A review on the ecotoxicity of macrocyclic lactones and benzimidazoles on aquatic organisms.

Despite its wide production and several applications, veterinary antiparasitics from macrocyclic lactones and benzimidazole classes have not received much scientific attention concerning their environmental risks. Thus, we aimed to provide insights into the state of the environmental research on macrocyclic lactone and benzimidazole parasiticides, emphasizing their toxicity to non-target aquatic organisms. We searched for relevant information on these pharmaceutical classes on PubMed and Web of Science. Our search yielded a total of 45 research articles. Most articles corresponded to toxicity testing (n = 29), followed by environmental fate (n = 14) and other issues (n = 2) of selected parasiticides. Macrocyclic lactones were the most studied chemical group (65% of studies). Studies were conducted mainly with invertebrate taxa (70%), with crustaceans being the most predominant group (n = 27; 51%). Daphnia magna was the most used species (n = 8; 15%). Besides, it also proved to be the most sensitive organism, yielding the lowest toxicity measure (EC50 0.25 µg/L for decreased mobility after 48 h-abamectin exposure) reported. Moreover, most studies were performed in laboratory settings, tracking a limited number of endpoints (acute mortality, immobility, and community disturbance). We posit that macrocyclic lactones and benzimidazoles warrant coordinated action to understand their environmental risks.

Gamma-Decanolactone Alters the Expression of GluN2B, A1 Receptors, and COX-2 and Reduces DNA Damage in the PTZ-Induced Seizure Model After Subchronic Treatment in Mice.

Gamma-decanolactone (GD) has been shown to reduce epileptic behavior in different models, inflammatory decreasing, oxidative stress, and genotoxic parameters. This study assessed the GD effect on the pentylenetetrazole (PTZ) model after acute and subchronic treatment. We evaluated the expression of the inflammatory marker cyclooxygenase-2 (COX-2), GluN2B, a subunit of the NMDA glutamate receptor, adenosine A1 receptor, and GD genotoxicity and mutagenicity. Male and female mice were treated with GD (300 mg/kg) for 12 days. On the tenth day, they were tested in the Hot Plate test. On the thirteenth day, all animals received PTZ (90 mg/kg), and epileptic behavior PTZ-induced was observed for 30 min. Pregabalin (PGB) (30 mg/kg) was used as a positive control. Samples of the hippocampus and blood were collected for Western Blotting analyses and Comet Assay and bone marrow to the Micronucleus test. Only the acute treatment of GD reduced the seizure occurrence and increased the latency to the first stage 3 seizures. Males treated with GD for 12 days demonstrated a significant increase in the expression of the GluN2B receptor and a decrease in the COX-2 expression. Acute and subchronic treatment with GD and PGB reduced the DNA damage produced by PTZ in males and females. There is no increase in the micronucleus frequency in bone marrow after subchronic treatment. This study suggests that GD, after 12 days, could not reduce PTZ-induced seizures, but it has been shown to protect against DNA damage, reduce COX-2 and increase GluN2B expression.

Effect of macrocyclic lactones on nontarget coprophilic organisms: a review.

Macrocyclic lactones are frequently used dewormers in livestock farms around the world. Due to their wide spectrum of action against nematodes and arthropods and their practicality of application at very low doses, their use has become massive since their discovery. These compounds are eliminated in a large percentage in the feces of animals, causing adverse effects on coprophilic fauna. Several research groups around the world have been devoted to evaluating these effects on this fauna. The aim of this review is to register the adverse effects of the concentrations in which macrocyclic lactones are eliminated in the feces of domestic animals and the importance of the coprophilic and edaphilous fauna on the degradation of the feces of the animals. The documented data shows that the use of macrocyclic lactones has a high toxicological risk for the different species that colonize the dung, thus causing an adverse effect on its disintegration and its subsequent incorporation into the soil. Even so, more studies at the regional level and their standardization are necessary to make the comparison between different areas possible.

Gamma-hexalactone flavoring causes DNA lesion and modulates cytokines secretion at non-cytotoxic concentrations.

BACKGROUND: The γ-hexalactone is a flavoring agent for alcoholic beverages, teas, breads, dairy products, coffees, buttery products among others. It presents low molecular weight and exhibits sweet fruity aroma with nuances of nuts. As far as we know, both literature and government regulations have gaps regarding the safe use of the γ-hexalactone. In this context, the main objective of this work was to evaluate the effects of γ-hexalactone through in silico and in vitro approaches. METHODS: The in silico analysis was performed through four free online platforms (admetSAR, Osiris Property Explorer®, pkCSM platform and PreADMET) and consisted of comparative structural analysis with substances present in databases. The computational prediction was performed in the sense of complement and guide the in vitro tests. Regarding in vitro investigations, screening of cytotoxicity (assessed by cell proliferation and viability parameters) in lymphocytes exposed to γ-hexalactone for 72 h were carried out previously to determine non-cytotoxic concentrations. Following this screening, concentrations of 5.15, 0.515, and 0.0515 µM were selected for the study of the respective potentials: genotoxic (assessed by DNA comet assay), chromosomal mutation (analysis of micronucleus frequency) and immunomodulatory (cytokine quantification using ELISA immunoassay). The results of in vitro assays were compared by one-way analysis of variance (ANOVA), followed by Bonferroni's post hoc test, conducted by statistic software. RESULTS: The platform PreADMET pointed out that γ-hexalactone is potentially mutagenic and carcinogenic. The comet assay data corroborate with these results demonstrating that γ-hexalactone at 5.15 µM caused lymphocytes DNA damage. In relation to cytokine secretion, the results indicate that lymphocytes were activated by γ-hexalactone at non-cytotoxic concentrations, involving an increase in the IL-1 levels in all tested concentrations, ranging from approximately 56 to 93%. The γ-hexalactone only at 5.15 µM induced increase in the levels of IL-6 (~ 60%), TNF-α (~ 68%) and IFN-γ (~ 29%), but decreased IL-10 (~ 46%) in comparison with the negative control (p < 0.05). No change was observed in total lymphocytes or in cell viability at the concentrations tested. CONCLUSIONS: In summary, the γ-hexalactone demonstrated immunomodulatory and genotoxic effects at non-cytotoxic concentrations in healthy lymphocytes.

Structure-based design of δ-lactones for new antifungal drug development: susceptibility, mechanism of action, and toxicity.

Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.

Evaluation of 1,3-benzoxathiol-2-one Derivatives as Potential Antifungal Agents.

BACKGROUND: Over the last few years, fungal infections have emerged as a worrisome global public health problem. Candidiasis is a disease caused by Candida species and has been a problem worldwide mainly for immunosuppressed patients. Lately, the resistant strains and side effects have been reported as important issues for treating Candidiasis, which have to be solved by identifying new drugs. OBJECTIVE: The goal of this work was to synthesize a series of 1,3-benzoxathiol-2-one derivatives, XYbenzo[ d][1,3]oxathiol-2-ones, and evaluate their antifungal activity against five Candida species. METHODS: In vitro antifungal screening test and minimum inhibitory concentration determination were performed according to CLSI protocols using ketoconazole as the reference drug. The cytotoxicity of the most active compounds was evaluated by hemolysis and MTT (Vero cells) assays. RESULTS: Compounds 2 (XY = 6-hydroxy-5-nitro, MIC = 4-32 µg/mL) and 7 (XY = 6-acetoxy-5-nitro, MIC =16-64 µg/mL) showed good results when compared with current antifungals in CLSI values (MIC = 0.04-250 µg/mL). These compounds exhibited a safer cytotoxicity as well as a lower hemolytic profile than ketoconazole. CONCLUSION: Overall, the in vitro results pointed to the potential of compounds 2 and 7 as new antifungal prototypes to be further explored.

Toxicity of squamocin on Aedes aegypti larvae, its predators and human cells.

BACKGROUND: The mosquito Aedes aegypti transmits a virus that causes diverse human diseases, and control of the vector is an important strategy to avoid disease propagation. Plants in the family Annonaceae are recognised as sources of molecules with uses in the medical and agriculture fields. Molecules of secondary metabolites of Annonaceae plants exhibit insecticidal potential against insect pests and vectors, especially acetogenins, showing high toxicity at low doses, which has encouraged research into producing new insecticide molecules. Herein, we identify an acetogenin from Annona mucosa seeds (chemical analysis) and provide the results of toxicity tests against larvae of A. aegypti (target insect) and its predators Culex bigoti and Toxorhynchites theobaldi (non-target insects) and cytotoxicity to human leukocytes. RESULTS: We identified squamocin (C37 H66 O7 ), a fatty acid with a bis-tetrahydrofuran ring. In A. aegypti, this compound caused behavioural disturbance before larval death and high mortality at low concentrations (LC50 = 0.01 µg mL-1 and LC90 = 0.11 µg mL-1 ). However, in predators and human leukocytes, squamocin showed no toxicity effect, indicating the selectivity of this molecule for non-target organisms. CONCLUSION: We identified squamocin from A. mucosa seeds, which exhibited lethal action against A. aegypti and showed selectivity for non-target insects and low cytotoxicity to human cells. © 2016 Society of Chemical Industry.

Polymatin A from Smallanthus macroscyphus leaves: A safe and promising antidiabetic compound.

Smallanthus macroscyphus is an herb native to South America whose leaves are a source of antidiabetic compounds, although complete information about their safe use is not available yet. This study was developed to evaluate the toxicity profile of both 10% decoction and the sesquiterpene lactone polymatin A from S. macroscyphus leaves through in vitro cytotoxicity assays and in vivo subchronic oral toxicity. Cell viability of Hep-G2, COS1, CHO-K1 and Vero cell lines decreased in a concentration-dependent manner when cells were incubated with 0.4-200 µg ml(-1) of dry extract or 0.12-60 µg ml(-1) of polymatin A. In subchronic studies, decoction was orally administered to Wistar rats for 90 days at daily doses of 70, 140 and 280 mg kg(-1) of dry extract, whereas polymatin A was administered in the same way at doses of 7, 14 and 28 mg kg(-1) . No toxicity signs or deaths were observed. There were no changes in the behavior, body or organ weights, hematological, biochemical or urine parameters of the rats. No histopathological lesions were observed in the examined organs. The results indicate that the 10% decoction and polymatin A from S. macroscyphus leaves may be considered as non-toxic substances at a wide range of doses, including the effective hypoglycemic dose. Copyright © 2016 John Wiley & Sons, Ltd.

In vitro and in vivo antileishmania activity of sesquiterpene lactone-rich dichloromethane fraction obtained from Tanacetum parthenium (L.) Schultz-Bip.

The discovery of new treatments for neglected diseases, including leishmaniasis, is a substantial challenge for scientific research. Plant extracts have shown potential in the selective treatment of tropical diseases. The present study evaluated the in vitro and in vivo antileishmania effects of a sesquiterpene lactone-rich dichloromethane fraction (DF) obtained from the aerial parts of Tanacetum parthenium (L.) Schultz-Bip. In vitro studies of the DF indicated an IC50 of 2.40±0.76 µg mL(-1) against the promastigote form and 1.76±0.25 µg mL(-1) against the axenic amastigote form of Leishmania amazonensis. In vivo intramuscular treatment with DF decreased the growth and size of footpad lesions in mice. The DF also significantly decreased the parasite population compared with animals that were treated with the reference drug. Plasma malondialdehyde levels were increased slightly by the DF, attributable to its parthenolide-rich composition that causes cellular apoptosis, compared with the control group, demonstrating treatment efficacy without toxicity or genotoxicity. Because the isolation and purification of plant compounds are costly and time-consuming and generate low yields, extract fractions, such as the DF studied herein, represent a promising alternative for the treatment of leishmaniasis.

Evaluation of the genotoxic activity of ethanol extract and secondary metabolites isolated from Aiouea trinervis Meisn. (Lauraceae).

Aiouea trinervis Meisn. is a shrub that grows in the "Cerrado" (a savanna ecosystem) of Brazil. In this study, fractionation of ethanol extracts (EEs) from the leaves of A. trinervis led to the isolation of butanolides, namely isoobtusilactone A and obtusilactone A, as well as lignans, namely sesamin, methylpiperitol, and polyprenol-12. Their structures were determined by spectroscopic analyses. The genotoxic properties were evaluated for mutagenic and recombinogenic effects using the wing spot test (somatic mutation and recombination test, SMART) on Drosophila melanogaster. The standard and high bioactivation crosses were used. The latter cross is characterized by high sensitivity to promutagens and procarcinogens. EEs were evaluated at concentrations of 0.625, 1.25, and 2.5 mg/mL. Butanolides (isoobtusilactone A and obtusilactone A) were evaluated at concentrations of 0.1, 0.2, and 0.3 mg/mL. The results observed in both crosses were similar and indicated that EEs from the leaves of A. trinervis did not show genotoxicity at the doses that were used. However, the individuals resulting from standard and high bioactivation crosses that were treated with isoobtusilactone A and obtusilactone A showed statistically significant increases in mutant spots compared to those that were obtained in the negative control. Similar results were obtained between standard and high bioactivation crosses, indicating that butanolides had a genotoxic activity.

Genotoxic evaluation of the antimalarial drugs artemisinin and artesunate in human HepG2 cells and effects on CASP3 and SOD1 gene expressions.

The malaria treatment recommended by the World Health Organization involves medicines derived from artemisinin, an active compound extracted from the plant Artemisia annua, and some of its derivatives, such as artesunate. Considering the lack of data regarding the genotoxic effects of these compounds in human cells, the objective of this study was to evaluate the cytotoxicity and genotoxicity, and expressions of the CASP3 and SOD1 genes in a cultured human hepatocellular liver carcinoma cell line (HepG2 cells) treated with artemisinin and artesunate. We tested concentrations of 2.5, 5, 7.5, 10, and 20 µg/mL of both substances with a resazurin cytotoxicity assay, and the concentrations used in the genotoxicity experiments (2.5, 5, and 10 µg/mL) and gene expression analysis (5 µg/mL) were determined. The results of the comet assay in cells treated with artemisinin and artesunate showed a significant dose-dependent increase (P < 0.001) in the number of cells with DNA damage at all concentrations tested. However, the gene expression analysis revealed no significant change in expression of CASP3 or SOD1. Our data showed that although artemisinin and artesunate exhibited genotoxic effects in cultured HepG2 cells, they did not significantly alter expression of the CASP3 and SOD1 genes at the doses tested.

Repeated-dose toxicological studies of Tithonia diversifolia (Hemsl.) A. gray and identification of the toxic compounds.

ETHNOPHARMACOLOGICAL RELEVANCE: Tithonia diversifolia (Hemsl.) A. Gray has been commonly used in folk medicine to treat abscesses, microbiological infections, snake bites, malaria and diabetes. Both anti-inflammatory and anti-malarial properties have been identified using appropriate assays, but the effective doses have demonstrated toxic effects for the experimental animals. Most of the pharmacological activities have been attributed to sesquiterpene lactones (STLs) and some chlorogenic acid derivatives (CAs) in the leaves of this species. This work aimed to evaluate the repeated-dose toxicity of an aqueous extract (AE) from Tithonia diversifolia leaves and to compare the results with an extract rich in STLs (LRE) and a polar extract (PE) without STLs but rich in CAs. The purpose of this work was to provide insights into the identity of the compounds responsible for the toxic effects of Tithonia diversifolia. MATERIALS AND METHODS: The major classes of compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling using previously isolated or standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days. RESULTS: The AE is composed of both STLs and CAs, the LRE is rich in STLs, and the PE is rich in CAs. The AE caused alterations in haematological parameters but few alterations in biochemical parameters and was relatively safe at doses lower than 100mg/kg. However, the PE and LRE demonstrated several adverse effects by damaging the liver and kidneys, respectively. CONCLUSION: STLs and CAs can be toxic in prolonged use at higher doses in extracts prepared from Tithonia diversifolia by affecting the kidneys and liver.

Safety assessment of aqueous extract from leaf Smallanthus sonchifolius and its main active lactone, enhydrin.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaves of Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson (yacon) have been used since pre-Columbian times in the Andean region to prepare medicinal herbal tea with beneficial health properties. However, there are still disagreements about the safe use. This work was carried out to evaluate the toxicity profile of both, 10% decoction of yacon leaves and their major active lactone, enhydrin. MATERIALS AND METHODS: In vitro cytotoxicity assays were performed with Hep-G2, COS1, CHO-K1 and Vero cell lines using a test of metabolic competence based upon assessment of mitochondrial performance. In vivo toxicity study was performed in adult Wistar rats. In the acute oral toxicity each group of rats was orally given a single dose of 10% decoction or enhydrin. General condition, behavior and mortality were recorded for up to 14 days post treatment. In subchronic toxicity studies, both products were given orally for 90 days to rats. Body weight and food intakes were observed weekly. Hematological, clinical chemistry parameters and organ weight were determined in all animals at the end of the experimental period. RESULTS: Cell viability decreased in a concentration dependent fashion when cells were incubated with 2-200 µg of 10% decoction and 0.015-7.5 µg of enhydrin. In acute study in rats, there were no deaths or signs of toxicity observed after oral administration of single doses of 10% decoction or enhydrin at any dose level up to the highest dose tested (14.0 g/kg and 0.32 g/kg, respectively). In subchronic studies in rats, both products administered orally for 90 days at daily doses of 0.07, 0.14 and 0.28 g 10% decoction/kg and 0.4, 0.8 and 8.0 mg enhydrin/kg, did not caused haematological, biochemical and histological alterations. CONCLUSIONS: The results presented in this paper lead us to the conclusion that the use of 10% decoction and enhydrin is safe in rat at doses in which it is demonstrated the hypoglycaemic effect.

Microbial transformation of the sesquiterpene lactone tagitinin C by the fungus Aspergillus terreus.

The biotransformation of the sesquiterpene lactone tagitinin C by the fungus Aspergillus terreus MT 5.3 yielded a rare derivative that was elucidated by spectrometric methods. The fungus led to the formation of a different product through an unusual epoxidation reaction between C4 and C5, formation of a C3,C10 ether bridge, and a methoxylation of the C1 of tagitinin C. The chemical structure of the product, namely 1ß-methoxy-3α-hydroxy-3,10ß-4,5α-diepoxy-8ß-isobutyroyloxygermacr-11(13)-en-6α,12-olide, is the same as that of a derivative that was recently isolated from the flowers of a Brazilian population of Mexican sunflower (Tithonia diversifolia), which is the source of the substrate tagitinin C. The in vitro cytotoxic activity of the substrate and the biotransformed product were evaluated in HL-60 cells using an MTT assay, and both compounds were found to be cytotoxic. We show that soil fungi may be useful in the biotransformation of sesquiterpene lactones, thereby leading to unusual changes in their chemical structures that may preserve or alter their biological activities, and may also mimic plant biosynthetic pathways for production of secondary metabolites.

Assessment of the mutagenic, recombinagenic and carcinogenic potential of orlistat in somatic cells of Drosophila melanogaster.

In this study the mutagenic, recombinagenic, carcinogenic and anticarcinogenic potential of orlistat was assessed using the somatic mutation and recombination test (SMART) and the epithelial tumor detection test (wts). The experiments were conducted on Drosophila melanogaster. In the assessment using SMART, larvae, descendants from the standard (ST) cross and the high bioactivation (HB) cross, were treated chronically with three orlistat concentrations. The results revealed a recombinagenic effect, associated with orlistat, in the descendants of the HB cross, at all three levels of concentration. Homologous recombination can function as a determinant at different stages of carcinogenesis. For verification, larvae from the wts test, descendants of the wts/TM3 virgin female and mwh/mwh male cross, were treated with the same three orlistat concentrations separately and in association with mitomicin C (0.1mM). The results did not, however, provide evidence that orlistat has carcinogenic potential nor was it associated with the reduction of tumors induced by mitomicin C in D. melanogaster.

Lethal effect of dehydroleucodine (DhL) on amphibian Bufo arenarum embryos.

The dehydroleucodine is a sesquiterpene lactone isolated from Artemisia douglasiana Besser which is used in popular medicine. Toxicity tests using embryos of amphibian have been widely used in order to predict toxic effects of different compounds. However, to our knowledge, there are not studies focussed on the toxic effects of dehydroleucodine on Bufo arenarum, which is an anuran widely distributed in South America. The effect of dehydroleucodine on the survival of embryos was evaluated in an acute test during the early life stage of B. arenarum embryos. Lethality and the degree of adverse effects were dehydroleucodine dose-dependent. Overall, amphibian early life stages appeared to be more susceptible to the embryotoxicity associated with exposure to dehydroleucodine, especially at concentration greater that 3mM. This increased susceptibility may result from the relatively high rate of cellular differentiation and morphogenesis that occurs at this early stage of development.

Renal toxicity caused by oral use of medicinal plants: the yacon example.

AIM OF THE STUDY: Yacon [Smallanthus sonchifolius (Poepp. & Endl.) H. Robinson, Asteraceae] is an Andean species that has traditionally been used as an anti-diabetic herb in several countries around the world, including Brazil. Its hypoglycaemic action has recently been demonstrated in normal and diabetic rats. However, studies about the safety of prolonged oral consumption of yacon leaf extracts are lacking. Thus, this work was undertaken to evaluate the repeated-dose toxicity of three extracts from yacon leaves: the aqueous extract (AE) prepared as a tea infusion; the leaf-rinse extract (LRE), which is rich in sesquiterpene lactones (STLs); and a polar extract from leaves without trichomes, or polar extract (PE), which lacks STLs but is rich in chlorogenic acids (CGAs). MATERIALS AND METHODS: The major classes of the compounds were confirmed in each extract by IR spectra and HPLC-UV-DAD profiling as well as comparison to standard compounds. The toxicity of each extract was evaluated in a repeated-dose toxicity study in Wistar rats for 90 days. RESULTS: The PE was rich in CGAs, but we did not detect any STLs. The AE and LRE showed the presence of STLs. The polar extract caused alterations in some biochemical parameters, but the animals did not show signs of behavioural toxicity or serious lesions in organs. Alterations of specific biochemical parameters in the blood (creatinine 7.0 mg/dL, glucose 212.0 mg/dL, albumin 2.8 g/dL) of rats treated with AE (10, 50 and 100 mg/kg) and LRE (10 and 100 mg/kg) pointed to renal damage, which was confirmed by histological analysis of the kidneys. CONCLUSIONS: The renal damage was associated with increased blood glucose levels after prolonged oral administration of the AE. This observation suggested that the hypoglycaemic effect observed after treatment for 30 days in an earlier study is reversible and was likely the result of renal injury caused by the toxicity of yacon. Because STLs were detected in both AE and LRE, there is strong evidence that these terpenoids are the main toxic compounds in the leaves of the yacon. Based on our results, we do not recommend the oral use of yacon leaves to treat diabetes.

Insecticidal, mutagenic and genotoxic evaluation of annonaceous acetogenins.

Annonaceous acetogenins represent a class of bioactive compounds whose primary mode of action is the inhibition of NADH-ubiquinone oxidoreductase (Mitochondrial Complex I). Given the potential pesticidal use of these compounds, we evaluated the effects of seven acetogenins: squamocin (1), molvizarin (2), itrabin (3), almuñequin (4), cherimolin-1 (5), cherimolin-2 (6), and tucumanin (7) isolated from Annona cherimolia Mill. against Ceratitis capitata Wiedemann (Tephritidae). These acetogenins did not display insecticidal action at 250 microg of treatment per g of adult diet. However, the oviposition capacity of C. capitata females was significantly altered by some of the acetogenins at this concentration. The most potent compounds were itrabin, molvizarin and squamocin. Moreover, significant differences were detected in the preference of oviposition sites when itrabin and squamocin were spread on the surface of artificial fruits at doses of 30 microg/cm2. Additionally, we investigated the mutagenic effects displayed by itrabin, as well as the phytotoxic and genotoxic action of squamocin and itrabin. Both compounds displayed slight phytotoxic and genotoxic effects on roots of Allium cepa at 2.5 microg/mL though no mutagenic effects were detected at 0.25, 0.5 and 2.5 microg/mL on Salmonella typhimurium strains TA98 and TA100.

Role of lactone ring in structural, electronic, and reactivity properties of aflatoxin B1: a theoretical study.

This study involved quantum mechanical calculations to explain the chemical behavior of the lactone ring of aflatoxin B1, which is a carcinogenic hazardous compound. The aflatoxin B1 compound, produced by the fungi Aspergillum flavus, was studied with the B3LYP/6-311+G(d,p) method; its reactivity properties were accounted for by means of the calculated geometrical and electronic parameters. The results obtained indicate that the fused A, B, C, and D rings of aflatoxin adopt a continuous planar conformation. The carbon atom of the lactone group presents a highly electrophilic character, since the population analysis yields a high positive charge for this atom, whereas high negative charges were recorded for both oxygen sites of that group. Thus, in an acidic aqueous medium, the oxygen atoms could be protonated and the carbon site may suffer a nucleophilic attack by water. Accordingly, the OC-O bond length has been lengthened substantially. So it was demonstrated that the lactonic ring of aflatoxin B1 is hydrolyzed under acidic conditions by an acid-acyl bimolecular mechanisms, A(AC)2, suggesting the deletion of its carcinogenic properties.

Synthesis and cytotoxic activity of alpha-santonin derivatives.

Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC(50) values in the range of 0.36-14.5 microM, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development.