oxide, trans-communol, 13-epi-torulosol), serratane triterpenoids (3beta-methoxyserrat-14-en-21-one), and beta-sitosterol were the main neutral constituents, whereas serratanoids (3beta-methoxyserrat-14-en-21-one) alone dominated among the neutral compounds of the outer bark extract. Most of the neutral components and the labdane type acids were detected for the first time in organs and tissues of P. thunbergii. The distribution of lipophilic metabolites in the studied parts of P. thunbergii shoot system may be applied for chemotaxonomy purposes. Diversified accumulation of extractive substances in different organs of the plant should be taken into account for isolation of specific components from the pine raw material.

New Serratene Triterpenoids from Palhinhaea cernua and Their Cytotoxic Activity

Four new serratene triterpenoids, 3β,21β,24-trihydroxyserrat-14-en-24-(4'-hydroxybenzoate) (1), 3β,21α,24-trihydroxyserrat-14-en-3-(4'-hydroxybenzoate) (2), 3β,14α,15α,21α-tetrahydroxyserrat-14-en-3-(3'-methoxyl-4'-hydroxybenzoate) (3), and 3β,14α,15α,21α-tetrahydroxyserrat-14-en-21-acetyl-3-(4'-hydroxybenzoate) (4), together with two known ones, 5 and 6, were isolated from whole plants of Palhinhaea cernua. The structures of these new compounds were elucidated by spectroscopic methods. All the six compounds were tested for their in vitro cytotoxicity against three human cancer cell lines (K562, SMMC-7721, and SGC7901). Compound 5 showed cytotoxicity against the three test cell lines with IC₅₀ values of 20.3, 34.0, and 22.5 ug/mL, respectively. Compound 1 showed slight cytotoxicity against K562 cell lines with IC₅₀ value of 56.1 ug/mL, while no obvious inhibitory effects were detected for other compounds.

Lycophlegmariols A–D: Cytotoxic serratene triterpenoids from the club moss Lycopodium phlegmaria L.

Lycopodium serratene triterpenoids, along with an abietane-type diterpene were isolated from the methanol extract of club moss Lycopodium phlegmaria L. The structures of these hitherto unknown lycopodium terpenoids were elucidated on the basis of spectroscopic analysis. Pentacyclic triterpenoids, 21β-hydroxy-serrat-14-en-3α-ol (1) and 21β-hydroxy-serrat-14-en-3α-yl acetate (2) were isolated together with four serratene triterpeneoids established as 21β,29-dihydroxyserrat-14-en-3α-yl dihydrocaffeate (lycophlegmariol A, 5), 21β,24,29-trihydroxyserrat-14-en-3β-yl dihydrocaffeate (lycophlegmariol B, 6), 21α,24-dihydroxyserrat-14-en-3β-yl 4-hydroxycinnamate (lycophlegmariol C, 7), and 14β,21α,29-trihydroxyserratan-3β-yl dihydrocaffeate (lycophlegmariol D, 8) as well as a known lycophlegmarin (9). An abietane-type diterpene, 8,11,13-abietatriene-3β,12-dihydroxy-7-one (margocilin, 10), was isolated for the first time from a Lycopodium plant. Lycophlegmariol B (6), D (8) and compound 1 showed inhibitory effects against MOLT-3 acute lymphoblastic leukemia (T-lymphoblast) with IC50 of 14.7, 3.0 and 2.9μM, respectively.

Serratene Triterpenoids from Palhinhaea cernua var. sikkimensis

Seven new serratene triterpenoids, 3alpha,21beta,29-trihydroxy-16-oxoserrat-14-en-24-oic acid (1), 3beta,21beta,29-trihydroxy-16-oxoserrat-14-en-24-oic acid (2), 3beta,21beta,29-trihydroxyserrat-14-en-24-oic acid 3beta-(4-hydroxybenzoate) (3), 3beta,21beta,29-trihydroxyserrat-14-en-24-oic acid 3beta-(4-hydroxy-3-methoxybenzoate) (4), 3beta,14alpha,15alpha,21beta,29-pentahydroxyserrat-14-en-24-oic acid 3beta-(4-hydroxybenzoate) (5), 3alpha,21beta,24,29-tetrahydroxyserrat-14-en-16-one (6), 3alpha,21beta,30-trihydroxyserrat-14-en-16-one (7) were isolated from Palhinhaea cernua var. sikkimensis, together with twelve known compounds (8-19). Their chemical structures were elucidated on the basis of spectroscopic evidence and comparison with literature values.

Polyhydroxyserratane triterpenoids from Diphasiastrum complanatum

Serratane triterpenoids were identified from Diphasiastrum complanatum (L.) Holub, including serratane-3α,14α,15α,20β,21β,24,29-heptol ( 1), 3α,20β,21β-trihydroxyserrat-14-en-24-oic acid ( 2), 3β,20β,21β-trihydroxyserrat-14-en-24-oic acid ( 3), 3α,20β,21β-trihydroxy-16-oxoserrat-14-en-24-oic acid ( 4), and 16-oxolyclanitin-29-yl E-4′-hydroxyl-3′-methoxycinnamate ( 5) on the basis of their spectroscopic data as well as nine known analogs.

Three New Serratane Triterpenoids from Phlegmariurus squarrosus.

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Three New Serratane Triterpenoids from Phlegmariurus squarrosus

AbstractThree new serratane triterpenoids, (3α,14α,15α,21α)‐3,14,15,21,29‐pentahydroxyserratan‐24‐oic acid (1), (3α,21β)‐serrat‐14‐ene‐3,21,24,30‐tetraol (2), and (3α,21α)‐serrat‐14‐ene‐3,21,24,29‐tetraol (3), were isolated from Phlegmariurus squarrosus, together with eight known compounds. Their chemical structures were elucidated on the basis of in‐depth spectroscopic analyses.

Two serratane triterpenes from the stem bark of Picea jezoensis var. hondoensis

Two serratane triterpenoids were isolated from the stem bark of Picea jezoenis var. hondoensis, together with two known compounds, 3β-methoxyserrat-14-en-21-one and 3β-methoxyserrat-14-en-21α-ol. The serratane triterpenoids were characterized as 14β,15β-epoxy-3α-methoxyserratan-21β-ol and 3α-methoxy-21β-hydroxyserrat-14-en-16-one, on the basis of chemical and spectroscopic evidence.

Two serratane triterpenes from the stem bark of Picea jezoensis var. hondoensis

Two new serratane triterpenoids were isolated from the stem bark of Picea jezoensis var. hondoensis, together with three known compounds, 3β-hydroxyserrat-14-en-21-one, 21α-hydroxy-3β-methoxyserrat-14-en-30-al and 29- nor-3 β-methoxyserrat-14-en-21-one. The structures of the new compounds were characterized as 21α-hydroxy-3β-methoxyserrat-14-en-29-al and 29- nor-3 α-methoxyserrat-14-en-21-one, on the basis of spectrocopic analysis.