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Compounds having nonlinear optical (NLO) characteristics have been proved to have a significant role in many academic and industrial areas; particularly, their leading role in surface interfaces, solid physics, materials, medicine, chemical dynamics, nuclear science, and biophysics is worth mentioning. In the present study, novel peptoids (1–4) were prepared in good yields via Ugi four-component reaction (Ugi-4CR). In addition to synthetic studies, computational calculations were executed to estimate the molecular electrostatic potential, natural bond orbital (NBO), frontier molecular orbital analysis, and NLO properties. The NBO analysis confirmed the stability of studied systems owing to containing intramolecular hydrogen bonding and hyperconjugative interactions. NLO analysis showed that investigated molecules hold noteworthy NLO response as compared to standard compounds that show potential for technology-related applications.

Cocona fruits are a popular food and medicinal fruit used mainly in the Amazon and several countries of South America for the preparation of several food products such as drinks, jams and milk shakes. In this study five ecotypes of cocona native to Peru have been studied regarding their nutritional and antioxidants values plus antihyperlipidemic activities. Seventy bioactive compounds have been detected in Peruvian cocona ecotypes including several phenolic acids, aminoacids and flavonoids; of those six were spermidines, (peaks 1, 2, 25, 26, 38 and 39), thirteen were aminoacids, (peaks 3,‐9, 11‐13, 16, 17, 22‐24), eighteen flavonoids (peaks 28, 30‐32 45,46, 48‐53 56, 57, 61 and 64‐66), twelve were phenolics (peaks 19, 21, 27, 29, 34, 35, 36, 42, 43, 44, 54, and 59), two carotenoids, (peak 62 and 63), eight were lipid derivatives (peaks 37, 55, 58, 60 and 67‐70), one sugar (peak 47), four terpenes (peaks 33, 40, 41 and 47), two amides, (peaks 10 and 18), one aldehyde, (peak 15), and three saturated organic acids, (peaks 4, 5 and 20). Hypercholesterolemic rats administered with pulp of the ecotypes CTR and SRN9 showed the lowest cholesterol and triglyceride levels after treatment (126.74 ± 6.63; 102.11 ± 9.47; 58.16 ± 6.64; 61.05 ± 4.00 mg/dL, for cholesterol, triglycerides, high‐density lipoprotein and low‐density lipoprotein respectively, for the group treated with SRN9 pulp, and 130.09 ± 8.55; 108.51 ± 10.04; 57.30 ± 5.72; and 65.41 ± 7.68 mg/dL, for cholesterol, triglycerides, HDL and LDL lipoproteins respectively for the group treated with CTR pulp). The ecotypes proved to be good sources of natural antioxidants and their consumption represent an alternative for the prevention of atherosclerosis. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Funding: This research was funded by the Project Concytec – Banco Mundial “Mejoramiento y Ampliación de los Servicios del Sistema Nacional de Ciencia Tecnología e Innovación Tecnológica” 8682, through its executing unit Fondecyt [Contrato N° 119‐2018‐FONDECYT‐BM‐IADT‐MU]. M. J. S acknowledge fondecyt 1180059.

Lycium minutifolium J. Remy (Solanaceae) is commonly used as an infusion in traditional medicine to treat stomach pain, meteorism, intestinal disorders, stomach ailments, and other severe problems including prostate cancer and stomach cancer. From the EtOAc extract of L. minutifolium bark five known metabolites were isolated using chromatographic techniques. The gastroprotective effects of the EtOAc fraction and edible infusion extract of the bark were assayed on the hydrochloric acid (HCl)/EtOH induced gastric ulcer model in mice to support the traditional use of the plant. The EtOAc extract and the edible infusion showed gastroprotective effect at dose of 100 mg/kg reducing lesions by 31% and 64%, respectively. The gastroprotective action mechanisms of the edible infusion at a single oral dose of 100 mg/kg were evaluated suggesting that prostaglandins, sulfhydryl groups, and nitric oxide are involved in the mode of gastroprotective action. The UHPLC analysis coupled to high-resolution mass spectrometry of the edible infusion showed the presence of twenty-three compounds. Our results can support the gastroprotective properties of the edible infusion extract, and at least can validate in part, the ethnopharmacological uses of the plant.

Myrtenal is a natural monoterpene isolated from essential oils of several plants and their derivates have shown to have several biological properties including cytotoxicity. The cytotoxic activity of these derivates are being investigated for their antitumor effect leading to the development of potential anticancer agents. In this study, novels Myrtenyl grafted pseudo-peptides were designed, synthesized and functionally characterized as possible therapeutic agents for cancer treatment. Thirteen novel Myrtenyl grafted pseudo-peptides were prepared in high atom economy and efficiency by a classic Ugi-4CR and sequential post-modification. Their structures were confirmed by NMR, and ESI-MS, and its cytotoxic activity was evaluated in three cancer cell lines and primary CD4+ T cells at different proliferative cycles. Our results revealed that some of these compounds showed significant cytotoxicity against human gastric, breast and colon adenocarcinoma cells lines, but not against human dermal fibroblast cell line. Moreover, from the thirteen novel myrtenyl synthesized the compound (1R,5S)-N-{[1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-N-[2-(cyclohexylamino)-2&ndash, oxoethyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carboxamide (3b) proved to be the best candidate in terms of acceptable EC50, and Emax values in cancer cell lines and at inducing cytotoxicity in CD4+ T cells undergoing active proliferation, without affecting non-proliferating T cells. Overall, the synthesis and characterization of our Myrtenyl derivates revealed novel potential anticancer candidates with selective cytotoxic activity.

A straightforward one-pot vs. stepwise esterification of lapachol was performed to obtain highly diversified heterocycles. Whereas the one-pot esterification leads to mono esterified lapachol, the stepwise approach generated benzo[h]chromene. Furthermore, benzo[h]chromene architectures with embedded triazole moieties were synthesized through late-stage functionalization of the benzo[h]chromene terminal alkyne moiety by copper catalyzed 1,3-dipolar cycloaddition (CuAAC) in a one-pot procedure.

A new library of twenty triazole-lapachol and nor-lapachol derivatives was synthesized. The compounds were evaluated against the epimastigotes form of Trypanosoma cruzi and promastigotes of Leishmania braziliensis and L. infantum. The cytotoxicity of the compounds was determined on murine fibroblasts and used to assess the selectivity index. The introduction of triazole rings in the naphthoquinone derivatives improved activity against the parasitic protozoa T. cruzi and Leishmania species. Some of the derivatives were three to six times more potent than benznidazole against T. cruzi, with similar or slightly better selectivity indexes. The results against L. braziliensis showed that the derivatives 5b and 5e were the most selective compounds. However, they were less selective than the reference compound, miltefosine. Among all products, the derivative 3a was the most selective compound against L. infantum. Nevertheless, it was less potent and less selective than miltefosine. Also, the minimum inhibitory concentration values of the derivatives against nine different bacteria were determined. Moderate antibacterial activity was observed for compound 5c against Staphylococcus aureus.

The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti-inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8%–57.4% and 0.0%–97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro-inflammatory enzymes, compared to the parent terpenes and non-steroidal anti-inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6–15 within COX-2 and 15-LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non-covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r 2 = 0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds. Fil: Theoduloz, Cristina. Universidad de Talca; Chile Fil: Alzate-Morales, Jans. Universidad de Talca; Chile Fil: Jiménez-Aspee, Felipe. Universidad de Talca; Chile Fil: Isla, Maria Ines. Universidad Nacional de Tucumán; Argentina. INBIOFIV; Argentina Fil: Alberto, Maria Rosa. Universidad Nacional de Tucumán; Argentina Fil: Pertino, Mariano Walter. Universidad de Talca; Chile Fil: Schmeda-Hirschmann, Guillermo. Universidad de Talca; Chile

Naturally occurring terpenes were combined by click reactions to generate sixteen hybrid molecules. The diterpene imbricatolic acid (IA) containing an azide group was used as starting compound for the synthesis of all the derivatives. The alkyne group in the terpenes cyperenoic acid, dehydroabietinol, carnosic acid &gamma, lactone, ferruginol, oleanolic acid and aleuritolic acid was obtained by esterification using appropriate alcohols or acids. The hybrid compounds were prepared by combining the IA azide function with the different terpene-alkynes under click chemistry conditions. The cytotoxic activity of the terpene hybrids 1&ndash, 16 was assessed against Vero cells and tumour cell lines (HEP-2, C6 and Raw 264.7). Compounds 1, 2, 3 and 7 showed cytotoxic activity against the tested cell lines. The antiviral activity of the compounds was evaluated against HSV-1 KOS, Field and B2006 strain. For the pairs of hybrid compounds formed between IA-diterpene (compounds 3&ndash, 8, except for compound 7), a moderate activity was observed against the three HSV-1 strains with an interesting selectivity index (SI &ge, 10, SI = CC50/CE50) for some compounds.

The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti-inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 µmol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 µmol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti-inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes.

Abietane diterpenes exhibit an array of interesting biological activities, which have generated significant interest among the pharmacological community. Starting from the abietane diterpenes carnosic acid and carnosol, twenty four new triazole derivatives were synthesized using click chemistry. The compounds differ in the length of the linker and the substituent on the triazole moiety. The compounds were assessed as antiproliferative and antifungal agents. The antiproliferative activity was determined on normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells while the antifungal activity was assessed against Candida albicans ATCC 10231 and Cryptococcus neoformans ATCC 32264. The carnosic acid γ-lactone derivatives 1–3 were the most active antiproliferative compounds of the series, with IC50 values in the range of 43.4–46.9 μM and 39.2–48.9 μM for MRC-5 and AGS cells, respectively. Regarding antifungal activity, C. neoformans was the most sensitive fungus, with nine compounds inhibiting more than 50% of its fungal growth at concentrations ≤250 µg·mL−1 . Compound 22, possessing a p-Br-benzyl substituent on the triazole ring,showed the best activity (91% growth inhibition) at 250 µg·mL−1 In turn, six compounds inhibited 50% C. albicans growth at concentrations lower than 250 µg·mL−1. Para citar este articulo: Pertino, M.W.; Theoduloz, C.; Butassi, E.; Zacchino, S.; Schmeda-Hirschmann, G. Synthesis, Antiproliferative and Antifungal Activities of 1,2,3-Triazole-Substituted Carnosic Acid and Carnosol Derivatives. Molecules 2015, 20, 8666-8686. Fil: Pertino, Mariano Walter. Universidad de Talca. Instituto de Química de Recursos Naturales; Chile. Fil: Theoduloz, Cristina. Universidad de Talca. Facultad de Ciencias de la Salud; Chile. Fil: Butassi, Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Farmacognosia; Argentina. Fil: Zacchino, Susana. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Farmacognosia; Argentina. Fil: Schmeda-Hirschmann, Guillermo. Universidad de Talca. Instituto de Química de Recursos Naturales; Chile.

The pathogenesis of many viral infections lies on the damage caused by the immune response against the virus. Current antiviral drugs do not act on the inflammatory component of the disease. Thus, new compounds that inhibit both viral multiplication and the immunopathology elicited by the virus are an approach that should be considered. In the present study, we identified two jatropholones (2A and 5B) and one carnosic acid derivative (9C) that significantly inhibited multiplication of TK+ and TK− strains of HSV-1 in Vero cells. Compounds 2A, 5B and 9C also prevented HSV-1- and TLRs-induced inflammatory response in cultivated murine macrophages. In macrophages infected with HSV-1, the inhibitory effect of compounds 2A, 5B and 9C on TNF-α and IL-6 production could be associated with the block of ERK pathway, whereas NF-κB pathway was not hampered by any of the compounds. Besides, 2A, 5B and 9C also inhibited ERK pathway and reduced TNF-α production in macrophages stimulated with TLR2, TLR4 or TLR9 agonists and were able to hinder IL-6 secretion after activation with TLR2 or TLR4, but not with TLR9. The immunomodulatory effect of 2A, 5B and 9C in macrophages infected with HSV-1 may be a consequence of the inhibition of ERK pathway activated by TLRs. The availability of compounds with both antiviral and immunomodulatory properties which affect TLR signaling pathways might be a useful strategy to control the progress of virus-induced disease. Fil: Bueno, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Michelini, Flavia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Pertino, Mariano Walter. Universidad de Talca; Chile Fil: Arredondo Gómez, Magda Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Schmeda Hirschmann, Guillermo. Universidad de Talca; Chile Fil: Alche, Laura Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Dehydroabietic acid (DHA) is a naturally occurring diterpene with different and relevant biological activities. Previous studies have shown that some DHA derivatives display antiproliferative activity. However, the reported compounds did not include triazole derivatives. Starting from DHA (8,11,13-abietatrien-18-oic acid), and its alcohol dehydroabietinol (8,11,13-abietatrien-18-ol), four alkyl esters were prepared. The alkyl terpenes were treated with different aromatic azides to synthesize hybrid compounds using click chemistry. Some 16 new DHA hybrids were thus synthesized and their structures were confirmed by spectroscopic and spectrometric means. The antiproliferative activity of the new compounds was assessed towards human cell lines, namely normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells. Better antiproliferative effect was found for compound 5, with an IC50 of 6.1 μM and selectivity on SK-MES-1 cells. Under the same experimental conditions, the IC50 of etoposide, was 1.83 µM.

New diterpenylquinones, combining a diterpene diacid and a naphthoquinone, were prepared from junicedric acid and lapachol. The new derivatives were assessed as gastroprotective agents by the HCl-EtOH-induced gastric lesions model in mice as well as for basal cytotoxicity on the following human cell lines: Normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). Several of the new compounds were significantly active as antiulcer agents and showed selective cytotoxicity against AGS cells.

Following our studies on the gastroprotective effect and cytotoxicity of terpene derivatives, new amides were prepared from the diterpene 8(17)-labden-15,19-dioic acid (junicedric acid) and its 8(9)-en isomer with C-protected amino acids (amino acid esters). The new compounds were evaluated for their gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice, as well as for cytotoxicity using the following human cell lines: normal lung fibroblasts (MRC-5), gastric adenocarcinoma cells (AGS) and liver hepatocellular carcinoma (Hep G2). A dose-response experiment showed that at 25 mg/kg the C-15 leucyl and C-15,19-dileucylester amides of junicedric acid reduced gastric lesions by about 65.6 and 49.6%, respectively, with an effect comparable to lansoprazole at 20 mg/kg (79.3% lesion reduction). The comparison of the gastroprotective effect of 18 new amino acid ester amides was carried out at a single oral dose of 25 mg/kg. Several compounds presented a strong gastroprotective effect, reducing gastric lesions in the 70.9-87.8% range. The diprolyl derivative of junicedric acid, the most active product of this study (87.8% lesion reduction at 25 mg/kg) presented a cytotoxicity value comparable with that of the reference compound lansoprazole. The structure-activity relationships are discussed.

Carnosic acid (1) has been shown to possess gastroprotective activity in vitro and in vivo. However, little is known of the gastroprotective effect or cytotoxicity of carnosic acid gamma-lactone (3). To determine structure-activity relationships, a series of 17 esters of 3 were prepared including aliphatic, aromatic, and heterocyclic derivatives. Also, two units of 3 were coupled with succinic and phthalic acid as linkers. The compounds were assessed for their gastroprotective effect in the HCl/EtOH-induced gastric lesions model in mice and for cytotoxicity in human lung fibroblasts, human adenocarcinoma AGS cells, and Hep G2 hepatocellular carcinoma cells. At a single oral dose of 40 mg/kg, the gastroprotective effect increased moderately with the length of the alkyl chain. The best effects were observed for the butyrate (9) and chloroacetate (6) derivatives. Activity of fatty acid esters increased with chain length but decreased with unsaturation. The best gastroprotective effect, with lowest cytotoxicity, was found for the palmitate (11) and oleate (12) derivatives.

From the aerial parts of a Chilean sample of Rosmarinus officinalis L., a diterpene was isolated whose spectroscopic data and physical constants were coincident with that of rosmaridiphenol. However, careful examination of the spectroscopic data and chemical reactions led to a different structure, where the carbonyl function has to be placed at C-1 instead of C-20. The correct structure of rosmaridiphenol should therefore be changed to 11,12-dihydroxy-8,11,13-icetexatrien-1-one.

Extracts from the Andean lichens Protousnea poeppigii and Usnea florida displayed antimicrobial activity against the pathogenic fungi Microsporum gypseum, Trichophyton mentagrophytes and T. rubrum with MIC values between 50 and 100 µg/mL. From the active extracts, four main metabolites were isolated and identified as the new depside, isodivaricatic acid, and the known metabolites 5-propylresorcinol, divaricatinic acid and usnic acid. Isodivaricatic acid and divaricatinic acid presented antifungal effect towards M. gypseum with a MIC of 50 µg/mL and against T. mentagrophytes and T. rubrum and with MIC values of 50 and 100 µg/mL, respectively. The new isodivaricatic acid was active towards Leishmania amazonensis, Leishmania brasiliensis and Leishmania infantum promastigotes with 100% lysis at 100 µg/mL. The activity of the new compound decreased on acetylation of the hydroxy groups as well as on methylation of the acid function. The structures were elucidated by spectroscopic means. The spectroscopic data of isodivaricatic acid are presented here for the first time. Copyright © 2007 John Wiley & Sons, Ltd.

Anew jatrophone derivative (6), jatrophone (3), jatropholone A (4) and jatropholone B (5), acetyl aleuritolic acid (1), cyperenoic acid (2) and a monoterpene were isolated from the rhizomes of the Paraguayan crude drug Jatropha isabelli. The compounds were characterized by spectroscopic means. The gastroprotective effect of jatrophone, jatropholone A and B as well as 9 beta,13 alpha-dihydroxyisabellione 6 and the triterpene 1 was assessed in the HCl/EtOH-induced gastric lesions model in mice. Jatrophone elicited a strong gastroprotective effect with no significant differences between 25, 50 or 100 mg/kg and reducing lesions from 88 to 93%. The jatropholones A and B showed remarkable differences in the gastroprotective assay. Jatropholone A presented a dose-related response, with maximum effect (54% lesion reduction) at the highest dose (100 mg/kg), jatropholone B showed a strong action at all the doses, reducing lesions by 83-91%. The cytotoxicity of the compounds was assessed towards fibroblasts and AGS cells. Jatrophone was toxic against both cell lines (IC50 values: 2.8 and 2.5 mu M, respectively). Jatropholone B (5) was not cytotoxic while jatropholone A (4) displayed a selective effect against AGS cells (IC50: 49 mu M). The relevance of stereochemistry in the biological effects is clear comparing the effect of jatropholone A and B against AGS cells, with IC50 values of 49 and g 1000 mu M for the beta and alpha C-16 isomers, respectively. The results provide scientific support for the use of qyagua rovaq as a gastroprotective crude drug in Paraguayan traditional medicine. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Tropical parasitic diseases such as Chagas disease and leishmaniasis are considered a major public health problem affecting hundreds of millions of people worldwide. As the drugs currently used to treat these diseases have several disadvantages and side effects, there is an urgent need for new drugs with better selectivity and less toxicity. Structural modifications of naturally occurring and synthetic compounds using click chemistry have enabled access to derivatives with promising antiparasitic activity. The antiprotozoal activity of the terpenes dehydroabietic acid, dehydroabietinol, oleanolic acid, and 34 synthetic derivatives were evaluated against epimastigote forms of Trypanosoma cruzi and promastigotes of Leishmaniabraziliensis and Leishmania infantum. The cytotoxicity of the compounds was assessed on NCTC-Clone 929 cells. The activity of the compounds was moderate and the antiparasitic effect was associated with the linker length between the diterpene and the triazole in dehydroabietinol derivatives. For the oleanolic acid derivatives, a free carboxylic acid function led to better antiparasitic activity.

Carnosic acid (CA) and its semisynthetic derivatives display relevant gastroprotective effects on HCl/ethanol induced gastric lesions in mice. However, little is known on the mechanisms of action of the new compounds. The aim of the present work was to assess the gastroprotective action mechanisms of CA and its derivatives using human cell culture models. A human gastric adenocarcinoma cell line (AGS) and lung fibroblasts (MRC-5) were used to reveal the possible mechanisms involved. The ability of the compounds to protect cells against sodium taurocholate (NaT)-induced damage, and to increase the cellular reduced glutathione (GSH) and prostaglandin E2 (PGE2) content was determined using AGS cells. Stimulation of cell proliferation was studied employing MRC-5 fibroblasts. Carnosic acid and its derivatives 10–18 raised GSH levels in AGS cells. While CA did not increase the PGE2 content in AGS cells, all derivatives significantly stimulated PGE2 synthesis, the best effect being found for the 12-O-indolebutyrylmethylcarnosate 13. A significant increase in MRC-5 fibroblast proliferation was observed for the derivatives 7 and 16–18. The antioxidant effect of the compounds was assessed by the inhibition of lipid peroxidation in human erythrocyte membranes, scavenging of superoxide anion and DPPH discoloration assay. The new CA derivatives showed gastroprotective effects by different mechanisms, including protection against cell damage induced by NaT, increase in GSH content, stimulation of PGE2 synthesis and cell proliferation.

Hybrid compounds are relevant products when searching for structure-activity relationships of natural products. Starting from the naturally occurring triterpene oleanolic acid, alkyl esters were prepared and treated with different aromatic azides using click chemistry to produce hybrid compounds. Some 18 new oleanolic acid derivatives were synthesized and the structures were confirmed by spectroscopic and spectrometric means. The antiproliferative activity of the new derivatives was evaluated towards normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), promyelocytic leukemia (HL-60), lung cancer (SK-MES-1) and bladder carcinoma (J82) cells. The alkyne esters 1 and 3 showed activity on all cell lines but without selectivity (19.6-23.1 μM and 14.1-56.2 μM, respectively), their respective methyl esters were inactive. Compounds with a benzene and p-anisole attached to the triazole ring, showed no antiproliferative effect. Introduction of a chlorine atom into the benzene ring (compound 9) elicited a selective effect against AGS cells (IC50 value: 8.9 μM). The activity was lost when the COOH function at C-28 was methylated. Better antiproliferative effect was found for compounds 11 and 15 bearing a p-toluenesulphonyl group, with values in the range of 10.8-47.1 μM and 11.5-22.2 μM, respectively. The effect, however, was not associated with selectivity.

Several diterpenes with the labdane skeleton show biological activity, including antiproliferative effects. Most of the research work on bioactive labdanes has been carried out on naturally occurring diterpenes and semisynthetic derivatives, but much less is known on the effects of diterpene dimers. The aim of the present work was to synthesize dimeric diterpenes from the labdane imbricatolic acid using esters, ethers and the triazole ring as linkers. Some 18 new derivatives were prepared and the compounds were evaluated for antiproliferative activity on human normal fibroblasts (MRC-5) and the following human tumor cell lines: AGS, SK-MES-1, J82 and HL-60. The diethers 8–10, differing in the number of CH2 units in the linker, presented better antiproliferative activity with a maximum effect for the derivative 9. The best antiproliferative effect against HL-60 cells was found for compounds 3 and 17, with IC50 values of 22.3 and 23.2 μM, lower than that found for the reference compound etoposide (2.23 μM). The compounds 9, 17 and 11 were the most active derivatives towards AGS cells with IC50 values of 17.8, 23.4 and 26.1 μM. A free carboxylic acid function seems relevant for the effect as several of the compounds showed less antiproliferative effect after methylation.

The stem bark of Tabebuia species and the rhizomes of Jatropha isabelii are used in Paraguayan traditional medicine to treat gastric lesions and as anti-inflammatory agents. The sesquiterpene cyperenoic acid obtained from J. isabelii has been shown to display a gastroprotective effect in animal models of induced gastric ulcers while the quinone lapachol shows several biological effects associated with the use of the crude drug. The aim of this work was to prepare hybrid molecules presenting a terpene and a quinone moiety and to obtain an assessment of the gastroprotective activity of the new compounds using human cell cultures (MRC-5 fibroblasts and AGS epithelial gastric cells). Eight compounds, including the natural products and semisynthetic derivatives were assessed for proliferation of MRC-5 fibroblasts, protection against sodium taurocholate-induced damage, prostaglandin E2 content, and stimulation of cellular-reduced glutathione synthesis in AGS cells. The following antioxidant assays were performed: DPPH discoloration, scavenging of the superoxide anion, and inhibition of induced lipoperoxidation in erythrocyte membranes. 3-Hydroxy-β-lapachone (3) and cyperenoic acid (4) stimulated fibroblast proliferation. Lapachol (1), dihydroprenyl lapachol (2), 3-hydroxy-β-lapachone (3), and lapachoyl cyperenate (6) protected against sodium taurocholate-induced damage in AGS cells. Lapachol (1) and dihydroprenyl lapachoyl cyperenate (7) significantly stimulated prostaglandin E2 synthesis in AGS cells. Compounds 3, 4, and 7 raised reduced glutathione levels in AGS cells. The hybrid compounds presented activities different than those of the starting sesquiterpene or quinones.

The correction of patented structure 1 of rosmaridiphenol, an antioxidant isolated from rosemary, Rosmarinus officinalis, was made recently. The correct structure is proposed as 11,12-dihydroxy-8,11,13-icetexatrien-1-one (2a) based on 2D NMR data. In order to further support the structure, this work reports the single-crystal X-ray analysis, the complete (1)H NMR assignment by full spin-spin simulation, and the absolute configuration of the diacetate 2b derived via vibrational circular dicroism measurements in comparison with density functional theory calculated data.

International audience; Starting from the diterpene (4S,9R,10R) methyl 18-carboxy-labda-8,13(E)-dien-15-oate (PMD) and its 8(9)-en isomer [PMD 8(9)-en], 11 amides were prepared and assessed for a gastroprotective effect in the ethanol/HCl-induced gastric lesions model in mice. Basal cytotoxicity of the compounds was determined on the following human cell lines: normal lung fibroblasts (MRC-5), gastric epithelial adenocarcinoma (AGS), and hepatocellular carcinoma (Hep G2). All compounds are described for the first time. At the single oral dose of 0.1 mg/kg, compounds 1, 10, and 11 presented a strong gastroprotective effect, at least comparable with that of the reference compound lansoprazole at 1 mg/kg, reducing gastric lesions by 76.7, 67.7, and 77.2 %, respectively. The leucyl amide methyl ester 3, tryptophanyl amide methyl ester 5, and benzyl amide 6 of PMD presented a selective basal cytotoxicity on Hep G2 cells with IC50 values of 136.8, 105.3, and 94.2 µM, respectively, while the IC50 values towards AGS cells were 439.5, 928.0, and 937.3 µM, respectively. The three compounds did not affect fibroblast viability with IC50 values > 1000 µM. Compounds 7, 8, 10, and 11 showed no toxic effect against the three selected cell lines.

Carnosic acid (CA) is the main phenolic diterpene of rosemary (Rosmarinus officinalis L., Lamiaceae) and presents gastroprotective effect in vitro and in vivo. To determine structure-activity relationships, seventeen esters and ethers of CA were prepared, comprising aliphatic, aromatic, and heterocyclic compounds. The naturally occurring 12-O-methylcarnosic acid (14) was also included in the study. The compounds were evaluated for their gastroprotective activity in the HCl/EtOH-induced gastric lesions model in mice, and for cytotoxicity in human adenocarcinoma AGS cells, Hep G2 hepatocellular carcinoma cells, and human lung fibroblasts. At 10 mg/kg, some of the CA derivatives (5, 8, 9, 12, 14, and 18) were more effective preventing gastric lesions than the reference compound lansoprazole at the same dose. The dibenzoate 9, diindoleacetate 12, and the derivative 18 showed the best gastroprotective effect combined with the lowest cytotoxicity.

The antiproliferative activity of the diterpenes jatropholone A and B, 16 semi-synthetic derivatives thereof, and that of jatrophone and its three derivatives was assessed on human cell cultures. The cells used comprised normal lung fibroblasts (MRC-5), gastric adenocarcinoma (AGS), leukemia (HL-60), lung cancer (SK-MES-1), and bladder carcinoma (J82). Jatropholone A ( 1) was inactive against all the tumor cell lines; however, its acetylation rendered a compound with antiproliferative activity. The epimeric jatropholone B ( 8) was active against all the cancer cell lines, and its derivatives presented different effects on the selected cell lines. While jatrophone ( 19) showed strong anticancer activity, its derivatives 9beta,13alpha-dihydroxyisabellione and 13alpha-hydroxy-9 beta-acetoxyisabellione were less active.

The gastroprotective effect of the diterpenes jatropholone A, jatropholone B and 16 semisynthetic derivatives was assessed in the HCl/ethanol-induced gastric lesion model in mice and the cytotoxicity was determined towards fibroblasts and AGS cells. In a dose-response study, jatropholone B reduced gastric lesions by 65% at 6 mg/kg and jatropholone A by 54% at 100 mg/kg. The jatropholone B derivatives 9 - 14 and the compounds 15 - 18 were compared at a single oral dose of 25 mg/kg while the jatropholone A derivatives 2 - 7 were assessed at 100 mg/kg. A decrease in gastroprotective activity was observed for the ether as well as for the ester derivatives of jatropholone B. The methyl and propyl ethers of jatropholone A were more gastroprotective than the natural product. The placement of an additional methyl group at C-2 in the jatropholone B derivatives led to a loss of selectivity, the methyl and propyl ethers lack a gastroprotective effect. Jatropholone B was not toxic towards AGS cells and fibroblasts. Jatropholone A was active only against AGS cells. The gastroprotective effect of the epimeric jatropholones was selective showing a higher effect for jatropholone B. These results further support that the stereochemistry of the methyl group at C-2 in the jatropholones plays a relevant role in preventing the gastric lesions in mice. The compounds 3, 5 - 7, 10 and 12 - 18 are described for the first time.

Biotransformation of the diterpene jatrophone (1) by Aspergillus niger ATCC 16404 afforded the new diterpene 9β -hydroxyisabellione (2). The compounds were characterized by spectroscopic analysis. The cytotoxicity of the compounds as IC₅₀ values on AGS and lung fibroblasts was 2.4 and 2.8 μM for compound 1 and 53.1 and 260 μM for 2, respectively. Microbial transformation of 1 into compound 2 strongly reduced the cytotoxicity and enhanced the selectivity against AGS cells.

The gastroprotective effect of the sesquiterpene cyperenoic acid and seven semi-synthetic derivatives was assessed in the HCl/ethanol-induced gastric ulcer model in mice. At doses of 25, 50 and 100 mg kg−1, cyperenoic acid showed a dose-dependent gastroprotective effect reducing the lesions by 45 and 75% at 50 and 100 mg kg−1, respectively. Seven derivatives of the sesquiterpene were prepared and their gastroprotective activity compared at 50 mg kg−1. The cytotoxicity of the compounds was evaluated in fibroblasts and AGS cells. At 50 mg kg−1, patchoulan-15-oic acid (compound 8) presented the best gastroprotective effect, reducing the gastric lesions by 86%, with a similar effect to lansoprazole at 20 mg kg−1. The gastroprotective effect of cyperenol, cyperenoic acid methyl ester and the ethylamide and butylamide from cyperenoic acid were in the same range, reducing the gastric lesions by 72–77%. Cyperenol and cyperenoic acid methyl ester, however, were more cytotoxic with IC50 (concentration that produces a 50% inhibitory effect) values of 44 and 75, 48 and 75 μM against AGS cells and fibroblasts, respectively. The best gastroprotective effect with lower cytotoxicity was found for the compound 8, cyperenoic acid and the p-anisidyl derivative 7.

Biotransformation of the diterpene jatrophone (1) by Aspergillus niger ATCC 16404 afforded the new diterpene 9β -hydroxyisabellione (2). The compounds were characterized by spectroscopic analysis. The cytotoxicity of the compounds as IC50 values on AGS and lung fibroblasts was 2.4 and 2.8 μM for compound 1 and 53.1 and 260 μM for 2, respectively. Microbial transformation of 1 into compound 2 strongly reduced the cytotoxicity and enhanced the selectivity against AGS cells.