Icetexane Diterpenoids Research Articles

The Anti-Arthritic Potential of the Ethanolic Extract of Salvia Lachnostachys Benth. Leaves and Icetexane Dinor-Diterpenoid Fruticuline B.

The decoction of Salvia lachnostachys Benth. leaves is used in Brazilian folk medicine for anti-spasmodic, antipyretic, and anxiolytic purposes. Some of the biological effects of an S. lachnostachys extract have been shown to be anti-inflammatory, anti-cancer, and antidepressant effects. In addition, this medicinal plant produces several compounds including icetexane diterpenoids, such as fruticuline A and fruticuline B. The aim of the present work was to evaluate the anti-hyperalgesic and anti-inflammatory properties of fruticuline B (FRUT B) and the ethanolic extract obtained from the leaves of S. lachnostachys (EESL) in experimental mouse models. EESL (30, 100, and 300 mg/kg) and FRUT B (1 mg/kg) were evaluated in articular inflammation-induced models in Swiss mice. In articular inflammation induced by Zymosan, EESL (300 mg/kg) and FRUT B (1 mg/kg) significantly reduced mechanical hyperalgesia (83.17% inhibition for EESL and 81.19% for FRUT B); edema (68.75% reduction for EESL and 33.66% for FRUT B); leukocyte migration (81.3% for EESSL and 92.2% for FRUT B), and nitric oxide production (88.3% for EESL and 74.4% for FRUT B). The exposure to fruticuline B significantly inhibited the edema (51.5%), mechanical (88.12%) and cold hyperalgesia (80.8%), and myeloperoxidase (MPO) (63.4%) activity 24 h after CFA injection. In the pleurisy model, FRUT B reduced 89.1% of leukocyte migration and 50.3% in nitric oxide production. Four hours after carrageenan injection, FRUT B (1 mg/kg) diminished 89.11% of mechanical hyperalgesia, 65.8% of paw edema, and 82.12% of the response to cold hyperalgesia. In the MTT test, EESL and fruticuline B caused no cytotoxicity. The present study revealed, for the first time, the anti-arthritic and anti-nociceptive effects of FRUT B, pointing out the therapeutic potential of the species to control inflammation and nociception. Future studies are needed to evaluate other biological properties of fruticuline B and to better understand its mechanism of action.

Recent Developments with Icetexane Natural Products.

Icetexane diterpenoids are a diverse family of natural products sourced from several species of terrestrial plants. Icetexanes exhibit a broad array of biological activities and together with their complex 6-7-6 tricyclic scaffolds, they have piqued the interest of synthetic organic chemists, natural products chemists, and biological investigators over the past four decades and were reviewed 13 years ago. This review summarizes icetexane natural products isolated since 2009, provides an overview of new synthetic approaches to the icetexane problem, and proposes an additional classification of icetexanes based on novel structures that are unlike previously isolated materials.

Icetexane diterpenoids as Cav3.2 T-type calcium channel inhibitors from Salvia prattii and analgesic effect of their Semi-synthesized derivatives

Ten new icetexane diterpenoids, salpratins E–N (1–10) and a known analogue (11) were characterized from Salvia prattii Hemsl. Structurally, 1 is the first 19(4 → 3)-abeo-icetexane diterpenoid featuring with a 6/7/6 ring system. The structures of isolated compounds were determined by comprehensive analyses of spectroscopic data, ECD calculation, and single-crystal X-ray diffraction. Biological studies initially revealed that 1, 7, 10, and 11 are notable Cav3.2 T-type Ca2+ channel (TTCC) inhibitors with IC50 values of 2.9, 5.1, 2.3, and 3.2 μM, respectively. Five icetexane related derivatives (13–17) were synthesized from an abietane type precursor, (+)-carnosic acid (12), for the purpose of overcoming the poor water solubility of aforementioned active compounds and further investigating diverse diterpenes with valuable activity. Among them, 13 and 14 showed potent inhibitions on Cav3.2, having IC50 values of 6.7 and 2.4 μM, respectively. Significantly, they exhibited dose-dependent (1, 3, and 10 mg/kg) and comparable analgesic effects as that of Z944, a TTCCs inhibitor under clinical trial for pain management, in the mouse acetic acid writhing test. These findings further enrich structural diversity and bioactivity of Salvia diterpenoids, as well as provide promising structural templates for the development of Cav3.2 analgesics.

Bioactive icetexane and abietane diterpenes from Isodon phyllopodus

A new icetexane diterpenoid, 11, 12, 20α-trihydroxyl-7β-methoxyicetexa-8, 11, 13-triene-19, 10-lactone [Phyllane A (1)], and a new abietane diterpenoid, 7β, 20-epoxy-3β, 17-acetoxy-abieta-8, 11, 13-teriene-11, 12-diol [phyllane B (2)], along with two known compounds (3 and 4) were isolated from the methanol (MeOH) extract of twigs and leaves of the folk medicinal Isodon phyllopodus. Their structures were determined by spectroscopic analyses including 2 D NMR spectral data, and further confirmed by X-ray single crystal diffraction. Moreover, the compounds were evaluated for their cytotoxicity and anti-HIV activities, and phyllane A showed anti-HIV activity with an IC50 value of 15.7 μM, but phyllane B was found to be cytotoxic to the A549 host cells with a CC50 value of 108.5 μM.

Diterpenoids from Rosmarinus officinalis L. and their nitric oxide inhibitory activity

AbstractOne icetexane diterpenoid, demethylsalvicanol (1) and four abietane diterpenoids, sageone (2), 20‐deoxocarnosol (3), 11,12,20‐trihydroxy‐abieta‐8,11,13‐triene (4), and 7αα‐ethoxyrosmanol (5) were isolated from the n‐hexane layer of the leaves and twigs of Rosmarinus officinalis L. Chemical structures of compounds were identified by ESI‐MS, 1D‐, 2D‐NMR spectra and by comparison of the spectral data in the literature. Compounds 1‐5 were evaluated anti‐inflammatory activity by inhibitory NO production, LPS stimulated on RAW 264.7 cells. At a concentration of 100 μM, compound 4 exhibited inhibitory percentage of 34.7±1.8 %, meanwhile compounds 1‐3 and 5 showed cytotoxic effect. After dilution to concentration of 20 μM, except compound 1 and 2, compounds 3‐5 did not show cytotoxic effect. Their NO inhibitory productions were ranging from 20.5±2.4 % to 26.7±1.9 %. Compounds 1, 3 and 4 have been reported for the first time from the Rosmarinus genus.

Gold-Catalyzed Synthesis of Icetexane Cores: Short Synthesis of Taxamairin B and Rosmaridiphenol.

We report the short synthesis of two natural products, rosmaridiphenol and taxamairin B, from key intermediates 5a and 5b, which were prepared from enynals 8a and 9b, respectively, by using a gold-catalyzed cyclization reaction. This approach can be widely applied in the synthesis of [6,7,6]-fused tricyclic compounds found in many icetexane diterpenoids.

Tandem [5 + 2]/[4 + 2] Cycloadditions To Construct the [6-7-6] Tricyclic Skeleton of Icetexane Diterpenes: Total Synthesis of Euolutchuol E, Przewalskine E and Brussonol.

The collective total synthesis of the icetexane diterpenoids euolutchuol E, przewalskine E, and brussonol is described. An efficient synthetic strategy features two key transformations: (a) a tandem [5 + 2]/[4 + 2] cycloaddition reaction strategy to efficiently build the full-carbon skeleton of the icetexane diterpenoids; (b) an efficient aromatization of the C-ring of the icetexane diterpenoids using SeO2.

Spirodesertols A and B, two highly modified spirocyclic diterpenoids with an unprecedented 6-isopropyl-3H-spiro[benzofuran-2,1′-cyclohexane] motif from Salvia deserta

Two highly modified spirocyclic diterpenoids with an unprecedented 6-isopropyl-3H-spiro[benzofuran-2,1′-cyclohexane] motif and four new icetexane diterpenoids were isolated from Salvia deserta. 1 showed more potent cytotoxicity than cis-platin.

Two novel terpenoids from the cultured Perovskia atriplicifolia

Two new terpenoids, named biperovskatone B (1) and 1α- hydroxyl demethylsalvicanol quinine (2), were isolated from the cultured Perovskia atriplicifolia. Their structures were elucidated by comprehensive analyses of the MS, IR, 1D and 2D NMR spectra. Compound 1 was a novel diterpenoid dimer, containing two different rearranged 9(10 → 20)-abeoabietane type diterpenoid fragments. Compound 2 was a new icetexane diterpenoid with characteristic ortho-quinone carbonyl groups. Both compounds were assayed for their anti-HBV activity in vitro. Results suggested compounds 1 and 2 showed noticeable anti- anti-HBV activity, inhibiting the replication of HBV DNA with IC50 values of 10.78 and 8.61 μM, respectively.

A Strategy toward Icetexane Natural Products.

Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6-7-6 tricyclic core structure of these interesting synthetic targets based on a two-step enolate alkylation and ring-closing metathesis reaction sequence.

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.

Sageone, a diterpene from Rosmarinus officinalis, synergizes with cisplatin cytotoxicity in SNU-1 human gastric cancer cells

Background and PurposeChemotherapy resistance is a major obstacle for the effective treatment of cancers. Although several studies have described the anticancer properties of rosemary extract and its components, the detailed mechanisms of action are poorly understood. MethodsActivity-guided fractionation and repeated chromatographic separation of the n-hexane fraction of the aqueous methanol extract over silica gel, RP C18, and Sephadex LH-20 led to the isolation of three compounds. The structures of the compounds were determined using 1H, 13C, and two-dimensional nuclear magnetic resonance spectroscopy, mass spectroscopy, and infrared spectroscopy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to evaluate the cytotoxicity of these compounds. Cell cycle, apoptotic cell populations, and mitochondrial membrane potential were analyzed by flow cytometry. Western blot analysis was conducted to detect apoptosis-related proteins. ResultsAn abietane diterpenoid, sageone (1), an icetexane diterpenoid, (–)-barbatusol (2), and a monoterpene, (+)-verbenone (3), were identified. Of these compounds, sageone (1) showed cytotoxicity against SNU-1 cells with an IC50 of 9.45 ± 1.33 µM. Sageone reduced the expression of Akt dramatically, as opposed to cisplatin, which increased phosphorylated Akt. Sageone combined with a subtoxic dose of cisplatin had synergistic effects on apoptosis induction in SNU-1 cells, as confirmed by calculating the combination index. Co-treatment was significantly more effective than monotherapy at reducing cell viability and inducing apoptosis, as determined by analyzing DNA fragmentation. The combined treatment of sageone and cisplatin markedly reduced Akt expression and phosphorylation, accompanied by increases in cleaved caspase-3, -9 and PARP. ConclusionThis is the first time compounds 1 and 2 have been isolated from R. officinalis. Sageone induced apoptosis in SNU-1 human gastric cancer cells and notably enhanced the cytotoxicity of cisplatin in SNU-1 cells, which are known to be resistant to cisplatin. These findings suggest that sageone represents a promising anticancer agent against gastric cancer that warrants further study.

Icetexane diterpenoids from Perovskia atriplicifolia.

Five new icetexane diterpenoids, namely, perovskatones B-D (1, 3, 4), 1α-hydroxybrussonol (2), and 1α-hydroxypisiferanol (5), were isolated from Perovskia atriplicifolia, together with a new natural product (6) and two known compounds, przewalskin E (7) and brussonol (8). The structures of the new compounds were elucidated by detailed analyses of their MS, IR, 1D, and 2D NMR data. Compounds 1-8 were assayed for their inhibitory hepatitis B virus activities in the HepG 2.2.15 cell line. The results suggested that compounds 1 and 2 possessed noticeable anti-hepatitis B virus activity in vitro, suppressing the replication of hepatitis B virus DNA with selectivity index values of 154.3 and 137.7, respectively.

Antioxidant, hepatoprotective and cytotoxic effects of icetexanes isolated from stem-bark of Premna tomentosa

The study investigates the antioxidant, hepatoprotective and antiproliferative effects of novel icetexane diterpenoids (ice 1–4) isolated from hexane extract of stem bark of Premna tomentosa. A549, HT-29, MCF-7, MDA-MB-231, A431 cells were used to assess the antiproliferative activity by MTT assay. Cell death induced by apoptosis was determined by morphological assessment studies using acridine orange/ethidium bromide staining (dual staining), mitochondrial potential measurement by JC-1 staining, and cell cycle analysis by propidium iodide staining method by Muse cell analyser. Anti oxidant activity was investigated by in vitro assays such as DPPH, nitric oxide and superoxide scavenging activities. Hepatoprotective activity was determined in vitro with HepG2 cells and in vivo by tBHP induced hepatic damage mice model. Based on the in vitro cytotoxic assays and morphological assessment studies using fluorescence microscopic study (acridine orange and ethidium bromide double staining) and mitochondrial potential measurements, it was found that ice 2 and 3 possess good antiproliferative effect via mitochondrial mediated apoptosis in human lung and breast cancer cells. Results of in vitro antioxidant studies demonstrated that ice-4 has showed good antioxidant activity. The restoration of serum levels of SGOT, SGPT and ALKP, liver GSH status and reduction or inhibition of lipid peroxidation in liver of tBHP intoxicated mice after administration of ice-4 at dose of 250mg/kg indicated its potential use for hepatoprotective activity.

Diterpenoids from the Twigs and Leaves of Fokienia hodginsii

Five new isopimarane diterpenoids, fokihodgins A-E (1-5), four new labdane diterpenoids, fokihodgins F-I (6-9), and one new icetexane diterpenoid, fokihodgin J (10), as well as 18 known diterpenoids were isolated from Fokienia hodginsii. The structures of the new compounds were determined on the basis of their spectroscopic analysis, and the absolute configurations of 1 and 6 were established by X-ray crystallographic analysis. Compound 9 showed moderate cytotoxicity against HL-60 and SMMC-7721 cell lines, with IC50 values of 9.10 and 7.50 μM, respectively.

Synthetic studies on the icetexones: enantioselective formal syntheses of icetexone and epi-icetexone

Two strategies for the synthesis of the icetexane diterpenoids icetexone and epi-icetexone that rely on Ga(III)-catalyzed cycloisomerization of alkynyl indene substrates to yield fused [6-7-6] tricycles have been explored. In the first approach, access to a tricycle bearing a gem-dimethyl group paved the way for explorations of C–H functionalization of one of the methyl groups in close proximity to a hydroxyl-directing group. This approach was ultimately unsuccessful and led only to ring cleaved products. In the second approach, an alkynyl indene substrate bearing a cyano substituent was utilized, which was effective in providing a functional handle to access the icetexone subclass of diterpenoids. A key epoxide opening/diazene rearrangement sequence was utilized to complete a formal synthesis of icetexone and epi-icetexone, which is discussed in detail. Furthermore, the cyano-containing substrate has been prepared in enantioenriched form using a Rh-catalyzed conjugate addition reaction, which now provides a route to the enantioselective synthesis of these natural products.

Obtusinones D and E, linear and angular fused dimeric icetexane diterpenoids from Premna obtusifolia roots

Two new dimeric icetexane diterpenoids, obtusinones D and E (1 and 2), were isolated from the root extracts of Premna obtusifolia. Obtusinone D (1) represents the first example of a novel linear fused dimeric icetexane, whereas obtusinone E (2) is an angular fused icetexane. The structures of 1 and 2 were elucidated on the basis of 1D and 2D NMR spectral data analysis.

11,12-Dihy-droxy-10,6,8,11,13-icetexapentan-1-one.

The title compound [systematic name: 14,15-dihy­droxy-7,7-dimethyl-13-(propan-2-yl)tricyclo­[9.4.0.03,8]penta­deca-1(11),3(8),9,12,14-pentaen-4-one], C20H24O3, is a new icetexane diterpenoid which was isolated from the roots of Premna obtusifolia (Verbenaceae). The mol­ecule has three fused rings: a cyclo­hexenone, a central cyclo­heptene and a benzene ring. The cyclo­hexenone ring is in an envelope conformation, whereas the cyclo­heptene ring is in a twisted boat conformation. Intra­molecular O—H⋯O hydrogen bonds generate S(5) and S(8) ring motifs. In the crystal, mol­ecules are linked into dimers through O—H⋯O hydrogen bonds. These dimers are arranged in to sheets parallel to the ac plane. C—H⋯O and weak C—H⋯π inter­actions are also present.

New diterpenoids and cytotoxic and anti-inflammatory diterpenoids from Amentotaxus formosana

Two new abietane diterpenoids, ramentoxide ( 1) and ramentoxidone ( 2) and a new icetexane diterpenoid, amentonone ( 3) were isolated from the barks of Amentotaxus formosana. The structures of 1– 3 were determined by spectroscopic methods. Known compounds brevitaxin ( 4), and (+)-ferruginol ( 5) and ent-kaur-16-en-15-one ( 6) isolated from this plant revealed potent cytotoxic activity against human breast adenocarcinoma cells, MCF-7 cells with an IC 50 value of 0.08 ± 0.05 μg/mL, and significant anti-inflammatory activities, respectively.

ChemInform Abstract: An Epoxide Ring‐Opening Approach for a Short and Stereoselective Synthesis of Icetexane Diterpenoids.

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