Marcelo J. P. Ferreira

Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo.

Background 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. Methodology/Principal Findings 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. Conclusions/Significance The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

Isolation of an antileishmanial and antitrypanosomal flavanone from the leaves of Baccharis retusa DC. (Asteraceae).

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.

Use of self-organizing maps and molecular descriptors to predict the cytotoxic activity of sesquiterpene lactones

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.

Chemosystematic studies of natural compounds isolated from Asteraceae: characterization of tribes by principal component analysis

Univ Nice, Equipe Chimiometrie & Modelisat, Lab Aromes Syntheses & Interact, F-06108 Nice 2, France

13C NMR spectroscopy of monoterpenoids

C NMR, and their subse-quent development over the years, structure elucida-tion ofnatural products hasbecome commonpractice.As a consequence, several new isolated terpenoids,including mono-, di-, tri- and sesquiterpenes, havehad their structure established. Today studies onthousands of terpenoids have been reported but theirchemical shift data are still scattered in the literature.Much of the impetus for the study of the

Self-organizing maps of molecular descriptors for sesquiterpene lactones and their application to the chemotaxonomy of the Asteraceae family.

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.

Computer-aided method for identification of components in essential oils by 13C NMR spectroscopy

Abstract The aim of this paper is to present a procedure based on analyses of 13 C NMR data for identification of known and new chemical constituents in essential oils. A novel program developed to analyze complex mixtures of terpenoid compound was evaluated for the identification of components in the essential oils from leaves of Piper cernuum and Piper regnellii .

Automatic identification by 13C NMR of substituent groups bonded in natural product skeletons.

The aim of this paper is to present a procedure that utilizes 13C NMR for identification of substituent groups which are bonded to carbon skeletons of natural products. For so much was developed a new version of the program MACRONO, that presents a database with 161 substituent types found in the most varied terpenoids. This new version was widely tested in the identification of the substituents of 60 compounds that, after removal of the signals that did not belong to the carbon skeleton, served to test the prediction of skeletons by using other programs of the expert system SISTEMAT.

Automatic identification of terpenoid skeletons through 13C nuclear magnetic resonance data disfunctionalization

Abstract The proposal of this paper is to present a procedure that utilizes 13 C NMR for terpenoid skeletons identification. By this reason, a novel program named REGRAS was developed for the specialist system SISTEMAT. This program carries out an analysis of the 13 C NMR data from a given compound and, from ranges of chemical shifts, recognizes the chemical functions existing on specific positions of carbon skeletons. At the end of this procedure, the program matches the types of carbon atoms obtained against a database, displaying as analysis results the likely skeletons of the questioned substance. The program REGRAS was tested on skeleton elucidation of 35 compounds from the most varied classes of terpenoids, exhibiting excellent results in skeleton prevision precesses.

A Trinuclear Oxo-Chromium(III) Complex Containing the Natural Flavonoid Primuletin: Synthesis, Characterization, and Antiradical Properties

A new trinuclear oxo-centered chromium(III) complex with formula [Cr3O(CH3CO2)6(L)(H2O)2] (L = 5-hydroxyflavone, known as primuletin) was synthetized and characterized by ESI mass spectrometry, thermogravimetry, and 1H-NMR, UV-Vis, and FTIR spectroscopies. In agreement with the experimental results, DFT calculations indicated that the flavonoid ligand is coordinated to one of the three Cr(III) centers in an O,O-bidentate mode through the 5-hydroxy/4-keto groups. In a comparative study involving the uncoordinated primuletin and its corresponding complex, systematic reactions with the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) showed that antiradical activity increases upon complexation.