Comparison of the gastroprotective effect of a diterpene lactone isolated from Croton cajucara with its synthetic derivatives

The effect of three new derivatives from dehydrocrotonin (DHC-compound I) on gastric damage indifferent animal models including gastric ulceration induced by a necrotic agent and hypothermic restrained-stress was studied: compound 11 (produced by reducing the cyclohexenone moiety of DHC with NaBH4): compound III (produced by reducing the carbonyls with LiAlH4); and compound IV (produced by transforming the lactone moiety into an amide). Their structures were confirmed on the basis of chemical and physicochemical evidence. When previously administered (p.o.) at a dose of 100 mg/kg, compound II significantly (P < 0.01) reduced gastric injury induced by HCl/ethanol (78%) and indomethacin (88%) better than did reference compound 1 (48 and 43%, respectively). But the anti-ulcerogenic activity of compound II was completely abolished by the stress-induced ulcer. Reduction of carbonyls with LiAlH4 (compound 111) caused decreased activity, markedly when no protective effect in any of the models was applied (P > 0.05). However, compound IV, in which the lactone moiety was changed into an amide. when administered at the same dose (100 mg/kg, p.o.), was more effective. The presence of a lactone moiety or Michael acceptor is probably essential for the anti-ulcerogenic effect of these compounds. (C) 2003 Elsevier B.V. Ireland Ltd. All rights reserved.

Jatrowediol, a lathyrane diterpene from Jatropha weddelliana

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

New tetra-acetylated oligosaccharide diterpene from Cupania vernalis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Jatrowedione, a lathyrane diterpene from Jatropha weddelliana

3-Acetylaleuritolic acid, sitosterol and a novel lathyrane diterpene, jatrowedione, have been isolated from the roots of Jatropha weddelliana. The elucidation of the structure of the latter was accomplished by detailed NMR investigation, and the relative configuration was established by difference NOE experiments. (C) 1998 Published by Elsevier B.V. Ltd. All rights reserved.

Diterpene esters of aristolochic acids from Aristolochia pubescens

From the acetone and ethanol extracts of the tubercula of Aristolochia pubescens, two diterpene esters of aristolochic acids were isolated, together with 23 known compounds. The structures of the compounds were determined on the basis of spectroscopic analysis. (C) 2003 Elsevier Ltd. All rights reserved.

Natural trans-crotonin: the antiulcerogenic effect of another diterpene isolated from the bark of Croton cajucara Benth.

The nor-clerodane diterpene trans-crotonin isolated from the bark of Croton cajucara BENTH. was investigated for its ability to prevent the formation of gastric-mucosa ulceration in different experimental models in mice. The results obtained from crotonin were compared with those obtained with another diterpene, DHC (trans-dehydrocrotonin) in the same models. When previously administered (p.o.) at the dose of 100 mg/kg, crotonin, as well as DHC, significantly reduced (p<0.05) gastric injury induced by stress (72, 67%), indomethacin/bethanechol (78, 29%) and pylorus ligature (35, 30%). In the HCl/ethanol-induced gastric ulcer model, at oral doses of 100 and 250 mg/kg, crotonin significantly prevented (p<0.05) the formation of gastric lesions by 51 and 56%, respectively, when compared to the control group. Gastric injury was also of significantly less magnitude in the DHC treatment group (p<0.05). In the pylorus-ligature model, crotonin (p.o.), like cimetidine, increased the volume of gastric juice when compared to the control group (p<0.05). No significant modifications where found in gastric parameters such as pH or total acid content after oral crotonin treatment. However, systemic alterations were observed when crotonin (100 mg/kg) was previously administered intraduodenally to mice. We observed significant changes (p<0.001) in gastric-juice parameters such as an increase in volume and a decrease in gastric acidity. Those pre-treated with crotonin as well as with DHC did not increase free mucus production (p>0.05). The results suggest that crotonin presents a significant anti-ulcer effect when assessed in these ulcer-induced models. As with DHC, the antiulcerogenic effects of crotonin are probably related to anti-secretory or/and gastroprotective properties of this substance. In light of results obtained with DHC and natural trans-crotonin in the present study, we concluded that the A-ring of both diterpenes is not directly involved in the antiulcerogenic activity.

Investigation of anti-inflammatory and antinociceptive activities of trans-dehydrocrotonin, a 19-nor-clerodane diterpene from Croton cajucara .1.

The anti-inflammatory and antinociceptive effects of trans-dehydrocrotonin, isolated from the bark of Croton cajucara (Euphorbiaceae), were investigated using several animal models. The trans-dehydrocrotonin produced a significant inhibition of carrageenin-induced paw edema and cotton pellet granuloma in rats. It also inhibited the writhings in mice induced by acetic acid, but did not show a significant effect in the hot-plate test in mice. The LD(50) of t-DCTN was 555.0 mg/kg (p.o.) for mice.

A new ent-kaurane diterpene from stems of Alibertia macrophylla K. Schum. (Rubiaceae)

Phytochemical investigations of the stems of a specimen of Alibertia macrophylla led to the isolation and characterization of the new diterpene ent-kaurane-2β,3α,16α-triol (1), along with triterpenes 2-8, iridoids 9-12, and phenolic acids 13-15. The structure of 1 was established based on spectroscopic studies (1H- and 13C-NMR, IR, and HR-ESI-MS). This is the first report of the isolation of a diterpene from the Alibertia genus in Rubiaceae. © 2007 Verlag Helvetica Chimica Acta AG.

Assessment of the chemopreventive effect of casearin B, a clerodane diterpene extracted from Casearia sylvestris (Salicaceae)

Studies have shown that Casearia sylvestris compounds protect DNA from damage both in vitro and in vivo. Complementarily, the aim of the present study was to assess the chemopreventive effect of casearin B (CASB) against DNA damage using the Ames test, the comet assay and the DCFDA antioxidant assay. The genotoxicity was assessed by the comet assay in HepG2 cells. CASB was genotoxic at concentrations higher than 0.30μM when incubated with the FPG (formamidopyrimidine-DNA glycosylase) enzyme. For the antigenotoxicity comet assay, CASB protected the DNA from damage caused by H2O2 in the HepG2 cell line in concentrations above 0.04μM with post-treatment, and above 0.08μM with pre-treatment. CASB was not mutagenic (Ames test) in TA 98 and TA 102. In the antimutagenicity assays, the compound was a strong inhibitor against aflatoxin B1 (AFB) in TA 98 (>88.8%), whereas it was moderate (42.7-59.4%) inhibitor against mytomicin C (MMC) in TA 102. Additionally, in the antioxidant assay using DCFDA, CASB reduced reactive oxygen species (ROS) generated by H2O2. In conclusion, CASB was genotoxic to HepG2 cells at high concentrations; was protective of DNA at low concentrations, as shown by the Ames test and comet assay; and was also antioxidant. © 2012 Elsevier Ltd.

The semi-synthetic kaurane ent-16 alpha-methoxykauran-19-oic acid induces vascular relaxation and hypotension in rats

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Antiulcerogenic effect and cytotoxic activity of semi-synthetic crotonin obtained from Croton cajucara Benth.

Trans-dehydrocrotonin, the major diterpene isolated from the bark of Croton cajucara, has good antiulcerogenic activity which, however, is accompanied by toxic effects. on the basis of these results, a semi-synthetic crotonin, named 4SRC, was prepared to determine whether this substance has similar antiulcerogenic activity with lower or no toxicity. The natural crotonin was also isolated from the bark of C. cajucara but was not used due to the small amount obtained. The cytotoxic effect of semi-synthetic crotonin, expressed as cell viability, was assessed in (a) lung fibroblast cell line (V79) derived from Chinese hamsters, a system commonly used for cytotoxicity studies, and (b) rat hepatocytes isolated from male Wistar rats. After treatment, cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction (MTT reduction), total acid content and neutral red uptake assays. To evaluate V79 cell viability, different concentrations of semi-synthetic crotonin were incubated with the cells. To evaluate the antiulcerogenic effects of semi-synthetic crotonin (50, 100 and 200 mg/kg), we used the models of gastric ulcer induced by ethanol/HCl, stress, indomethacin/bethanechol, and ethanol in male Swiss mice and male Wistar rats. The substance had an IC50 = 500 muM in the neutral red uptake and MTT reduction tests and an IC50 = 200 muM in the nucleic acid content test. With regard to hepatocyte viability after treatment with semi-synthetic crotonin at different concentrations, semi-synthetic crotonin had an IC50 = 10-500 muM in the nucleic acid content and MTT reduction tests and an IC50 = 120 muM in the neutral red uptake test. In another experiment, V79 cells were incubated with the metabolites produced by hepatocytes treated with different concentrations of semi-synthetic crotonin. After a 4-h incubation, semi-synthetic crotonin had an IC50 = 500 muM in the MTT reduction and neutral red uptake tests and an IC50 = 370 muM in nucleic acid content test. The substance had significant antiulcerogenic activity in all models studied, suggesting the presence of a possible antisecretory effect combined with a cytoprotective effect. For this reason, the effect of semi-synthetic crotonin was also evaluated on biochemical parameters of gastric juice and gastric wall mucus, both obtained from pylorus-ligated mice. No significant differences were observed in these parameters between semi-synthetic crotonin-treated and control animals. The results obtained with semi-synthetic crotonin are promising, with a significant preventive effect against gastric ulcer induced by different agents. Our data also show that semi-synthetic crotonin was less toxic than dehydrocrotonin and that the cytotoxic effects decreases with the time that isolated hepatocytes were in culture. (C) 2003 Elsevier B.V. B.V. All rights reserved.

Effect of essential oil obtained from Croton cajucara Benth. on gastric ulcer healing and protective factors of the gastric mucosa

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Chemopreventive activity of compounds extracted from Casearia sylvestris (Salicaceae) Sw against DNA damage induced by particulate matter emitted by sugarcane burning near Araraquara, Brazil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ethanolic extract of Casearia sylvestris and its clerodane diterpen (caseargrewiin F) protect against DNA damage at low concentrations and cause DNA damage at high concentrations in mice's blood cells

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)