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PubMed1983

Irritant diterpene ester promoters of mouse skin: contributions to etiologies of environmental cancer and to biochemical mechanisms of carcinogenesis.

One of the most advanced experimental models for investigations of the metabolic fate and of mechanisms of action of initiators and promoters at the cell and/or the molecular level is the three-stage initiation/promotion/progression model of carcinogenesis in mouse skin. In etiologic investigation by experimental analyses of local lifestyle-associated esophageal cancer on the Caribbean island of Curacao, based on this model initiators of the solitary carcinogenic PAH type and promoters of the cocarcinogenic diterpene ester (tigliane) type were suggested as putative principal risk factors. In metabolic investigations it was shown that 7,12-dimethylbenz(a)anthracene (DMBA) requires metabolic activation to yield "ultimate initiator(s)," whereas TPA and its diterpene ester congeners are "ultimate promoters" themselves. Yet naturally occurring "cryptic" forms of diterpene ester irritants and promoters require metabolic activation. To show structure/activity relationships, selected new diterpene structures of the tigliane, ingenane, and daphnane types and their irritant and promoting activities in mouse skin are presented in this paper. Common structural features of the diterpene moieties relevant for interaction with cellular receptors are identified. Synthetic modification of the ester moieties reveals highly unsaturated analogs of 12-O-tetradecanoylphorbol-13-acetate (TPA) allowing for dissection of the promotional stage in the mouse skin model in two operationally defined substages, PI and PII. In many tissues and cells, TPA and congeners induce various different biological effects, e.g., phospholipid synthesis is stimulated in epidermis, virus synthesis is stimulated in human lymphoblastoid cell lines carrying latent genomes of Epstein-Barr virus (EBV), and prostaglandin E2 is rapidly released from mouse peritoneal macrophages. Altogether a remarkable biological and biochemical pleiotropism of diterpene ester promoters is indicated. In investigations of the molecular mechanism of action of diterpene esters, non-promoting short chain phorbol esters, such as phorbol-12,13-dipropionate (PDPr) were shown to inhibit diterpene ester-induced promotion in vivo. In radioligand assays employing (20-3H)PDPr as well as (20-3H)TPA, specific binding to the particulate fractions of mouse skin and other mouse organs, including the brain, is seen. Inhibition of specific binding by a series of diterpene esters is correlated with their irritant and promoting activities.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Biosynthesis of rice phytoalexins: identification of putative diterpene hydrocarbon precursors.

A procedure for the preparation of a cell-free enzyme solution from rice leaves capable of catalyzing the biosynthesis of diterpene hydrocarbons from geranylgeranyl pyrophosphate or copalyl pyrophosphate as added substrates has been developed. The rates of synthesis of a group of "pimaradiene-like" diterpene hydrocarbons are about 75-fold higher with geranylgeranyl pyrophosphate as substrate and about 8-fold higher with copalyl pyrophosphate as substrate in comparison with extracts from untreated control leaves. The maximum rate of diterpene hydrocarbon biosynthesis is seen in extracts prepared at 40 h after uv irradiation. Five diterpene hydrocarbons (compounds A-E) were present in the hydrocarbon fraction biosynthesized from [3H]geranylgeranyl pyrophosphate in large-scale incubation mixtures prepared from uv-treated rice leaves. Three of these diterpenes were identified as ent-kaur-16-ene (B), ent-sandaracopimara-8(14), 15-diene (D), and 9 beta H-pimara-7,15-diene (E) from GC retention times and GC-MS spectral characteristics in comparison with those of authentic reference compounds. Compound C has spectral characteristics analogous to those of a pimaradiene, but a specific structural assignment from the data available was not possible. Similar incubations with [3H]copalyl pyrophosphate as the substrate and enzyme prepared from uv-treated rice leaves produced ent-kaurene (B), ent-sandaracopimara-8(14),15-diene (D), and compound C, but not 9 beta H-pimara-7,15-diene (E). These results are consistent with a proposed biosynthetic scheme in which 9 beta H-pimara-7,15-diene serves as a precursor of the momilactone family, and ent-sandaracopimara-8(14),15-diene serves as a precursor of the oryzalexin family of rice phytoalexins. ent-Kaurene was the only diterpene detected in incubation mixtures containing enzyme extract from untreated rice leaves and [3H]copalyl pyrophosphate as the substrate. It is suggested that kaurene biosynthesis in rice leaves is probably associated with gibberellin biosynthesis and the regulation of vegetative growth rather than stress metabolism. The diterpene cyclization enzymes in extracts of uv-treated rice leaves show only a relatively modest inhibition by the plant growth retardants AMO-1618 and Phosfon D. No evidence was obtained for the subcellular localization of these cyclization enzymes in organellar preparations; it is tentatively concluded that the enzymes are present predominantly in the extraorganellar cytoplasm of rice leaves.

Alkyl and Aryl Transferases↗
PubMed2003

In vitro antileishmanial effects of antibacterial diterpenes from two Ethiopian Premna species: P. schimperi and P. oligotricha.

BACKGROUND: Three antibacterial diterpenes: (5R,8R,9S,10R)-12-oxo-ent-3,13(16)-clerodien-15-oic acid (1), 16-hydroxy-clerod-3,13(14)-diene-15,16-olide (2) and ent-12-oxolabda-8,13(16)-dien-15-oic acid (3) were previously isolated form Premna schimperi and P. oligotricha. Since andrographolide and other structurally related diterpenes were shown to have antileishmanial activity, the aim of the present study was to assess the in vitro effect of premna diterpenes against Leishmania aethiopica; the causative agent of cutaneous leishmaniasis in Ethiopia. RESULTS: The diterpenes showed potent concentration-dependant suppressive effect on the viability of axenically cultured amastigotes of L. aethiopica. The clerodane diterpenes 1 and 2 were most active (LD50 values 1.08 and 4.12 microg/ml respectively) followed by andrographolide and 3. Compounds 1 and 2 appear to be over 20 and 10-times respectively more selective to leishmania amastigotes than the permissive host cell line, THP-1 cells or the promastigotes stage of the parasites. CONCLUSION: The clerodane diterpenes (1, 2) which were more potent and selective than labdanes (andrographolide and 3) are promising for further studies and/or development.

Animals↗
PubMed2004

Antiviral activity of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis against human immunodeficiency virus type 1 (HIV-1).

The antiviral effect of the CH(2)Cl(2)/MeOH-soluble fraction from the alga Dictyota menstrualis on HIV-1 replication was evaluated in vitro. The antiretroviral activity was attributed to two diterpenes: (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial, named Da-1, and (6R)-6-acetoxi-dichotoma-3,14-diene-1,17-dial, named AcDa-1. Da-1 or AcDa-1 were added to the culture medium of HIV-1-infected PM-1 cells at different times post-infection or during virus adsorption/penetration. The results indicated that the compounds affected an early step of the virus replicative cycle. Virus binding and entry into the host cells were evaluated in the presence of each diterpene, but no inhibitory effect was observed. To evaluate provirus DNA synthesis/integration into the host genome, the viral protease coding sequence was amplified from total cellular DNA. Proviral DNA was not detected in infected cells incubated with the diterpenes. To investigate the effect of the diterpenes on the reverse transcription of the viral genomic RNA, the recombinant HIV-1 reverse transcriptase (RT) was assayed in vitro in the presence of each diterpene. Da-1 and AcDa-1 inhibited the RNA-dependent DNA-polymerase activity of HIV-1 RT in a dose-dependent manner. Taken together, our results demonstrate that both diterpenes inhibit HIV-1 RT and consequently virus replication.

Adsorption↗
PubMed2002

Chemosystematic investigations of irregular diterpenes in Anisotome and related New Zealand Apiaceae.

A chemosystematic HPLC-UV and HPLC-MS investigation of New Zealand members of the Apiaceae was performed. Diterpenes were identified and quantified in methanolic extracts from subaerial parts of 28 taxa and 54 samples of Aciphylla, Anisotome, Apium, Gingidia, Lignocarpa, Oreomyrrhis, and Scandia. Six diterpenes (1-2, 4-7) and four polyacetylenes (8-11) were identified. The known compounds were the diterpenes anisotomenoic acid 1, anisotomene-1-ol 2, 16-acetoxyanisotomenoic acid 4 and anisotomene-1,12-diol 5; and the polyacetylenes falcarinol 8, falcarindiol 9, (+)-9(Z),17-octadecadiene-12,14-diyne-1,11,16-triol 10, and (+)-9(Z),17-octadecadiene-12,14-diyne-1,11,16-triol 1-acetate 11. New irregular diterpenes 13,14-dihydroanisotom-12E-ene-1,14-diol 6 and 14-methoxy-13,14-dihydroanisotom-12E-ene-1-ol 7 were isolated from A. haastii. Isomers of the new semi-synthetic diterpene 16-hydroxyanisotomenoic acid 3 were detected in extracts of Anisitone flexuosa. Structure elucidation was performed by HR mass spectrometry and 1D and 2D NMR spectroscopy. In crude extracts, compounds were identified by their HPLC retention times and their on-line HPLC-UV and MS spectra. Anisotomene diterpenes occurred in eight out of 16 species of the genus Anisotome, but were not detected in any of the other genera. In contrast, polyacetylenes were present in all the genera investigated.

Apiaceae↗
PubMed2002

New diterpenes and norditerpenes from the fruits of Vitex rotundifolia.

A new labdane-type diterpene, vitexifolin A (1), a new clerodane-type diterpene, vitexifolin B (2), a new abeoabietane-type diterpene, vitexifolin C (3), and two new norlabdane-type diterpenes, vitexifolin D (4) and vitexifolin E (5), were isolated from the fruits of Vitex rotundifolia, along with a known halimane-type diterpene, vitetrifolin D (6), two known norlabdane-type diterpenes, trisnor-gamma-lactone (7) and iso-ambreinolide (8), and three known flavonoids, casticin (9), artemetin (10), and 5,3'-dihydroxy-6,7,4'-trimethoxyflavanone (11). Their chemical structures were determined on the basis of spectroscopic data. Casticin (9) exhibited considerable growth inhibitory activity against human lung cancer cells (PC-12) and human colon cancer cells (HCT116) using the MTT assay.

Animals↗
PubMed1998

Absorption and urinary excretion of the coffee diterpenes cafestol and kahweol in healthy ileostomy volunteers.

OBJECTIVES: To determine the absorption and urinary excretion of the cholesterol-raising coffee diterpenes cafestol and kahweol in humans. SUBJECTS AND DESIGN: Nine healthy ileostomists consumed a dose of one, two or three cups of French-press coffee together with a standardized breakfast on three separate days in random order. Subsequently, ileostomy effluent was collected for 14 h and urine for 24 h. Stability of cafestol and kahweol was also assessed under simulated gastrointestinal tract conditions. MAIN OUTCOME MEASURES: Absorption of diterpenes, stability of diterpenes during incubation with gastrointestinal fluids, and urinary excretion of diterpenes. RESULTS: Corrected mean absorptions expressed as percentages of the amount consumed and the amount entering the duodenum were 67 and 88%, respectively, for cafestol, and 72 and 93%, respectively, for kahweol. We found losses of diterpenes during incubation in vitro with gastric juice (cafestol, 24%; kahweol, 32%), during storage with ileostomy effluent (cafestol, 18%; kahweol, 12%), and during freeze-drying (cafestol, 26%; kahweol, 32%). Mean excretion of glucuronidated plus sulphated conjugates in urine was 1.2% of the ingested amount for cafestol and 0.4% of the ingested amount for kahweol. CONCLUSIONS: About 70% of the ingested cafestol and kahweol is absorbed in ileostomy volunteers. Possibly, undetected metabolites are present in ileostomy effluent, resulting in lower absorption percentages. Only a small part of the diterpenes is excreted as a conjugate of glucuronic acid or sulphate in urine. Therefore, these compounds are extensively metabolized in the human body.

Adult↗
PubMed2003

Diterpenes from the roots of Euphorbia kansui and their in vitro effects on the cell division of Xenopus (part 2).

Four new ingenane-type diterpenes, 3-O-(2,3-dimethylbutanoyl)-13-O-dodecanoyl-20-O-acetylingenol (1), 3-O-(2,3-dimethylbutanoyl)-13-O-dodecanoyl-20-deoxyingenol (2), 3-O-(2E,4Z-decadienoyl)-20-deoxyingenol (3), and 3-O-(2E,4E-decadienoyl)-20-deoxyingenol (4), two new jatrophane-type diterpenes, kansuinins D (9) and E (10), and four known ingenane-type diterpenes were isolated from the root of Euphorbia kansui. Their structures were elucidated by spectroscopic and chemical analysis, and individual Xenopus cells at the blastular stage were cultured with the diterpenes to test for biological activity. 20-Deoxyingenol diterpenes 3 and 4 induced the greatest cell cleavage arrest (0.5 micro g/ml of each compound resulted in >75% cleavage arrest), but cell cleavage inhibitory activity became weak when C-16 had an acyl residue. In contrast, the jatrophane diterpene kansuinin D (9) showed no activity.

Animals↗
PubMed2002

Leaf Ests from Stevia rebaudiana: a resource for gene discovery in diterpene synthesis.

Expressed sequence tags (ESTs) are providing a new approach to gene discovery in plant secondary metabolism. Stevia rebaudiana Bert. leaves produce high concentrations of diterpene steviol glycosides and should be a rich source of transcripts involved in diterpene synthesis. In order to create a resource for gene discovery and increase our understanding of steviol glycoside biosynthesis, we sequenced 5,548 ESTs from a S. rebaudiana leaf cDNA library. The EST collection was fully annotated based on database search results. ESTs involved in diterpene synthesis were identified using published sequences as electronic probes, by keyword searches of search results, and by differential representation. A significant portion of the ESTs were specific for standard leaf metabolic pathways; energy and primary metabolism represented 17.6% and 13.1% of total transcripts respectively. Diterpene metabolism in S. rebaudiana represented 1.1% of total transcripts. This study identified candidate genes for 70% of the known steps in the steviol glycoside pathway. One candidate, kaurene oxidase, was the 8th most abundant EST in the collection. Identification of many candidate genes specific to the I -deoxyxylulose 5-phosphate pathway suggests that the primary source of isopentenyl diphosphate, a precursor of geranylgeranyl diphosphate, is via the non-mevalonic acid pathway. The use of ESTs has greatly facilitated the identification of candidate genes and increased our understanding of diterpene metabolism.

DNA, Complementary↗
PubMed2006

Production of indole diterpenes by Aspergillus alliaceus.

Production of two related indole diterpenes (differing by a dimethyl leucine side chain) by Aspergillus alliaceus was improved through several pilot scale fermentations. Media were optimized through focus primarily on initial increases, as well as mid-cycle additions, of carbon and nitrogen sources. Fermentation conditions were improved by varying ventilation conditions using various combinations of air flowrate and back-pressure set points. Production improvements were quantified based on total indole diterpene concentration as well as the ratio of the major-to-minor by-product components. Those changes with a positive substantial impact primarily on total indole diterpene concentration included early cycle glycerol shots and enhanced ventilation conditions (high air flowrate, low back-pressure). Those changes with a significant impact primarily on ratio included higher initial cerelose, soybean oil, monosodium glutamate, tryptophan, or ammonium sulfate concentrations, higher broth pH, and enhanced ventilation conditions. A few changes (higher initial glycerol and monosodium glutamate concentrations) resulted in less notable and desirable titer or ratio changes when implemented individually, but they were adopted to more fully realize the impact of other improvements or to simplify processing. Overall, total indole diterpene titers were improved at the 600 L pilot scale from 125-175 mg/L with a ratio of about 2.1 to 200-260 mg/L with a ratio of about 3.3-4.5. Thus, the ability to optimize total indole diterpene titer and/or ratio readily exists for secondary metabolite production using Aspergillus cultures.

Aspergillus↗
PubMed1979

Systemic promoting action and leukemogenesis in SWR mice by phorbol and structurally related polyfunctional diterpenes.

Phorbol and six structurally related compounds representing the polyfunctional diterpenes of the tigliane, ingenane, and lathyrane types were tested for systemic promoting and leukemogenic activity in SWR mice. For systemic initiation soon after birth, 15 microgram dimethylnitrosamine (DMN) was injected s.c. The diterpenes were administered i.p. either with or without prior systemic initiation with DMN. Systemic promotion was expressed for liver by induction of adenomas with all the diterpenes tested, some of them being more potent than phorbol. The relatively high dose of DMN used as initiator prevented an evaluation of promoting action in relation to lung carcinogenesis. The leukemogenic effect of phorbol in SWR mice was confirmed at three different dose levels. The other diterpenes tested had no significant leukemogenic activity. The leukemogenic action of phorbol was totally inhibited by prior DMN injection. The lack of correlation between promoting action in skin, systemic promoting action in liver and leukemogenic action, among the diterpenes tested, is discussed.

Animals↗
PubMed2001

Effects of six diterpenes on macrophage eicosanoid biosynthesis.

Six diterpenes (three clerodanes, two abietanes and one rosane) were tested for interactions with the cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism and for effects of nitric oxide production. Two abietane diterpenes, aethiopinone and 11,12-dihydroxy-6-oxo-8,11,13-abietatriene and the rosane lagascatriol showed a remarkable effect on COX-1 pathway of PGE2 release in calcium ionophore A23187-stimulated peritoneal macrophages. Only the two latter diterpenes showed inhibition on COX-2 pathway of PGE2 release in E. coli LPS-stimulated peritoneal macrophages. In addition, all compounds assayed were inhibitors of LTC4 release with IC50 < or = 10 microM. Clerodane diterpenes were inactive in COX assay. None of the diterpenes assayed, except 11,12-dihydroxy-6-oxo-8,11,13-abietatriene, affected NO production. The results obtained suggest that the cellular mechanisms of action of some of these substances may involve inhibition of cyclooxygenase/lipoxygenase pathways and nitric oxide production.

Animals↗
PubMed1998

Antimicrobial activity of the diterpenes flexibilide and sinulariolide derived from Sinularia flexibilis Quoy and Gaimard 1833 (Coelenterata: Alcyonacea, Octocorallia).

The soft coral Sinularia flexibilis is rarely overgrown by bacteria and algae. Various studies have shown that it contains diterpenes that protect it from competitors and predators. However, of the many diterpenoids isolated from S. flexibilis, only sinulariolide has been studied for antibiotic properties. Samples of soft corals were collected from Orpheus Island and freeze-dried for chemical extraction and isolation of pure diterpenes. Antimicrobial activity of the diterpenes was determined using the disc assay method with antibiotics as controls and the minimum inhibitory concentrations of the diterpenes were determined using the Tube Dilution Technique. Two out of the five diterpenes tested (sinulariolide and flexibilide), showed marked antimicrobial activity and inhibited growth of Gram-positive bacteria. Flexibilide was effective even at concentrations as low as 5 ppm, whereas sinulariolide was effective at concentrations of 10 ppm. These compounds show potential as antibiotics.

Animals↗
PubMed2026

Biosynthesis of Crinipellin Diterpenes in Mushroom Marasmius fiardii PR-910.

Crinipellins are a distinctive family of 5/5/5/5 tetracyclic diterpenoids previously reported exclusively from mushrooms of the genus Crinipellis. Despite extensive synthetic studies, the biosynthetic machinery responsible for crinipellin formation has remained elusive. Here, we identify the crinipellin biosynthetic gene cluster (mfd) from the mushroom Marasmius fiardii PR-910, a member of the family Marasmiaceae to which Crinipellis also belongs, although M. fiardii PR-910 itself has not been previously reported to produce crinipellins. Using a combination of site-directed mutagenesis guided by an AlphaFold3-generated structural model, stable isotope-labeling studies, density functional theory (DFT) calculations, and ab initio molecular dynamics (AIMD) simulations, the cyclization mechanism of the diterpene synthase MfdB, which constructs the fused tetraquinane scaffolds 1 and 2, was elucidated. Mutagenesis of MfdB uncovered cryptic cyclization pathways that generate structurally diverse diterpenes, including unprecedented bridged and rearranged diterpene skeletons (4-6), whose formation is supported by computational analyses, and further revealed an unusual arginine-rich diphosphate-binding architecture. Heterologous expression studies in Aspergillus oryzae and Saccharomyces cerevisiae established the oxidative functions of the cytochrome P450 enzymes MfdC, MfdD, and MfdE, leading to the production of 19 previously undescribed oxidized metabolites (16-34). Notably, MfdE, a member of the largely unexplored CYP_FUM15-like subfamily, catalyzes an unusual oxidative demethylation through C-C bond cleavage, expanding the known catalytic repertoire of fungal cytochrome P450 enzymes. Collectively, this work establishes the biosynthetic logic of crinipellin formation, reveals how terpene synthase plasticity generates cryptic diterpene scaffolds, and demonstrates how oxidative tailoring by multiple cytochrome P450 enzymes drives diterpene scaffold diversification.

Diterpenes↗
PubMed2002

Semisynthesis of rosmanol and its derivatives. Easy access to abietatriene diterpenes isolated from the genus Salvia with biological activities.

The known diterpenes rosmanol (3), rosmaquinone (4), 7-methoxyrosmanol (5), 7-ethoxyrosmanol (6), galdosol (7), and epirosmanol (8) have been obtained by partial synthesis from carnosol (2), an abundant natural product present in Salvia species. The physical and spectroscopic data of these semisynthetic diterpenes were identical to those of authentic natural samples and with data reported in the literature. These abietane diterpenes have very interesting biological activities and are present in the genus Salviain low quantities; thus, the semisynthetic approach described here represents an efficient alternative method to obtain these compounds. Additionally, the known diterpene 16-hydroxyrosmanol (10) and a new aromatic diterpene 11 were obtained from 16-hydroxycarnosol (9) by reaction with Ph3P/NBS in CH2Cl2. The structure of the new compound 11 was established from its spectroscopic data as 12,16-epoxycarnosol.

Abietanes↗
PubMed1997

Diterpenes from coffee beans decrease serum levels of lipoprotein(a) in humans: results from four randomised controlled trials.

OBJECTIVE: Unfiltered coffee raises serum LDL cholesterol in humans, owing to the presence of the diterpenes cafestol and kahweol. Norwegians with a chronic high intake of unfiltered coffee also has elevated serum levels of lipoprotein(a), an LDL-like particle which is insensitive toward dietary interventions. We now experimentally studied the influence of coffee diterpenes on lipoprotein(a) levels. DESIGN: Four randomised controlled trials. SUBJECTS: Healthy, normolipidemic volunteers. INTERVENTIONS: Coffee, coffee oil, and pure diterpenes for 4-24 weeks. MAIN OUTCOME MEASURES: The circulating level of lipoprotein(a). RESULTS: In 22 subjects drinking five to six strong cups of cafetiere coffee per day, the median fall in lipoprotein(a) was 1.5 mg/dL after two months (P = 0.03), and 0.5 mg/dL after half a year (P > 0.05), relative to 24 filter coffee drinkers. Coffee oil doses equivalent to 10-20 cups of unfiltered coffee reduced lipoprotein(a) levels by up to 5.5 mg/dL (P < 0.05) in two separate trials (n = 12-16 per group). A purified mixture of cafestol and kahweol, as well as cafestol alone, were also effective in reducing Lp(a) levels (n = 10). Averaged over the four trials, each 10 mg/d of cafestol (plus kahweol)--the amount present in two to three cups of cafetiere coffee--decreased Lp(a) levels by 0.5 mg/dL or 4% from baseline values after four weeks (n = 63). CONCLUSIONS: Coffee diterpenes are among the few dietary exceptions shown to influence serum lipoprotein(a) levels. However, the Lp(a)-reducing potency of coffee diterpenes may subside in the long run, and their adverse side effects preclude their use as lipoprotein(a)-reducing agents.

Adult↗
PubMed2002

Antinociceptive and gastroprotective effects of diterpenes from the flower buds of Egletes viscosa.

Centipedic acid and 12-acetoxy-hawtriwaic acid lactone, diterpenes isolated from the flower buds of Egletes viscosa (Asteraceae) were assayed for antinociceptive and gastroprotective activities in animal models of nociception and gastric ulcer. In the chemical nociception induced in mice by intraperitoneal acetic acid and subplantar formalin injections, both diterpenes (25 and 50 mg/kg, p. o.) exerted potent antinociception in a manner similar to indomethacin (5 mg/kg, p. o.). In the formalin test, only the late phase nociceptive response (20 - 25 min) and not the early phase response (0 - 5 min) was inhibited by these diterpenes. However, these compounds were found to be ineffective against thermal nociception in the hot-plate test. Further, the diterpenes reduced the severity of absolute ethanol-induced gastric lesions in rats. At the dose of 50 mg/kg, both centipedic acid and 12-acetoxy hawtriwaic acid suppressed the gastric lesions by 53 % and 63 %, respectively. Against the gastric ulceration induced by indomethacin, only centipedic acid (25 and 50 mg/kg) showed significant inhibition by about 47 - 49 %. The data suggested the gastroprotective and peripheral analgesic properties of diterpenes isolated from E. viscosa.

Acetic Acid↗
PubMed2005

Effects of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis on HIV-1 reverse transcriptase.

It has been recently demonstrated that HIV-1 reverse transcriptase is the target of two diterpenes, (6 R)-6-hydroxydichotoma-3,14-diene-1,17-dial (compound 1) and (6 R)-6-acetoxydichotoma-3,14-diene-1,17-dial (compound 2), that inhibit HIV-1 replication in vitro. In this work, the effects of both diterpenes on the kinetic properties of the recombinant HIV-1 reverse transcriptase (RT) enzyme were evaluated. RNA-dependent DNA-polymerase (RDDP) activity assays demonstrated that both diterpenes behave as non-competitive inhibitors with respect to dTTP and uncompetitive inhibitors with respect to poly(rA).oligo(dT) template primers. The K(i) values obtained for compounds 1 and 2 were 10 and 35 microM, respectively. Neither of these diterpenes affected the DNA-dependent DNA-polymerase (DDDP) activity of the HIV-1 RT. The RDDP activities of AMV-RT and MMLV-RT enzymes were also inhibited by compounds 1 and 2. In contrast to the HIV-1 enzyme, the DDDP activities of AMV-RT and MMLV-RT enzymes were significantly reduced by compound 1. Taken together, our results demonstrate that compound 1 is a more effective inhibitor of the viral reverse transcriptases from HIV-1, AMV and MMLV than compound 2. The kinetic behavior analyses of the HIV-1 RT demonstrate that both diterpenes have similar mechanisms of inhibition of RDDP activity.

Anti-HIV Agents↗