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Mariana H Massaoka,
Alisson L Matsuo,
Carlos R Figueiredo,
Camyla F Farias,
Natália Girola,
Denise C Arruda,
Jorge A B Scutti,
Paulete Romoff,
Oriana A Favero, Marcelo J P Ferreira,
João H G Lago,
Luiz R Travassos
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ABSTRACT: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. The purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naïve mice.
The jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). The free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.
The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.
PLoS ONE 01/2012; 7(6):e38698. · 4.09 Impact Factor
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ABSTRACT: The Asteraceae, one of the largest families among angiosperms, is chemically characterised by the production of sesquiterpene lactones (SLs). A total of 1,111 SLs, which were extracted from 658 species, 161 genera, 63 subtribes and 15 tribes of Asteraceae, were represented and registered in two dimensions in the SISTEMATX, an in-house software system, and were associated with their botanical sources. The respective 11 block of descriptors: Constitutional, Functional groups, BCUT, Atom-centred, 2D autocorrelations, Topological, Geometrical, RDF, 3D-MoRSE, GETAWAY and WHIM were used as input data to separate the botanical occurrences through self-organising maps. Maps that were generated with each descriptor divided the Asteraceae tribes, with total index values between 66.7% and 83.6%. The analysis of the results shows evident similarities among the Heliantheae, Helenieae and Eupatorieae tribes as well as between the Anthemideae and Inuleae tribes. Those observations are in agreement with systematic classifications that were proposed by Bremer, which use mainly morphological and molecular data, therefore chemical markers partially corroborate with these classifications. The results demonstrate that the atom-centred and RDF descriptors can be used as a tool for taxonomic classification in low hierarchical levels, such as tribes. Descriptors obtained through fragments or by the two-dimensional representation of the SL structures were sufficient to obtain significant results, and better results were not achieved by using descriptors derived from three-dimensional representations of SLs. Such models based on physico-chemical properties can project new design SLs, similar structures from literature or even unreported structures in two-dimensional chemical space. Therefore, the generated SOMs can predict the most probable tribe where a biologically active molecule can be found according Bremer classification.
Molecules 01/2012; 17(4):4684-702. · 2.39 Impact Factor
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ABSTRACT: Leishmaniasis and Chagas' are parasitic protozoan diseases that affect the poorest population in the world, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, novel, safe and more efficacious drugs are essential. In this work, the CH(2)Cl(2) phase from MeOH extract from the leaves of Baccharis retusa DC. (Asteraceae) was fractioned to afford two flavonoids: naringenin (1) and sakuranetin (2). These compounds were in vitro tested against Leishmania spp. promastigotes and amastigotes and Trypanosoma cruzi trypomastigotes and amastigotes. Compound 2 presented activity against Leishmania (L.) amazonensis, Leishmania (V.) braziliensis, Leishmania (L.) major, and Leishmania (L.) chagasi with IC(50) values in the range between 43 and 52 μg/mL and against T. cruzi trypomastigotes (IC(50)=20.17 μg/mL). Despite of the chemical similarity, compound 1 did not show antiparasitic activity. Additionally, compound 2 was subjected to a methylation procedure to give sakuranetin-4'-methyl ether (3), which resulted in an inactive compound against both Leishmania spp. and T. cruzi. The obtained results indicated that the presence of one hydroxyl group at C-4' associated to one methoxyl group at C-7 is important to the antiparasitic activity. Further drug design studies aiming derivatives could be a promising tool for the development of new therapeutic agents for Leishmaniasis and Chagas' disease.
Experimental Parasitology 11/2011; 130(2):141-5. · 2.12 Impact Factor
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Thiago R Morais,
Paulete Romoff,
Oriana A Fávero,
Juliana Q Reimão,
Walkyria C Lourenço,
André G Tempone,
Angelica D Hristov,
Silvia M Di Santi,
João Henrique G Lago,
Patricia Sartorelli, Marcelo J P Ferreira
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ABSTRACT: Leishmaniasis, Chagas disease, and malaria affect the poorest population around the world, with an elevated mortality and morbidity. In addition, the therapeutic alternatives are usually toxic or ineffective drugs especially those against the trypanosomatids. In the course of selection of new anti-protozoal compounds from Brazilian flora, the CH(2)C(l2) phase from MeOH extract obtained from the leaves of Pentacalia desiderabilis (Vell.) Cuatrec. (Asteraceae) showed in vitro anti-leishmanial, anti-malarial, and anti-trypanosomal activities. The chromatographic fractionation of the CH(2)Cl(2) phase led to the isolation of the bioactive compound, which was characterized as jacaranone [methyl (1-hydroxy-4-oxo-2,5-cyclohexandienyl)acetate], by spectroscopic methods. This compound showed activity against promastigotes of Leishmania (L.) chagasi, Leishmania (V.) braziliensis, and Leishmania (L.). amazonensis showing an IC(50) of 17.22, 12.93, and 11.86 μg/mL, respectively. Jacaranone was also tested in vitro against the Trypanosoma cruzi trypomastigotes and Plasmodium falciparum chloroquine-resistant parasites (K1 strain) showing an IC(50) of 13 and 7.82 μg/mL, respectively, and was 3.5-fold more effective than benznidazole in anti-Trypanosoma cruzi assay. However, despite of the potential against promatigotes forms, this compound was not effective against amastigotes of L. (L.) chagasi and T. cruzi. The cytotoxicity study using Kidney Rhesus monkey cells, demonstrated that jacaranone showed selectivity against P. falciparum (21.75 μg/mL) and a selectivity index of 3. The obtained results suggested that jacaranone, as other similar secondary metabolites or synthetic analogs, might be useful tolls for drug design for in vivo studies against protozoan diseases.
Parasitology Research 05/2011; 110(1):95-101. · 2.15 Impact Factor
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ABSTRACT: The essential oils from leaves and stem barks of Drimys brasiliensis Miers (Winteraceae), collected in July and December 2008, were analyzed by GC/FID and GC/MS. The stem bark oils were composed mainly of monoterpenes (July, 45 +/- 3%; December, 92 +/- 4%), while the oils from leaves showed the predominance of sesquiterpenes (July, 47 +/- 1%; December, 55 +/- 1%). The variation in the relative amount of constituents could be associated, at least in part, to several microclimatic parameters such as precipitation, temperature and/or phenological state, which were different for each collection of D. brasiliensis.
Natural product communications 02/2011; 6(2):243-5. · 1.24 Impact Factor
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Helvetica Chimica Acta 12/2010; 93(12):2478 - 2487. · 1.48 Impact Factor
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ABSTRACT: The chemical composition and seasonal variation throughout one year of the essential oils from leaves of Baccharis microdonta and B. elaeagnoides, collected in Campos do Jordão, SP, were investigated. The composition of the latter species has been described for the first time. By GC (RI) and GC/MS analysis, 43 compounds were identified, and a predominance of oxygenated sesquiterpene derivatives was found in both species. The main components of the B. microdonta oils were elemol (31; 11.7-30.6%), spathulenol (34; 4.7-9.1%), β-caryophyllene (19; 3.7-6.2%), and germacrene D (24; 2.9-12.2%), and those of the B. elaeagnoides oils were 34 (10.1-21.5%), viridiflorol (35; 3.6-18.4%), 24 (0.9-13.8%), and 19 (3.5-9.4%). The identified compounds were grouped according to their respective C-skeletons, and the percentages of occurrence of the C-skeletons in the essential oils of leaves collected in the four seasons allowed identifying the preferential accumulation of different types of C-skeletons as well as the seasonal variation of the biosynthetic routes over the studied period.
Chemistry & Biodiversity 11/2010; 7(11):2771-82. · 1.80 Impact Factor
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ABSTRACT: This article describes the integration of the LSD (Logic for Structure Determination) and SISTEMAT expert systems that were both designed for the computer-assisted structure elucidation of small organic molecules. A first step has been achieved towards the linking of the SISTEMAT database with the LSD structure generator. The skeletal descriptions found by the SISTEMAT programs are now easily transferred to LSD as substructural constraints. Examples of the synergy between these expert systems are given for recently reported natural products.
Natural product communications 05/2010; 5(5):763-70. · 1.24 Impact Factor
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ABSTRACT: This paper describes a new module of the expert system SISTEMAT used for the prediction of the skeletons of neolignans by 13C NMR, 1H NMR and botanical data obtained from the literature. SISTEMAT is composed of MACRONO, SISCONST, C13MACH, H1MACH and SISOCBOT programs, each analyzing data of the neolignan in question to predict the carbon skeleton of the compound. From these results, the global probability is computed and the most probable skeleton predicted. SISTEMAT predicted the skeletons of 75% of the 20 neolignans tested, in a rapid and simple procedure demonstrating its advantage for the structural elucidation of new compounds.
Natural product communications 05/2010; 5(5):755-62. · 1.24 Impact Factor
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ABSTRACT: In the course of selection of new bioactive compounds from Brazilian flora, the crude MeOH extract from the leaves of Baccharis retusa DC. (Asteraceae) showed potential against Leishmania sp. and Trypanosoma cruzi. Chromatographic fractionation of the dichloromethane phase from MeOH extract yielded great amounts of the bioactive derivative, which was characterized as 5,6,7-trihydroxy-4'-methoxyflavanone. The structure of this compound was established on the basis of spectroscopic data analysis, mainly nuclear magnetic resonance and mass spectrometry.
Parasitology Research 02/2010; 106(5):1245-8. · 2.15 Impact Factor
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ABSTRACT: Recebido em 2/9/09; aceito em 14/1/10; publicado na web em 23/4/10 The volatile oils from Nectandra megapotamica Spreng. leaves, collected in February and August of 2007 and at 7:00 and 12:00 h (samples A – D), were extracted by hydrodistillation and the chemical composition was analyzed by GC-FID and GC/MS. A total of nineteen compounds were identified with predominance of oxygenated sesquiterpenes, among them, a-bisabolol, was the main constituent (62.3–69.4 %). After chromatographic separation procedures, this compound was purified from crude oil and its structure was confirmed by analysis of NMR data. This paper describes for the first time the composition of the leaves volatile oil from N. megapotamica.
Quim. Nova. 01/2010; 33:1119-1121.
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Spectroscopy Letters 12/2008; 41(8):405-421. · 0.72 Impact Factor
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ABSTRACT: The methanol extract from aerial parts of the Peperomia blanda (Piperaceae) yielded two C-glycosyl-flavones. Their structures were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR, chemical transformation and comparison with the related known compounds. The structure of the new flavonoids were established as 4'-methoxy-vitexin 7-O-beta-D-xylopyranoside (1) (7-O-beta-D-xylopyranosyl-8-C-beta-D-glucopyranosyl-4'-methoxy-apigenin) and vicenin-2 (2). The antioxidant activity of both compounds was investigated using the DPPH assay. Both compounds showed only modest activity, with IC50 values of 357.2 microM for 1, and 90.5 microM for 2.
Fitoterapia 12/2008; 80(2):119-22. · 1.85 Impact Factor
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ABSTRACT: Some sesquiterpene lactones (SLs) are the active compounds of a great number of traditionally medicinal plants from the Asteraceae family and possess considerable cytotoxic activity. Several studies in vitro have shown the inhibitory activity against cells derived from human carcinoma of the nasopharynx (KB). Chemical studies showed that the cytotoxic activity is due to the reaction of alpha,beta-unsaturated carbonyl structures of the SLs with thiols, such as cysteine. These studies support the view that SLs inhibit tumour growth by selective alkylation of growth-regulatory biological macromolecules, such as key enzymes, which control cell division, thereby inhibiting a variety of cellular functions, which directs the cells into apoptosis. In this study we investigated a set of 55 different sesquiterpene lactones, represented by 5 skeletons (22 germacranolides, 6 elemanolides, 2 eudesmanolides, 16 guaianolides and nor-derivatives and 9 pseudoguaianolides), in respect to their cytotoxic properties. The experimental results and 3D molecular descriptors were submitted to Kohonen self-organizing map (SOM) to classify (training set) and predict (test set) the cytotoxic activity. From the obtained results, it was concluded that only the geometrical descriptors showed satisfactory values. The Kohonen map obtained after training set using 25 geometrical descriptors shows a very significant match, mainly among the inactive compounds (approximately 84%). Analyzing both groups, the percentage seen is high (83%). The test set shows the highest match, where 89% of the substances had their cytotoxic activity correctly predicted. From these results, important properties for the inhibition potency are discussed for the whole dataset and for subsets of the different structural skeletons.
European Journal of Medicinal Chemistry 02/2008; 43(10):2197-205. · 3.35 Impact Factor
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ABSTRACT: Some sesquiterpene lactones (SLs) are the active compounds of a great number of traditionally medicinal plants from the Asteraceae family and possess considerable cytotoxic activity. Several studies in vitro have shown the inhibitory activity against cells derived from human carcinoma of the nasopharynx (KB). In this study, we investigated a set of 37 different sesquiterpene lactones, represented by 4 skeletons (14 germacranolides, 6 elemanolides, 9 guaianolides and nor-derivatives, and 8 pseudoguaianolides), in what it says respect of their cytotoxic properties. The experimental results were submitted to a QSAR study. A single model for the entire data set was described using 3D molecular descriptors and genetic algorithms establishing structure-activity relationships among the compounds. Important properties for the inhibition potency are discussed for the whole data set and for subsets of the different structural skeletons.
Bioorganic & Medicinal Chemistry 05/2007; 15(8):2927-34. · 2.92 Impact Factor
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ABSTRACT: Feed-forward neural networks (FFNNs) were used to predict the skeletal type of molecules belonging to six classes of terpenoids. A database that contains the 13C NMR spectra of about 5000 compounds was used to train the FFNNs. An efficient representation of the spectra was designed and the constitution of the best FFNN input vector format resorted from an heuristic approach. The latter was derived from general considerations on terpenoid structures.
Analytica chimica acta 11/2006; 579(2):217-26. · 4.31 Impact Factor
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ABSTRACT: From the methanol extract of the aerial parts of Peperomia blanda (Piperaceae), two chromenes were isolated and characterized mainly through application of 2D-NMR spectroscopy. The structures were 2S-(4-methyl-3-pentenyl)-6-formyl-8-hydroxy-2,7-dimethyl-2H-chromene and 2S-(4-methyl-3-pentenyl)-5-hydroxy-6-formyl-2,7-dimethyl-2H-chromene named as blandachromenes I and II, respectively.
Phytochemistry 04/2006; 67(5):492-6. · 3.35 Impact Factor
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ABSTRACT: This paper describes the application of artificial neural nets as an alternative and efficient method for the classification of botanical taxa based on chemical data (chemosystematics). A total of 28,000 botanical occurrences of chemical compounds isolated from the Asteraceae family were chosen from the literature, and grouped by chemical class for each species. Four tests were carried out to differentiate and classify different botanical taxa. The qualifying capacity of the artificial neural nets was dichotomically tested at different hierarchical levels of the family, such as subfamilies and groups of Heliantheae subtribes. Furthermore, two specific subtribes of the Heliantheae and two genera of one of these subtribes were also tested. In general, the artificial neural net gave rise to good results, with multiple-correlation values R>0.90. Hence, it was possible to differentiate the dichotomic character of the botanical taxa studied.
Chemistry & Biodiversity 05/2005; 2(5):633-44. · 1.80 Impact Factor
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ABSTRACT: This paper provides a general survey of the occurrence of diterpenes in the Asteraceae. Data on 4351 botanical occurrences were obtained from the literature. These were grouped by skeleton for each genus. Then, the genera were grouped by subtribes, which, in turn, were gathered in tribes, followed by subfamilies. In spite of the low number of species containing diterpenes, it was possible to describe some structural features of these compounds, i.e. the skeletal types in various taxa and the positions in some skeletons that are always oxidized or never undergo oxidation in some genera. Thus, it was verified that: in the subfamily Cichorioideae, only a few of the studied species possess diterpenes, wherein kaurane is the most frequent diterpene skeleton. In the Asteroideae, the presence of diterpenes is much greater than that in the Cichorioideae and Carduoideae. At tribal taxonomic level, for example, the Astereae produce labdanes and clerodanes; Heliantheae and Eupatorieae produce kauranes and labdanes, respectively; and Calenduleae produce pimaranes. Some taxonomic implications are presented. © 2005 The Linnean Society of London, Botanical Journal of the Linnean Society, 2005, 147, 291–308.
Botanical Journal of the Linnean Society 03/2005; 147(3):291 - 308. · 2.82 Impact Factor
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Journal of Chemical Information and Modeling. 01/2005; 45:645-651.
