Abietane Diterpenoids Research Articles

Extraction of aromatic abietane diterpenoids from Salvia officinalis leaves by petroleum ether: Data resolution analysis

Salvia officinalis is the source of a vast variety of compounds valuable for pharmaceutical and food industry. The extractability of lipophilic diterpenoids from S. officinalis(L.) by petroleum ether is studied using Soxhlet, reflux, and percolation methods. The binding of the solute to the plant matrix is described by the Hill-Langmuir desorption model. The Monte Carlo sampling method is used to constrain the parameters of the extraction model and perform the resolution analysis of the extraction data. The percolation, followed by extraction at reflux, is demonstrated to be the most efficient method of extraction. The freely available content is estimated to be ye = 20.0 ± 2.9 mg g–1, while the total content in our case is shown to be 50–55 mg g–1 or higher. For engineering applications, the estimate of 60–70 mg g–1 is suggested as the upper limit.

South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches.

The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.

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.

Recent Advances in Kaempferia Phytochemistry and Biological Activity: A Comprehensive Review.

Background: Plants belonging to the genus Kaempferia (family: Zingiberaceae) are distributed in Asia, especially in the southeast region, and Thailand. They have been widely used in traditional medicines to cure metabolic disorders, inflammation, urinary tract infections, fevers, coughs, hypertension, erectile dysfunction, abdominal and gastrointestinal ailments, asthma, wounds, rheumatism, epilepsy, and skin diseases. Objective: Herein, we reported a comprehensive review, including the traditional applications, biological and pharmacological advances, and phytochemical constituents of Kaempheria species from 1972 up to early 2019. Materials and methods: All the information and reported studies concerning Kaempheria plants were summarized from library and digital databases (e.g., Google Scholar, Sci-finder, PubMed, Springer, Elsevier, MDPI, Web of Science, etc.). The correlation between the Kaempheria species was evaluated via principal component analysis (PCA) and agglomerative hierarchical clustering (AHC), based on the main chemical classes of compounds. Results: Approximately 141 chemical constituents have been isolated and reported from Kaempferia species, such as isopimarane, abietane, labdane and clerodane diterpenoids, flavonoids, phenolic acids, phenyl-heptanoids, curcuminoids, tetrahydropyrano-phenolic, and steroids. A probable biosynthesis pathway for the isopimaradiene skeleton is illustrated. In addition, 15 main documented components of volatile oils of Kaempheria were summarized. Biological activities including anticancer, anti-inflammatory, antimicrobial, anticholinesterase, antioxidant, anti-obesity-induced dermatopathy, wound healing, neuroprotective, anti-allergenic, and anti-nociceptive were demonstrated. Conclusions: Up to date, significant advances in phytochemical and pharmacological studies of different Kaempheria species have been witnessed. So, the traditional uses of these plants have been clarified via modern in vitro and in vivo biological studies. In addition, these traditional uses and reported biological results could be correlated via the chemical characterization of these plants. All these data will support the biologists in the elucidation of the biological mechanisms of these plants.

Novel abietane diterpenoids from Salvia prionitis

Two hitherto unknown highly modified abietane diterpenoids, namely salviapritin A (1) and salviapritin B (2), were isolated from the ethanol extract of Salvia prionitis, together with 17 known compounds. Their chemical structures were established by extensive spectroscopic methods (ESIMS, HRESIMS, 1D and 2D NMR) and by comparison of their NMR data with those of related analogues. Salviapritin A is the first example of a trinorabietane diterpenoid possessing an acenaphthylene skeleton from the Salvia genus. Additionally, a plausible biogenetic pathway for salviapritin B is proposed.

Anti-NLRP3 inflammasome abietane diterpenoids from Callicarpa bodinieri and their structure elucidation

Callicarpa bodinieri is a Chinese traditional medicine herb with anti-inflammatory activity in clinic. Herein, we report two new 9,10-seco and etherified abietane diterpenoids bodinieric acids J and K (1 and 2) and one known compound (3) isolated from the leaves and twigs of this plant. Their chemical structures were elucidated by detailed spectrometry data analysis and DP4 + NMR calculation methods. Hypothetical biosynthetic pathways of 1−3 were preliminarily speculated. Compound 3 inhibited inflammasome activation and exhibited blockage of NLRP3 inflammasome activation at non-cytotoxic concentrations in vitro.

Pharmacological Evaluation of Abietane Diterpenoids from Plectranthus bishopianus as Potent Antibacterial, Antioxidant and Their Cytotoxic Agents

Background: Lamiaceae is one of the large families that occur worldwide and has species that are adaptable to almost all habitats and altitudes. Plectranthus is an important genus of Lamiaceae, recognized globally as an ornamental as well as a medicinal herb with good economic interest. The Plectranthus species possess antiseptic, vermicidal and purgative activities. Objective: The isolated compounds (1-3) from Plectranthus bishopianus were tested for their preliminary pharmacological evaluation for antibacterial, antioxidant and cytotoxic activities. Materials and Methods: The Plectranthus bishopianus leaves were collected from the Western Ghats of India. Extractions followed by isolation of the three compounds and structures were identified by NMR, HRMS. Results: The isolated compounds, 6,7-dehydroroyleanone (1), 6β-hydroxy-7α-methoxyroyleanone (2) and 6β, 7α-dihyroxyroyleanone (3) showed good antioxidant activity by DPPH method. The results of the cytotoxicity evaluation of the compounds (1-3) displayed excellent activity against MCF-7 cell line with IC50 values at 3.8 µg/mL, 3.85 µg/mL and 3.7 µg/mL respectively, which is more potent than the reference standard cisplatin. Conclusion: The structures of isolated compounds were confirmed by NMR, LC-HRMS and further pharmacological evaluation was accomplished. In addition, the isolates (1-3) were subjected to insilico molecular properties prediction by employing Molinspiration software for calculating their oral bioavailability and predicted to possess excellent oral bioavailability.

A new demethyl abietane diterpenoid from the roots of Tripterygium wilfordii

A new demethyl abietane diterpenoid, Triptotin K (3) together with three known compounds, friedelin (1), canophyllal (2), and triptonoterpene (4) were isolated from the roots of Tripterygium wilfordii Hook. f. by silica gel column and preparative high performance liquid chromatography. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Triptotin K showed cytotoxic activities against KB, KBv200, HepG2, and MCF-7/ADM cells lines with IC50 values of 29.88, 36.50, 39.55, and 41.38 μM, respectively.

New 4,5-seco-20(10→5)-abeo-Abietane Diterpenoids with Anti-Inflammatory Activity from Isodon lophanthoides var. graciliflorus (Benth.) H.Hara.

Three new 4,5-seco-20(10→5)-abeo-abietane diterpenoids, 16-hydroxysalvilenone (1), 15-hydroxysalprionin (2), and 11β,15-dihydroxysalprionin-12-one (3), and nine known abietane diterpenoids, 4-12, along with one known sempervirane diterpenoid, hispidanol A (13), were isolated from the aerial parts of Isodon lophanthoides var. graciliflorus. The structures of compounds 1-3 were determined on the basis of spectroscopic methods including extensive analysis of NMR and mass spectroscopic data. All diterpenoids were tested for their TNF-α inhibitory effects on LPS-induced RAW264.7 cells. Compound 9 (16-acetoxyhorminone) was the most potent with an IC50 value of 3.97±0.70 μm.

High Yield of Bioactive Abietane Diterpenes in Salvia sclarea Hairy Roots by Overexpressing Cyanobacterial DXS or DXR Genes.

Abietane diterpenoids, containing a quinone moiety, are synthesized in the roots of several Salvia species. Promising cytotoxicity and antiproliferative activities have been reported for these compounds in various cell and animal models. We have recently shown that aethiopinone, an o-naphto-quinone diterpene, produced in the roots of different Salvia species, is selectively cytotoxic against the A375 melanoma cell line. To enhance the synthesis of this abietane diterpenoid, we have engineered the plastidial 2-C-methyl-D-erythritol 4-phosphate-derived isoprenoid pathway in Salvia sclarea hairy roots by ectopic expression and plastid targeting of cyanobacterial genes encoding the 1-deoxy-D-xylulose 5-phosphate synthase or 1-deoxy-D-xylulose-5-phosphate reductoisomerase gene, the first two enzymatic steps of the plastidial MEP pathway, from which plant diterpenes primarily derive. Plastid-targeted expression of 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase proteins significantly enhanced the yield of aethiopinone by a 3-fold and about 6-fold increase, respectively. The accumulation of other abietane-type diterpenes (ferruginol, salvipisone, and carnosic acid), with interesting antiproliferative activity, was also increased. Compared to our previous data obtained by overexpressing the plant orthologous 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase genes in S. sclarea hairy roots, the results presented here confirm that the bacterial 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme plays a major role than the DXS enzyme in the biosynthetic pathway of this class of compounds and that its ectopic expression does not conflict with active hairy root growth, resulting in a balanced trade-off between the transgenic hairy root final biomass and the increased content of o-naphto-quinone diterpenes, with interesting biological activities.

Labdane and Abietane Diterpenoids from Juniperus oblonga and Their Cytotoxic Activity.

A phytochemical investigation of the whole plant of Juniperus oblonga led to the isolation of one previously undescribed labdane diterpenoid, (4R,5S,9S,10R)-13-des-ethyl-13-oxolabda-8(17),11E-dien-19-oic acid (1), together with nine known diterpenoids (2–3, 6–12), two lignans (4, 5), and a coumarin (13). The structures of all the compounds were elucidated on the basis of spectrometric data, primarily one-dimensional (1D)- and two-dimensional (2D)-NMR and mass spectrometry. Electronic circular dichroism (ECD) calculations determined the absolute configuration of 1. In addition, the isolated compounds were evaluated for their cytotoxic activity against three human tumor cell lines (HepG2, MCF-7, and HeLa). 6,12-Dihydroxyabieta-5,8,11,13-tetraen-7-one (6) showed moderate cytotoxicity against all three cell lines with IC50 values ranging from 24.41 μM to 58.39 μM and trilobinone (10) showed weaker activity with IC50 values ranging from 56.93 μM to 79.98 μM. None of the isolated diterpenoids have been previously reported from Juniperus oblonga, and five compounds are here reported from the genus Juniperus for the first time.

New cadinane sesquiterpenoids from Mikania micrantha

Chemical investigation of the aerial parts of Mikania micrantha led to the isolation of eight sesquiterpenoids and ten diterpenoids, including five cadinane sesquiterpenoids (1−5), three bisabolene sesquiterpenoids (6 − 8), nine ent-kaurane diterpenoids (9–17), and an abietane diterpenoid (18). Among them, 1 − 3 are new and feature a rare lactone or furan ring derived from C-6 isopropyl group side chain. Compound 18 was isolated from genus Mikania for the first time, and was also the first example of abietane-type diterpenoids from this plant. Their structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, and ECD). All compounds were examined for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage cells, and compound 18 exhibited pronounced inhibition on NO production (IC50 = 11.04 µM), being comparable to the positive control, quercetin (IC50 = 11.15 µM).

Is Hyptis lacustris A. St.-Hil. ex Benth. (Lamiaceae) extract a good candidate for antibacterial uses?

More than 70% of drugs approved during the last three decades to treat bacterial infection are derived from natural products. Lamiaceae is one of the ten most researched families regarding its medicinal uses. Hyptis Jacq. (Lamiaceae) is used in popular medicine of several countries, including northeast part of Brazil, for the treatment of gastrointestinal infections, cramps, pains, skin diseases, malaria, respiratory diseases, and insect repellent. Hyptis lacustris A. St.-Hil. ex Benth. is used by Yanesha tribe of Peru for the treatment of cutaneous leishmaniasis. In vitro studies confirmed its ethnopharmacological use, in which 95% ethanol extract showed Inhibitory Concentration of 50% lower than 10 μg mL−1 against axenic amastigotes of Leishmania amazonensis. For its use in traditional medicine, the aim of this research was to investigate the antibacterial activity of hydroethanol crude extract and its four fractions (hexane, dichloromethane, ethyl acetate, and hydromethanol) against three bacteria strains (Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli), and the activity of three compounds isolated from Hyptis lacustris against Bacillus subtilis. The extract was produced by maceration of stems and leaves in 70% ethanol, and its fractions were produced by partition using hexane, dichloromethane, and ethyl acetate. Fractions were chemically characterized using gas chromatography coupled with mass spectrometry and high-performance liquid chromatography coupled with a diode array detector. Compounds from fractions with high antibacterial activity were purified and identified through Nuclear Magnetic Resonance and Mass Spectrometry. The antibacterial activity of extract, fractions, and isolated compounds were screened by a broth microdilution method in 96-wells microplate. Major constituents in the hexane fraction are terpenoids, being abietane diterpenoids the most prominent class. 8β-hydroxy-9(11),13-abietadien-12-one was identified in Hyptis for the first time. Hexane fraction was the most active against Bacillus subtilis, isolated compounds were also active against B. subtilis. The high activity of the hexane fraction is probably due to its major composition of abietane diterpenoids, class of compounds with renowned activity against Gram-positive bacteria. Results point out to a potential antibacterial activity of Hyptis lacustris against Gram-positive bacteria, mainly its Hexane fraction.

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies.

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1β2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.

Cytotoxicity and Chemotherapeutic Potential of Natural Rosin Abietane Diterpenoids and their Synthetic Derivatives.

Cancer is a major cause of morbidity and mortality worldwide. Chemotherapeutic agents currently used in cancer treatment are associated with severe side effects and development of resistance. Thus, there is a pressing need for novel and more potent anticancer drugs with high selectivity for tumor cells and reduced toxicity to normal tissue. Natural products remain an important source of bioactive compounds and drug prototypes that can lead to new and more effective antitumor agents. Coniferous plants are rich in abietane diterpenoids with a wide range of biological activities that provide useful templates for synthetic modification. Abietic acid and dehydroabietic acid (DHA), the major diterpenic resin acids from Pinus rosin, and dehydroabietylamine found in commercial disproportionated rosin amine, display antibacterial and antitumor properties. These compounds and their synthetic derivatives have been reported as promising anticancer agents with potent growth inhibitory activity against several types of human cancer cell lines, including breast, ovarian, prostate, colon, liver, lung and cervical carcinoma cells. Their mechanisms of action are diverse and include DNA binding, induction of apoptosis or oncosis, tubulin polymerization inhibition and disruption of intracellular cholesterol transport. This review covers the main aspects of natural rosin abietane diterpenoids (abietic acid, DHA and DHAA) and synthetic derivatives concerning their anti-proliferative, cytotoxic and antitumor activities, mechanisms of action and structure- activity relationships relevant for the development of novel anticancer agents for cancer chemotherapy.

Titanium‐promoted Intramolecular Photoenolization/Diels–Alder Reaction to Construct Polycyclic Terpenoids: Formal Synthesis of Mycoleptodiscin A

Summary of main observation and conclusionA titanium‐promoted intramolecular photoenolization/Diels–Alder (PEDA) reaction was developed to construct the core skeleton of aromatic polycyclic terpenoids bearing an all‐carbon quaternary center on the benzylic position. Titanium(IV) isopropoxide [Ti(Oi‐Pr)4] plays a key role during the photo cycloaddition, which may help to accelerate the interaction between dienophile and the stereo‐hindered diene species as well as control the diastereoselectivity. This photolysis provides a new solution for the stereospecific formation core structures of aromatic abietane diterpenoids and sesquiterpenoids, which have multiple functional groups for the further transformations. As a synthetic application, it was successfully used in the synthesis of indolosesquiterpenoid mycoleptodiscin A.

Late-stage C-H amination of abietane diterpenoids.

This study aims at highlighting the synthetic versatility of the rhodium-catalyzed C-H amination reactions using iodine(iii) oxidants for the late-stage functionalization of natural products. Inter- and intramolecular nitrene insertions have been performed from various abietane diterpenoids, leading to the amination of the C-3, C-6, C-7, C-11 and C-15 positions. Ca. 20 aminated compounds have been isolated with yields of up to 86% and high levels of regio-, chemo- and stereoselectivities.

Two new abietane diterpenoids from the leaves of Rabdosia serra

Phytochemical investigation on the leaves of Rabdosia serra led to the isolation of two new abietane diterpenoids, raserranes A (1) and B (2), and four known phenylpropanoids (3–6). Their structures were determined by spectroscopic data. Compound 1 represented the rare examples of abietane diterpenoids featuring a 16-methoxycarbonyl group.

Caryopincaolide M, a rearranged abietane diterpenoid with new skeleton and a new iridoid from Caryopteris incana

Caryopincaolide M (1), a new rearranged abietane diterpenoid with an unusual pent-4-enoic acid group on a 6/6/5 tricyclic ring system, and 7-epi-8-dehydroxypatriscabrol (3), a new iridoid, together with 17 known compounds, have been isolated from the whole plant of Caryopteris incana (Thunb.) Miq. Their structures were elucidated on the basis of 1-D and 2-D NMR, IR, and mass spectroscopic data. Compounds 1-5 were evaluated for their inhibitory activities against enzyme α-glucosidase, and the results showed that only 1 has moderate inhibitory activity against enzyme α-glucosidase with IC50 at 528.3 ± 12.37mg/L.

A new tricyclic abietane diterpenoid from Salvia chloroleuca and evaluation of cytotoxic and apoptotic activities

In this study, sahandone (1) and a new diterpenoid named sahandol II (2) were isolated from the roots of Salvia chloroleuca Rech. f. & Aellen, Lamiaceae. The absolute configurations of compounds 1 and 2 were assigned by comparison of experimental electronic circular dichroism spectra and comparing with published data. Cytotoxic and apoptotic evaluation of the isolated compounds and the methanol crude extract and its subfractions including petroleum ether, dichloromethane, ethyl acetate, n-butanol and aqueous fraction on two human prostate cancer cell lines and a breast cancer cell lines, showed that non-polar and semi-polar subfractions had the potent cytotoxic effect on PC3 cells with the IC50 values of 24.19, 33.59, and 47.15μg/ml, respectively. Sub-G1 peak in flow cytometry histogram of cells treated with petroleum ether, dichloromethane and ethyl acetate subfractions showed the induction of apoptosis. Change in the Bax/Bcl-2 ratio and cleavage of poly ADP-ribose polymerase were observed.