Abietane diterpenoids with anti-neuroinflammation activity from Rosmarinus officinalis.

A total of 12 abietane diterpenoids were isolated and identified from Rosmarinus officinalis in which 6 ones were undescribed compounds. Their structures were illuminated by the HRESIMS, NMR, and ECD methods and named as rosmarinusin Q-V (1-6). It worthy mentioned that rosmarinusin Q was a novel abietane diterpenoid with 6/6/5 skeleton whose C ring was an α,ß-unsaturated five-element ketone. All the compounds and four compounds (13-16) reported in our previous paper were evaluated their anti-neuroinflammatory activities on the LPS-induced BV2 cells. Compounds 5, 8, 9, 11, and 15 displayed significant anti-neuroinflammatory activity at the concentration of 10, 20, and 40 µM respectively. These results confirmed that R. officinalis contained abundant abietane diterpenoids and these compounds showed potential values of anti-neuroinflammation which could be developed as neuroprotective agents for the treatment of nerve damage caused by inflammation.

Abietane diterpenoids and iridoids from Caryopteris mongolica.

Six new abietane diterpenoids (1-6) and five undescribed iridoids (7-11) have been isolated from the aerial parts of Caryopteris mongolica. The intricate structural characterization of these compounds was meticulously undertaken using an array of advanced spectroscopic techniques. This process was further enhanced by the application of DP4+ probability analyses and electronic circular dichroism (ECD) calculations. Following isolation and structural elucidation, the cytotoxicity of these compounds was evaluated. Among them, compound 3 stood out, displaying significant cytotoxic activity against HeLa cells with an IC50 value of 7.83 ± 1.28 µmol·L-1. Additionally, compounds 1, 2, 4, 9, and 10 manifested moderate cytotoxic effects on specific cell lines, with IC50 values ranging from 11.7 to 20.9 µmol·L-1.

Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus.

Six new ent-abietane diterpenoids, abientaphlogatones A-F (1-6), along with two undescribed ent-abietane diterpenoid glucosides, abientaphlogasides A-B (7-8) and four known analogs were isolated from the aerial parts ofPhlogacanthus curviflorus (P. curviflorus). The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD) spectra, and quantum chemical calculations. Notably, compounds 5 and 6 represented the first reported instances of ent-norabietane diterpenoids from the genus Phlogacanthus. In the ß-hematin formation inhibition assay, compounds 2, 4, 7-10, and 12 displayed antimalarial activity, with IC50 values of 12.97-65.01 µmol·L-1. Furthermore, compounds 4, 5, 8, and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H2O2 and MPP+.

16,17-dinor-abietane diterpenoids from Casearia kurzii.

Eleven undescribed 16,17-dinor-abietane diterpenoids, caseazins A-K (1-11), and ten known diterpenoids (12-21) were isolated from the twigs and leaves of Casearia kurzii (Flacourtiaceae). Caseazins A-K were the first abietane -type dinorditerpenoids to have been isolated from the plant of Casearia kurzii. Their chemical structures were elucidated using a combination of 1D and 2D NMR spectroscopy and mass spectrometry. The absolute configurations of 5 and 10 were established by electronic circular dichroism calculations. Moreover, compounds 2, 3, 13, 14, and 18 exhibited anti-inflammatory activity with IC50 values of 0.17, 0.36, 6.55, 1.30, and 4.53 µM, respectively. IL-1ß and caspase-1 analyses suggested that compound 14 inhibited NLRP3 inflammasome activation and blocked macrophage pyroptosis.

Cytotoxic ent-abietane diterpenoids from the leaves of Croton lachnocarpus Benth.

A phytochemical investigation on the 90% ethanol extract of the leaves of Croton lachnocarpus Benth. led to three new ent-abietane diterpenoids, 7ß,15-dihydroxy-ent-abieta-8,11,13-trien-3-one (1), 2ß,15-dihydroxy-ent-abieta-8,11,13-triene (2), and 7ß,13α,15-trihydroxy-ent-abieta-8(14)-en-3-one (3). Structural elucidation of all the compounds were performed by spectral methods such as 1 D and 2 D (1H-1H COSY, HMQC, NOESY and HMBC) NMR spectroscopy, in addition to electronic circular dichroism (ECD) spectra. The isolated compounds were tested in vitro for cytotoxic activity against 6 tumor cell lines. As a result, compound 3 exhibited some cytotoxicities against all the tested tumor cell lines with IC50 value less than 30 µM.

New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase.

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1-50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57-65.98 µM, emerged as being good inhibitors of α-GLy. Arylidene 1ß-hydroxy and 1ß,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26-29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35-38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 µM, being 1206 to 266 more active than acarbose (IC50 of 181.02 µM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 µM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.

Anti-inflammatory abietanes diterpenes and triterpenoids isolated from Clinopodium polycephalum.

Two previously undescribed diterpenes (1 and 2), as well as one curious triterpenoid were isolated from Clinopodium polycephalum, a medicinal plant distributed in southwestern and eastern China. Their structures were elucidated using MS analyses, UV spectrum, and extensive 2D-homo and heteronuclear NMR data interpretations. Among them, 1 had an unusual skeletal characteristic produced by a rare methyl migration pathway. All monomer compounds exhibited inhibitory effects on NO production in LPS-induced RAW 264.7 cells without affecting cell viabilities, which were comparable to that of positive control.

Cytotoxic abietane-type diterpenoids from roots of Salvia spinosa and their in Silico pharmacophore modeling.

The roots of Salvia spinosa L. (Lamiaceae) were extracted with hexane, dichloromethane (DCM) and ethyl acetate. The DCM extract exhibited cytotoxic activity (IC50 32.7 µg/mL) against MFC-7 breast cancer cell line in MTT colorimetric bioassay. Ferruginol (1), taxodione (2), 12-deoxy-6-hydroxy-6,7-dehydroroyleanone (3), 14-deoxycoleon U (4), 15-deoxyfuerstione (5) and taxodone (6) were isolated from the DCM roots extract. Their structures were elucidated by a combination of spectroscopic analyses including EIMS and 1H- and 13C NMR spectra. The cytotoxicity of compound 3 was determined against MCF-7 and K562 cell lines and compared with the other compounds. A pharmacophore model was built based on potent input compounds to resolve important pharmacophore features responsible for cytotoxic activity of the isolated compounds.

The radical scavenging activity of abietane diterpenoids: Theoretical insights.

Salvia species are frequently used in traditional medicine and are a source of diterpenoid antioxidants. In this study, the hydroperoxide radical scavenging activity of seven known abietane diterpenoids (ADs), isolated from Salvia barrelieri, are investigated using a quantum chemical approach. The ADs are 7-oxoroyleanone-12-methyl ether (1), 7a-acetoxyroyleanone-12-methyl ether (2), royleanone (3), horminone (4), 7-acetylhorminone (5), cryptojaponol (6), and inuroyleanol (7). It was found that formal hydrogen transfer is the main mechanism of the antiradical activity of these ADs in nonpolar environments, whereas the single electron transfer mechanism of anion states is favored in aqueous environment. The antioxidant activity of compounds 1-5 involves H-abstraction at the C7(15)-H bonds whereas for the compounds 6 and 7 the H abstraction takes place at the O12-H bond. The HOO• scavenging activity of compounds 1-5 is minor in all of the studied media, however 6 and 7 exhibit excellent antiradical activity in aqueous solution. Remarkably, the HOO• scavenging activity of compound 7 is substantially higher than that of Trolox, the reference antioxidant: the calculated rate constant was 122.3 times higher in polar and 6.1 times higher in nonpolar environments, respectively. Consistently 7 is a promising radical scavenger in physiological environments.

Antimycobacterial, Cytotoxic, and Antioxidant Activities of Abietane Diterpenoids Isolated from Plectranthus madagascariensis.

Medicinal plants of the Plectranthus genus (Lamiaceae) are well known for their ethnomedicinal applications. Plectranthus madagascariensis, which is native to South Africa, is traditionally used in the treatment of respiratory conditions, scabies, and cutaneous wounds. The phytochemical studies of P. madagascariensis led to the isolation of five known royleanone abietanes, namely, 6ß,7α-dihydroxyroyleanone (1), 7α-acetoxy-6ß-hydroxyroyleanone (2), horminone (3), coleon U quinone (4), and carnosolon (5). The relative configuration of compound 2 was established by X-ray analysis. Compounds 1-4 showed antimycobacterial activity (Minimum inhibitory concentration for 90% inhibition, MIC90 = 5.61-179.60 µM) against Mycobacterium tuberculosis H37Rv. Compound 4 and 5 showed comparable toxicity (Concentration for 50% inhibition, IC50 98.49 µM and 79.77 µM) to tamoxifen (IC50 22.00 µg/mL) against HaCaT cells. Compounds 1-5 showed antioxidant activity through single-electron transfer (SET) and/or hydrogen-atom transfer (HAT) with compound 5 being the most active antioxidant agent. Compounds 3 and 5 were isolated for the first time from P. madagascariensis. The observed results suggest P. madagascariensis as an important ethnomedicinal plant and as a promising source of diterpenoids with potential use in the treatment of tuberculosis and psoriasis.

Anticholinesterase and Antioxidant Activities of Natural Abietane Diterpenoids with Molecular Docking Studies.

BACKGROUND: Alzheimer's Disease (AD) is one of the most prevalent causes of dementia in the world, and no drugs available that can provide a complete cure. Cholinergic neurons of the cerebral cortex of AD patients are lost due to increased activity of cholinesterase enzymes. OBJECTIVE: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) are the two major classes of cholinesterases in the mammalian brain. The involvement of oxidative stress in the progression of AD is known. Thus, the objective of this study is to determine strong ChE inhibitors with anti-oxidant activity. METHODS: In this study, 41 abietane diterpenoids have been assayed for antioxidant and anticholinesterase (both for AChE and BuChE) properties in vitro, which were previously isolated from Salvia species, and structurally determined by spectroscopic methods, particularly intensive 1D- and 2DNMR and mass experiments. Molecular modeling studies were performed to rationalize the in vitro ChE inhibitory activity of several abietane diterpenoids compared with galantamine. RESULTS: Thirteen out of the tested 41 abietane diterpenoids exhibited at least 50% inhibition on either AChE or BuChE. The strongest inhibitory activity was obtained for Bractealine against BuChE (3.43 µM) and AChE (33.21 µM) while the most selective ligand was found to be Hypargenin E against BuChE enzyme (6.93 µM). A full correlation was not found between anticholinesterase and antioxidant activities. The results obtained from molecular modelling studies of Hypargenin E and Bractealine on AChE and BuChE were found to be in accordance with the in vitro anti-cholinesterase activity tests. CONCLUSION: Abietane diterpenoids are promising molecules for the treatment of mild-moderate AD.

Abietane Diterpenoids with Antioxidative Damage Activity from Rosmarinus officinalis.

Nine new and nineteen known compounds were isolated and identified from Rosmarinus officinalis under the guidance of bioassay and LCMS. They all belonged to abietane diterpenoids which enriched the types of compounds in R. officinalis, especially the discovery of a series of 20-norabietane diterpenoids (4, 6-9, and 26-27). The antioxidative damage activity of the compounds was tested on H2O2 damaged SH-SY5Y cells. Compounds 5, 6, and 7 presented moderate ability for promoting the growth of damaged cells. Compounds 10, 11, 13-20, 27, and 28 displayed a high antioxidative damage effect whose cell viability rates were more than 80%. The antioxidative damage effect of 11, 16, 18, and 20 were higher than that of EGCG (positive control) in which 11, 18, and 20 were the acetylated derivatives of carnosic acid (10), 7α-methoxy-isocarnosol (16), and carnosol (19), respectively. It suggested that 10-carboxyl/formyl of abietane diterpenoids was essential for maintaining the antioxidative damage activity and the adjacent hydroxyl groups on the benzene ring was less important for holding the bioactivity. These acetylated derivatives with high bioactivity and stability could be regarded as new sources of antioxidants or antioxidative damage agents being used in the food and medical industry.

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.

Isoforrethins A-D, four ent-abietane diterpenoids from Isodon forrestii var. forrestii.

Four new ent-abietane diterpenoids, isoforrethins A-D (1-4), were isolated from the aerial parts of Isodon forrestii var. forrestii by a variety of chromatographic techniques. Their structures were elucidated on the basis of spectroscopic data interpretation, single crystal X-ray diffraction, and quantum chemical calculation. All of these compounds were evaluated for their cytotoxicity against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW-480), and compound 4 showed significant inhibitory activities against SMMC-7721, A-549, MCF-7, and SW-480.

Cytotoxicity of abietane diterpenoids from Salvia multicaulis towards multidrug-resistant cancer cells.

Diterpenoids salvimulticanol (1) and salvimulticaoic acid (2) together with known diterpenoid (3-6) were isolated from Salvia multicaulis. Structures were elucidated by spectroscopic techniques including HRESIMS as well as 1D-, and 2D-NMR. In-vitro cytotoxicity was assayed against human cancer cell lines. As several metabolites exhibited activity against drug-resistance lines, compounds were screened against a panel of human drug-sensitive and multidrug-resistant cancer lines. A proposed biosynthetic pathway for these new diterpenoids (1-2) as well as the cytotoxic structure-activity relationship of all identified compounds were discussed. Compound 1 and 6 showed the most potent cytotoxicity with IC50 11.58 and 4.13 towards leukemia cell lines CCRF-CEM and CEM-ADR5000, respectively.

Cytotoxic diterpene quinones from Salvia tebesana Bunge.

A phytochemical investigation of the root extracts of Salvia tebesana Bunge led to the isolation of two new diterpenoids, tebesinone A (1) and tebesinone B (2), along with two known compounds, aegyptinone A (3) and aegyptinone B (4). The structures were established by spectroscopic analysis including 1D and 2D NMR and HRESIMS. The cytotoxic activities of the crude extracts and isolated compounds were evaluated against MCF-7, B16F10, PC-3 and C26 human cancer cell lines, in which compounds 2 and 3 showed significant cytotoxic activities (IC50 2.1-10.3 µM).

Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from Salvia ballotiflora.

From the aerial parts of Salvia ballotiflora, eleven diterpenoids were isolated; among them, four icetexanes and one abietane (1-5) are reported for the first time. Their structures were established by spectroscopic means, mainly ¹H- and 13C-NMR, including 1D and 2D homo- and hetero-nuclear experiments. Most of the isolated diterpenoids were tested for their antiproliferative, anti-inflammatory, and radical scavenging activities using the sulforhodamine B assay on six cancer cell lines, the TPA-induced ear edema test in mice, and the reduction of the DPPH assay, respectively. Some diterpenoids showed anti-proliferative activity, these being icetexanes 6 and 3, which were the most active with IC50 (µM) = 0.27 ± 0.08 and 1.40 ± 0.03, respectively, for U251 (human glioblastoma) and IC50 (µM) = 0.0.46 ± 0.05 and 0.82 ± 0.06 for SKLU-1 (human lung adenocarcinoma), when compared with adriamycin (IC50 (µM) = 0.08 ± 0.003 and 0.05 ± 0.003, as the positive control), respectively. Compounds 3 and 10 showed significant reduction of the induced ear edema of 37.4 ± 2.8 and 25.4 ± 3.0% (at 1.0 µmol/ear), respectively. Compound 4 was the sole active diterpenoid in the antioxidant assay (IC50 = 98. 4 ± 3.3), using α-tocopherol as the positive control (IC50 (µM) = 31.7 ± 1.04). The diterpenoid profile found is of chemotaxonomic relevance and reinforces the evolutionary link of S. ballotiflora with other members of the section Tomentellae.

Ent-Abietanoids Isolated from Isodon serra.

Four new ent-abietane diterpenoids, along with four known ones were isolated from the aerial parts of Isodon serra, a traditional Chinese folk medicine. The new diterpenoids were named as serrin K (1), xerophilusin XVII (2), and enanderianins Q and R (3 and 4), while the known ones were identified as rubescansin J (5), (3α,14ß)-3,18-[(1-methylethane-1,1-diyl)dioxy]-ent-abieta-7,15(17)-diene-14,16-diol (6), xerophilusin XIV (7), and enanderianin P (8), respectively. Their structures were elucidated by extensive spectroscopic analysis and comparison with the literature. Compound 1 showed remarkable inhibitory activity towards NO production in LPS-stimulated RAW264.7 cells (IC50 = 1.8 µM) and weak cytotoxicity towards five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480).

The roots of Salvia rhytidea: a rich source of biologically active diterpenoids.

Sahandinone (1), 12-deoxysalvipisone (2), miltirone (3), 7α-acetoxyroyleanone (4), and labda-7,14-dien-13-ol (5) were isolated from the roots of Salvia rhytidea Benth. (Lamiaceae). Their structures were elucidated by a combination of spectroscopic analyses including EIMS and NMR. The 13C NMR spectroscopic data were revised for the quaternary carbons of both 1 and 3 with the help of HMBC spectra in respect to the spectral data previously reported in the literature. Compounds 1 and 3, two very potent anticancer agents, were isolated in high yields from the roots of the plant. The biological activities of the plants' constituents were reported in the literature as antimicrobial, cytotoxic and antimalarial are discussed in this article.

Diterpenoids from Callicarpa kwangtungensis and their NO inhibitory effects.

A phytochemical investigation of the leaves of Callicarpa kwangtungensis led to the isolation of three new diterpenoids (1-3), callipenes A-C, and eleven known analogues (4-14). Their structures were established on the basis of extensive analysis of NMR spectroscopic data, X-ray diffraction data, and experimental and calculated electronic circular dichroism spectra. Compounds 1 and 2 are rare abietane diterpenoids possessing a peroxide bridge. All of the isolates were found to inhibit LPS-induced NO production in BV-2 cells.