Neo-clerodane Diterpenoids Research Articles

New neo-clerodane diterpenoids from Scutellaria barbata with cytotoxic activities

Two new neo-clerodane diterpenoids have been isolated from the whole plant of Scutellaria barbata D. Don, and their structures were established by detailed spectral analyses as scutehenanine H ( 1) and 6-(2,3-epoxy-2-isopropyl-n-propoxyl)barbatin C ( 2). In vitro, the isolated two new compounds showed significant cytotoxic activities against three human cancer lines, and gave IC 50 values in the range OF 2.0-4.2 μΜ.

Cytotoxic Neoclerodane Diterpenoids from Scutellaria barbata

Seven new neoclerodane diterpenoids, scutebatas A-G (1-7), have been isolated from Scutellaria barbata. Compounds 1-3 possess a rare alpha-hydroxy group in their alpha,beta-unsaturated lactone rings. Their structures were elucidated by spectroscopic analysis, and the relative configuration of scutebata A was deduced using ROESY data and the computational DFT method. Compounds 1, 2, 4, 5, and 6 were evaluated for in vitro cytotoxicity against six human cancer cell lines: HL-60, SMMC-7721, A-549, SK-BR-3, CACO-2, and PANC-1. Scutebata A (1) showed weak cytotoxicity against SK-BR-3 with an IC(50) value of 15.2 muM.

Further anti-feedant neo-clerodanes from Teucrium tomentosum

Reinvestigation of the acetone extract of Teucrium tomentosum yielded a new neo-clerodane diterpenoid, teuctomin (1), along with 6-O-acetyl-teucmicropodin (2), teugracilin-A (3), 6α-hydroxyteuscordin (4) and 6α-acetoxyteuscordin (5). The structure of the new compound was elucidated comprehensively using 1D and 2D NMR methods. Compounds showed effective antifeedancy against Plutella xylostella at 10 μg cm−2 of leaf area.

Scutebarbatines W-Z, New neo-Clerodane Diterpenoids from Scutellaria barbata and Structure Revision of a Series of 13-Spiro neo-Clerodanes

Four new neo-clerodane diterpenoids, scutebarbatines W-Z (1-4), were isolated from the ethanol extract of Scutellaria barbata (Labiatae), and their structures were elucidated on the basis of extensive spectroscopic studies. In addition, the proposed structures of at least seven 13-spiro subtype neo-clerodanes: scutehenanine B (5), scutebarbatine G (6), 6-O-nicotinoylscutebarbatine G (7), barbatin A (8), 6,7-di-O-nicotinoylscutebarbatine G (9), 6-O-nicotinoyl-7-O-acetylscutebarbatine G (10), and scutebarbatine F (11), reported by Dai and co-workers from the same species, were incorrectly assigned and have been revised by reanalysis of the published NMR data.

Two novel neo-clerodane diterpenoids from Scutellaria barbata

Two novel neo-clerodane diterpenoids, barbatellarines A (1) and B (2), were isolated from the whole plants of Scutellaria barbata, along with the known compound scutebarbatine F (3). The chemical structures and relative stereochemistry of the isolated compounds were established by NMR (1D and 2D) and mass spectroscopic analyses. Compounds 2 and 3 were evaluated for in vitro cytotoxic activity against the HL-60 (human leukemia), MCF7 (human breast cancer), and LLC (Lewis lung carcinoma) cancer cell lines. Compound 2 exhibited weak cytotoxic activity against HL-60 cells, with an IC(50) value of 41.4microM.

Salvinorins J from Salvia divinorum: Mutarotation in the Neoclerodane System

A search for biosynthetic precursors of salvinorin A (1) led to the isolation of a new neoclerodane diterpenoid hemiacetal mixture, salvinorins J (2), from the chloroform extract of Salvia divinorum. A leaf surface extraction method was used on S. divinorum, affording a chlorophyll-free extract containing predominantly neoclerodane diterpenoids, including the new salvinorins J (2) and 14 known analogues. Salvinorins J (2) represent an example of a neoclerodane hemiacetal (lactol) susceptible to mutarotation with the formation of an equilibrium mixture of C-17 epimers.

Second-generation synthesis of salvinorin A

Functionalization toward total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A was accomplished via three double sequences: bis-enol triflate synthesis, palladium-catalyzed double carbonylation to the bis-enol triflate, and samarium diiodide-mediated double conjugate reduction. The configuration at C-12 was controlled by chelation-controlled diastereoselective reduction.

Selective natural kappa opioid and cannabinoid receptor agonists with a potential role in the treatment of gastrointestinal dysfunction

Salvinorin A is the major active ingredient of Salvia divinorum, a plant used by the Mazatec Indians of Mexico for spiritual and medical purposes. Different preparations from S. divinorum are also used in traditional healing practices to treat gastrointestinal disorders, including diarrhea. The recent extensive research on salvinorin A and other neoclerodane diterpenoids derived from S. divinorum resulted in a large number of reports describing their isolation, synthesis and structure-activity relationship. This review summarizes the present knowledge on salvinorin A and its analogues, with a focus on the effects on gastrointestinal tissues. We furthermore discuss structural changes in salvinorin A that may facilitate future use of its derivatives in human disease.

Highly Oxygenated Diterpenoids Associated to the Central Nervous System: Syntheses of Salvinorin and Forskolin

Total synthesis of salvinorin A (1), a densely functionalized neoclerodane diterpenoid, having the most potent hallucinogenic activity and a selective κ–opioid agonist, has been completed in 20 steps starting from enantiomerically–pure Wieland–Miescher ketone derivative 23. Subsequently, alternative total synthesis of salvinorin A (1) has been developed via palladium–catalyzed double carbonylation to bis–enol triflate followed by samarium diiodide–mediated double conjugate reduction in 13 steps. Forskolin (2), a highly oxygenated labdane diterpenoid and an activator of adenylate cyclase, has been synthesized in 12 steps and 12% overall yield from ptychantin A (62), which has been isolated from liverwort Ptychanthus striatus in sufficient yield. Tuning of the synthetic pathway enabled more expedient synthesis of forskolin (2) in 11 steps with 17% overall yield from ptychantins A (62) and B (63). In addition, synthesis of 1,9–dideoxyforskolin (3), an inhibitor of glucose transporter, has been accomplished in 8 steps and 37% overall yield from ptychantin A (62).

Two New neo‐Clerodane Diterpenoids from Scutellaria barbata

Two new neo-clerodane diterpenoids, 6,7-dibenzoyloxybarbatin C (1, named barbatin D) and 6-(2-acetoxy-3-methylbutanoloxy)-7-(2-carbonyl-3-methylbutanoyloxy) barbatin C (2, named barbatin E) were isolated from the whole plant of Scutellaria barbata D. Don. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR analyses. In vitro, compounds 1-2 showed cytotoxic activities against three human cancer lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, and with IC(50) values in the range of 3.5-6.7 microM.

Four New Neoclerodane Diterpenoids from Ajuga decumbens

AbstractFour new neoclerodane diterpenoids, 15‐epilupulin A (1), 6‐O‐deacetylajugamarin (2), and ajugadecumbenins A (3) and B (4), were isolated from the whole plants of Ajuga decumbens. Their structures were elucidated on the basis of spectroscopic data and chemical correlations.

Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid Salvinorin A

Total synthesis of salvinorin A (1), a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective kappa-opioid agonist, was completed in 20 steps starting from enantiomerically pure hydroxy-Wieland-Miescher ketone 5.

New neo-Clerodane Diterpenoid Alkaloids from Scutellaria barbata with Cytotoxic Activities

Four new neo-clerodane diterpenoid alkaloids, named scutebarbatines I-L (1-4), were isolated from the whole plant of Scutellaria barbata D. DON. Their structures were established on the basis of detailed spectral analyses. In vitro, the four new compounds showed significant cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells), and gave IC(50) values in the range 3.2-8.3 microM.

Biosynthesis of salvinorin A proceeds via the deoxyxylulose phosphate pathway

Salvinorin A, a neoclerodane diterpenoid, isolated from the Mexican hallucinogenic plant Salvia divinorum, is a potent kappa-opioid receptor agonist. Its biosynthetic route was studied by NMR and HR-ESI-MS analysis of the products of the incorporation of [1- 13C]-glucose, [Me- 13C]-methionine, and [1- 13C; 3,4- 2H 2]-1-deoxy- d-xylulose into its structure. While the use of cuttings and direct-stem injection were unsuccessful, incorporation of 13C into salvinorin A was achieved using in vitro sterile culture of microshoots. NMR spectroscopic analysis of salvinorin A (2.7 mg) isolated from 200 microshoots grown in the presence of [1- 13C]-glucose established that this pharmacologically important diterpene is biosynthesized via the 1-deoxy- d-xylulose-5-phosphate pathway, instead of the classic mevalonic acid pathway. This was confirmed further in plants grown in the presence of [1- 13C; 3,4- 2H 2]-1-deoxy- d-xylulose. In addition, analysis of salvinorin A produced by plants grown in the presence of [Me- 13C]-methionine indicates that methylation of the C-4 carboxyl group is catalyzed by a type III S-adenosyl- l-methionine-dependent O-methyltransferase.

Unambiguous NMR spectral assignments of salvinorin A

The complete assignments of the (1)H and (13)C NMR spectra of the hallucinogenic neoclerodane diterpenoid salvinorin A were determined in three different NMR solvents using HSQC, HMBC and COSY. Solvent systems are described that allow the resolution of all (1)H signals. Virtual coupling was observed for the protons at C-2, C-3 and C-4 in the 600 MHz (1)H spectrum in CDCl(3). The complete assignments of the (1)H and (13)C NMR spectra of salvinorin B are also reported.

Five New neo-Clerodane Diterpenoid Alkaloids from Scutellaria barbata with Cytotoxic Activities

Five new neo-clerodane diterpenoid alkaloids, named scutebarbatine G (1), 6,7-di-O-nicotinoylscutebarbatine G (2), 6-O-nicotinoyl-7-O-acetylscutebarbatine G (3), scutebarbatine H (4) and 7-O-nicotinoylscutebarbatine H (5) were isolated from the whole plant of Scutellaria barbata D. DON. Their structures were elucidated by spectroscopic methods including extensive 1D and 2D NMR analyses. In vitro, compounds 1-5 showed significant cytotoxic activities against three human cancer lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, and gave IC(50) values in the range 3.4-8.5 microM.

Neo-Clerodane diterpenoids from Scutellaria barbata with cytotoxic activities

Three neo-clerodane diterpenoids, named barbatins A–C ( 1– 3), and the neo-clerodane diterpenoid nicotinyl ester, named scutebarbatine B ( 4), were isolated from the whole plant of Scutellaria barbata D. Don. Their structures were elucidated by spectroscopic analyses (UV, IR, HRFAB-MS, 1D NMR and 2D NMR). In vitro, compounds 1– 4 showed significant cytotoxic activities against three human cancer lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, with IC 50 values in the range 3.5–8.1 μM.

Isolation and characterisation of selected germander diterpenoids from authenticated Teucrium chamaedrys and T. canadense by HPLC, HPLC‐MS and NMR

Teucrium species, such as germander, are rich in neo-clerodane diterpenoids and have been used in traditional folk medicine for their stimulant, diuretic, antipyretic and antiseptic properties. However, the furano neo-clerodane diterpenoids present in germander have been implicated in the in vivo hepatotoxicity of this botanical. In this study, authenticated germander (Teucrium chamaedrys L. and Teucrium canadense L.) was used as the source material. Methanol extracts of powdered plant mate rial were prepared and analysed by HPLC using Synergi Max-RP columns with monitoring at 220 nm. Limited amounts of teucrin A and other diterpenoid standards were analysed on a Synergi Max-RP column in order to determine their retention times and to generate calibration curves. The same standards were subjected to concurrent mass spectral analysis. Teucrin A and diterpenoids such as dihydroteugin, teuflin, teuflidin and teucvidin were tentatively identified in the plant extracts by HPLC-MS and 1H-NMR experiments. For the isolation of teucrium diterpenoids on a semipreparative scale, a solid-phase extraction method was developed for the first time using styrene divinylbenzene and strata-X sorbents for teucrin A and teuflin, respectively. Semi-preparative HPLC of the methanol extract of the powdered aerial parts of Teucrium plants was carried out on a semipreparative Synergi Max-RP column with photodiode array detection in order to confirm the identities of some diterpenoids by HPLC-MS and NMR.

Four New neo-Clerodane Diterpenoid Alkaloids from Scutellaria barbata with Cytotoxic Activities

Four new neo-clerodane diterpenoid alkaloids, named scutebarbatines C-F (1-4), were isolated from the whole plants of Scutellaria barbata D. DON. Their structures were elucidated by spectral analyses (UV, IR, FAB-MS, 1D-NMR and 2D-NMR). In vitro, compounds 1-4 showed significant cytotoxic activities against three human cancer cell lines, namely, HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells, and gave IC(50) values in the range 3.9-7.8 muM.

Studies Towards the Synthesis of Salvinorin A

Salvinorin A 1, a psychoactive neoclerodane diterpenoid from the Mexican sage S. divinorum, has gained interest as a selective κ-opioid receptor agonist. Non-racemic 3-furylamines 9a and 9b have been prepared from (+)-pseudoephedrine and (–)-ephedrine for application in the stereoselective synthesis of the ketone ring of 1. Diels–Alder reaction of 9b with methyl acrylate in aqueous media, followed by selective ether bridge cleavage, has allowed access to the cyclohexenone 17 with preservation of stereochemistry at C2. A model route to the lactone ring has also been achieved through a one-pot deconjugation/esterification procedure of 2-bromocrotonyl chloride 20 to the furyl alcohol 19 followed by Reformatski-mediated ring closure.