Ent-kaurane Diterpenes Research Articles

The remarkable structural diversity achieved in ent-Kaurane Diterpenes by fungal biotransformations.

The use of biotransformations in organic chemistry is widespread, with highlights of interesting applications in the functionalization of natural products containing unactivated carbons, like the kaurane diterpenes. A number of compounds with kaurane skeletons can be isolated in large amounts from several plant species and a myriad of biological activities has been related to these compounds. Studies on structure versus activity have showed that, in most cases, in kaurane diterpenes, activity increases with the increase of functionalization. Since naturally occurring kaurane diterpenes usually have limited functional groups to be used as targets for semi-synthetic modifications, production of more polar derivatives from kaurane diterpenes have been achieved mostly through the use of fungal biotransformations. In this review, selected examples the wonderful chemical diversity produced by fungi in kaurane diterpenes is presented. This diversity includes mainly hydroxylation of nearly all carbon atoms of the kaurane molecule, many of them carried out stereoselectively, as well as ring rearrangements, among other chemical modifications. Sources of starting materials, general biotransformation protocols employed, fungi with most consistent regioselectivity towards kaurane skeleton, as well as biological activities associated with starting materials and products are also described.

<i>ent</i>-Kaurane and <i>ent</i>-Pimarane Diterpenes from <i>Siegesbeckia pubescens</i> Inhibit Lipopolysaccharide-Induced Nitric Oxide Production in BV2 Microglia

The extract of Siegesbeckia pubescens herb and its chemical constituents were tested for the ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 microglia. The methanol extract and the 90% MeOH fraction of S. pubescens effectively attenuated lipopolysaccharide-induced nitric oxide production. Several steps of chromatography yielded eight ent-kaurane diterpenes (1-8) and one ent-pimarane diterpene (9) from the 90% MeOH fraction. Among these compounds, compounds 2-9 showed significant inhibitory effect on lipopolysaccharide-induced nitric oxide production in BV2 microglia. Compounds 3 and 9 concentration-dependently decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), supported by quantitative real time polymerase chain reaction (PCR) and Western blot analysis. These results suggest that ent-kaurane and ent-pimarane diterpenes isolated from S. pubescens are expected to be potential candidates against neuroinflammation-related disease.

Hydrogenation of the Exocyclic Olefinic Bond at C-16/C-17 Position of ent-Kaurane Diterpene Glycosides of Stevia rebaudiana Using Various Catalysts

Catalytic hydrogenation of the exocyclic double bond present between C16 and C17 carbons of the four ent-kaurane diterpene glycosides namely rebaudioside A, rebaudioside B, rebaudioside C, and rebaudioside D isolated from Stevia rebaudiana has been carried out using Pt/C, Pd(OH)2, Rh/C, Raney Ni, PtO2, and 5% Pd/BaCO3 to their corresponding dihydro derivatives with 17α and 17β methyl group isomers. Reactions were performed using the above-mentioned catalysts with the solvents methanol, water, and ethanol/water (8:2) under various conditions. Synthesis of reduced steviol glycosides was performed using straightforward chemistry and their structures were characterized on the basis of 1D and 2D NMR spectral data, including a comparison with reported spectral data.

Synthesis and Sensory Evaluation of ent-Kaurane Diterpene Glycosides

Catalytic hydrogenation of the three ent-kaurane diterpene glycosides isolated from Stevia rebaudiana, namely rubusoside, stevioside, and rebaudioside-A has been carried out using Pd(OH)2 and their corresponding dihydro derivatives have been isolated as the products. Synthesis of reduced steviol glycosides was performed using straightforward chemistry and their structures were characterized on the basis of 1D and 2D NMR spectral data and chemical studies. Also, we report herewith the sensory evaluation of all the reduced compounds against their corresponding original steviol glycosides and sucrose for the sweetness property of these molecules.

Synthesis of ent-Kaurane Diterpene Monoglycosides

Synthesis of two ent-kaurane diterpene glycosides, steviol 19-O-β-D-glucopyranosiduronic acid (steviol glucuronide, 5 ), and 13-hydroxy ent-kaur-16-en-19-oic acid-β-D-glucopyranosyl ester (7) has been achieved from a common starting material, steviol, using phase transfer catalyst. Also, synthesis of an additional 17-nor-ent-kaurane glycoside, namely 13-methyl-16-oxo-17-nor-ent-kauran-19-oic acid-β-D-glucopyranosyl ester (10) was performed using the starting material isosteviol and similar synthetic methodology. Synthesis of all three steviol glycosides was performed using straightforward chemistry and their structures were characterized on the basis of 1D and 2D NMR as well as mass spectral (MS) data.

Components from the Steamed Leaves of Acanthopanax koreanum and their Effects on PPAR Activity in HepG2 Cells

Three ent-kaurane diterpenes (1-3), four lupane-triterpene glycosides (4-7), and an oleanane-triterpene glycoside (8) were isolated from the ethyl acetate and water extracts of the steamed leaves of Acanthopanax koreanum using a combination of various column chromatographies. The structures of the isolates were determined by 1H-, 13C-NMR spectroscopy and mass spectrometry. To investigate the biological effects of the eight compounds (1-8) on peroxisome proliferator-activated receptor gamma (PPARgamma), luciferase reporter assays were used. Among the tested compounds, ent-kaur-16-en-19-oic acid (1), 16alpha-hydroxy-ent-kauran-19-oic acid (2), and 17-hydroxy-ent-kaur-15-en-19-oic acid (3) showed considerable effects on PPARgamma activity, compared with the positive control, troglitazone. To evaluate specificity and sensitivity of the active compounds (1-3) in the regulation of transactivation of PPARs, Gal4-PPARs-LBD luciferase reporter assays were examined. In this study, the three ent-kaurane diterpenes (1-3) were found to up-regulate PPARbeta/delta and PPARgamma activities, whereas they did not activate PPARalpha activity.

Ent‐Kaurane Diterpenes and Further Constituents from Wedelia trilobata

AbstractTwo new ent‐kaurane diterpenes, wedelidins A (8) and B (9), together with eighteen other constituents, including the sesquiterpenoids 1 and 2, ent‐kaurane diterpenes 3–7, triterpenoids 10 and 11, steroids 12–14, and flavonoids 15–17 as well as benzene derivatives 18–20, were isolated from the aerial parts of Wedelia trilobata. The structures of wedelidins A (8) and B (9) were elucidated by extensive spectroscopic analyses (including UV, IR, NMR, and MS). Furthermore, the structures of compounds 2 and 3 were confirmed by X‐ray single‐crystal diffraction analyses.

Antityrosinase and Antioxidant Effects of ent-Kaurane Diterpenes from Leaves of Broussonetia papyrifera

Three new ent-kaurane type diterpenes, broussonetones A-C (1-3), were isolated from leaves of Broussonetia papyrifera, together with seven known compounds, and their structures determined by 1D and 2D NMR and MS methods. Compounds 1-3 were marginal inhibitors of tyrosinase. Antioxidant assays showed them also to be inhibitors of xanthine oxidase. The mild inhibition of tyrosinase and significant inhibition of xanthine oxidase suggests that 1-3 could be useful ingredients in the development of skin-protecting cosmetics.

Isolation of syringaldehyde from Mikania laevigata medicinal extract and its influence on the fatty acid profile of mice

The Mikania genus is widely known as "guaco" and is used to treat fever, rheumatism, flu and respiratory diseases. Our previous work evidenced the synergism among M. laevigata extract components to produce desirable effects, and included the coumarin precursor, o-coumaric acid as marker. Many Mikania species are producers of ent-kaurene diterpenes which presented antiespasmodic and relaxant activities on smooth muscle. Seeking to standardize the guaco extract, which is registered in the Brazilian Pharmacopoea, this paper deals with the determination of kaurenoic acid through LC-PDA and the isolation through LC of syringaldehyde. Kaurenoic acid was not found in the extract, and syringaldehyde is one of the major compounds of pharmacopoeal extract, together with coumarin and o-coumaric acid. Samples from the lung and liver of Balb-C isogenic allergic pneumonitis bearing mice, treated with the same extract, were analyzed through GC-FID, and the fatty acid content was determined and analyzed. The results obtained by measuring the arachidonic acid (ARA) and docosahexaenoic acid (DHA) in the liver and lung of treated animals demonstrated that the fatty acid composition is distinct in both tissues, and that in the liver, only the DHA was altered as a result of the treatments. DHA is absent in the lung and in both organs, no significant difference in ARA production was observed. The aqueous extract, coumarin and o-coumaric acid stimulated DHA synthesis in the liver (p < 0.05).

Structure elucidation of organic compounds from natural sources using 1D and 2D NMR techniques

In our continuing studies on Lamiaceae family plants including Salvia, Teucrium, Ajuga, Sideritis, Nepeta and Lavandula growing in Anatolia, many terpenoids, consisting of over 50 distinct triterpenoids and steroids, and over 200 diterpenoids, several sesterterpenoids and sesquiterpenoids along with many flavonoids and other phenolic compounds have been isolated. For Salvia species abietanes, for Teucrium and Ajuga species neo-clerodanes for Sideritis species ent-kaurane diterpenes are characteristic while nepetalactones are specific for Nepeta species. In this review article, only some interesting and different type of skeleton having constituents, namely rearranged, nor- or rare diterpenes, isolated from these species will be presented. For structure elucidation of these natural diterpenoids intensive one- and two-dimensional NMR techniques ( 1H, 13C, APT, DEPT, NOE/NOESY, 1H– 1H COSY, HETCOR, COLOC, HMQC/HSQC, HMBC, SINEPT) were used besides mass and some other spectroscopic methods.

New Diterpenoids from Tricalysia dubia

Tricalysia dubia (Rubiaceae), an evergreen shrub or tree, is widely distributed in Taiwan, the southern parts of China and Japan. From the leaves of this plants, unique rearranged ent-kaurane glycosides A – G, and the ent-kaurane glycosides H – O, have been isolated. In our presentation, six rearranged ent-kaurane diterpenes, tricalysiolides A – F [1], tricalysiamides A – D [2], tricalysiolide H, tricalysiones A and B [3], and a known diterpene, cafestol from the wood of this plant are reported, especially their cytotoxic activity against P388 leukemia cells in mice as well as the structure elucidation using spectral analyses and chemical methods.

Potential anti-allergic ent-kaurene diterpenes from the bark of Suregada multiflora

Two ent-kaurene diterpenes, ent-16-kaurene-3β,15β,18-triol ( 1) and ent-3-oxo-16-kaurene-15β,18-diol ( 2), were isolated from a dichloromethane extract of the bark of Suregada multiflora along with five known diterpenes: ent-16-kaurene-3β,15β-diol ( 3), abbeokutone ( 4), helioscopinolide A ( 5), helioscopinolide C ( 6) and helioscopinolide I ( 7). Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1– 7 possessed appreciable anti-allergic activities in RBL-2H3 cells model with IC 50 values ranging from 22.5 to 42.2 μM.

Tricalysiolide G and tricalysiols A and B: rearranged ent-kaurane-type and ent-kaurane-type diterpenoids from the leaves of Tricalysia dubia (Lindl.) Ohwi

Three rearranged ent-kaurane diterpenes with the cafestol-type framework have been isolated from the leaves of Tricalysia dubia. Two were found to be known diterpenoids, tricalysiolides B and C. Tricalysiolide B was isolated as colorless prisms in this experiment and its three-dimensional structure was determined by X-ray crystallography. The remaining diterpenoid was a new compound and was named tricalysiolide G. Two new ent-kaurane-type diterpenoids, given the trivial names tricalysiol A and tricalysiol B, were also isolated. The structures of the new compounds were elucidated from spectroscopic evidence.

Synthesis of 1- O-monoacyl or 12- O-monoacyl, 1-,12- O-diacyl-, and 11,12-dehydrated excisanin A 7,14-acetonides and their cytotoxic activity

1- O-Monoacyl, 12- O-monoacyl, 1-,12- O-diacyl, and 11,12-dehydrated excisanin A 7,14-acetonides were synthesized from excisanin A isolated from Rabdosia excisa. The structure and cytotoxic activity relationships (SAR) of the natural parent ent-kaurene diterpenes and these semisynthetic analogues were studied by using P388 murine leukemia cells.

Tricalysiolides A (Ia)—F (IIb), New Rearranged ent‐Kaurane Diterpenes from Tricalysia dubia.

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Kaurene diterpenes from Laetia thamnia inhibit the growth of human cancer cells in vitro

Four ent-kaurene diterpenes were isolated from the leaves of Laetia thamnia L.: ent-kaur-16-en-19-oic acid ( 1a), ent−3β-hydroxykaur-16-ene ( 2), ent-kaur-16-en-3α,19-diol ( 3a), and ent-17-hydroxykaur-15-en-19-oic acid ( 4). The methyl ester ( 1b) of compound 1a and the acetate diester ( 3b) of compound 3a were prepared, and all compounds were evaluated for cytotoxicity against human prostate (22Rv1, LNCaP), colon (HT29, HCT116, SW480, SW620), and breast (MCF-7) tumor cells at concentrations ranging from 6 to 50 μg/mL. The kaurenes showed activity in all cell lines tested, with the prostate cells demonstrating the most sensitivity as follows: 22 Rv1 cells towards 1a (IC 50 5.03 μg/mL) and 1b (IC 50 6.81 μg/mL), and LNCaP towards 2 (IC 50 12.83 μg/mL) and 4 (IC 50 17.63 μg/mL).

Tricalysiolides A–F, new rearranged ent-kaurane diterpenes from Tricalysia dubia

Six rearranged ent-kaurane diterpenes, tricalysiolides A–F, having the cafestol-type carbon framework were isolated from the wood of Tricalysia dubia (Rubiaceae). Their absolute structures were determined on the basis of the 2D NMR spectroscopy, X-ray crystallographic analysis, and chemical methods.

Ent-kaurane glycosides and sesquiterpene lactones of the hirsutinolide type from Vernonia triflosculosa

Investigation of the aerial parts of Vernonia triflosculosa afforded three hirsutinolides of which 8α-(4α-hydroxymethacryloyloxy)-10α-hydroxy-1,13-dimethoxy-hirsutinolide is new, three ent-kaurane diterpenes, among which the 19-[α- l-arabinopyranosyl-(1 → 2)-β- d-glucopyranosyl] esters of 16β-hydroxy- ent-kauran-19-oic acid and of 16β,17-hydroxy- ent-kauran-19-oic acid are also new. Diterpenes are reported here for the first time in the large genus Vernonia. Their structures were elucidated using 1D and 2D NMR measurement as well as ESI, CIMS, and HRMS analysis. Two hirsutinolides were studied for their NF-κB DNA binding activity in HaCaT cells (a human cell line similar to keratinocytes) and for their inhibition on IL-8 production in HeLa cells.

Studies of ent-kaurane diterpenes from Oyedaea verbesinoides for their inhibitory activity on vascular smooth muscle contraction

From the aerial parts of Oyedaea verbesinoides nine ent-kauranes and a sesquiterpene were isolated. ent-9α-Hydroxy-kaur-16-en-19-oic acid, ent-15β-tigloyloxy-9α-hydroxy-kaur-16-en-19-oic acid, ent-15β-angeloyloxy-9α-hydroxy-kaur-16-en-19-oic acid, ent-16α-hydroxykaurane and 1α-angeloyloxy-carotol are new for the genus or the species and ent-15β-angeloyloxy-7α,9α-dihydroxy-kaur-16-en-19-oic acid is reported for the first time. Structure elucidation was based on one and two dimensional NMR as well as ESI and CI-MS analysis. Some diterpenes were proven to exhibit inhibitory effects on smooth muscle contraction on rat aorta.

Inhibition of the Nuclear Factor κB (NF-κB) Pathway by Tetracyclic Kaurene Diterpenes in Macrophages: SPECIFIC EFFECTS ON NF-κB-INDUCING KINASE ACTIVITY AND ON THE COORDINATE ACTIVATION OF ERK AND p38 MAPK

The anti-inflammatory action of most terpenes has been explained in terms of the inhibition of nuclear factor kappaB (NF-kappaB) activity. Ent-kaurene diterpenes are intermediates of the synthesis of gibberellins and inhibit the expression of NO synthase-2 and the release of tumor necrosis factor-alpha in J774 macrophages challenged with lipopolysaccharide. These diterpenes inhibit NF-kappaB and IkappaB kinase (IKK) activation in vivo but failed to affect in vitro the function of NF-kappaB, the phosphorylation and targeting of IkappaBalpha, and the activity of IKK-2. Transient expression of NF-kappaB-inducing kinase (NIK) activated the IKK complex and NF-kappaB, a process that was inhibited by kaurenes, indicating that the inhibition of NIK was one of the targets of these diterpenes. These results show that kaurenes impair the inflammatory signaling by inhibiting NIK, a member of the MAPK kinase superfamily that interacts with tumor necrosis factor receptor-associated factors, and mediate the activation of NF-kappaB by these receptors. Moreover, kaurenes delayed the phosphorylation of p38, ERK1, and ERK2 MAPKs, but not that of JNK, in response to lipopolysaccharide treatment of J774 cells. The absence of a coordinate activation of MAPK and IKK might contribute to a deficient activation of NF-kappaB that is involved in the anti-inflammatory activity of these molecules.