Scielo RSS <![CDATA[Journal of the Brazilian Chemical Society]]> vol. 28 num. 3 lang. en <![CDATA[SciELO Logo]]> <![CDATA[The Challenge of Including Chemodiversity, and the Potential Economic Use of New Natural Compounds and Processes, in the BIOTA/FAPESP Program]]> <![CDATA[Microbial Symbionts of Insects are the Focus of the First International Cooperative Biodiversity Group (ICBG) in Brazil]]> The basic aim of the ICBG (International Cooperative Biodiversity Group) program is to benefit both the host country and the global scientific community by discovering and developing new solutions to human health problems based on previously unexplored genetic resources. The first ICBG in Brazil is jointly supported by the Fogarty International Center of the National Institutes of Health (FIC/NIH) in the USA and by the São Paulo Research Foundation (FAPESP) in Brazil. The ongoing ICBG, developed under the BIOTA-FAPESP Program, is based on the highly evolved fungus-growing ant multilateral symbiosis between three mutualists and one parasite. The project aligns chemical ecology and therapeutic application, increasing the chances of discovering new antifungal, antibacterial, anticancer and antiprotozoal hits and leads. In this article we describe the rationale of the ICBG and the legal requirements to develop this type of international collaborative project in Brazil. <![CDATA[The Influence of Brazilian Biodiversity on Searching for Human Use Pharmaceuticals]]> This relatively short review will cover the history of some potential drug entities whose beginnings were from Brazilian flora and fauna that led to scientific findings many years later that could not even have been thought of at the time of their initial discovery. The first two are the discoveries of the effects of peptidic toxins from the highly poisonous snake Bothrops jararaca upon the control of bradykinins that led to the angiotensin converting enzyme inhibitors, and the identification of pederin from the blister beetle Paederus species that 50 plus years later led to brand new discoveries as the source of many marine sponge metabolites. All occurred well before the Convention on Biological Diversity (CBD), in 1992. Then come discussions on lapachol and its congeners and then the potential for the investigation of microbes that are associated with insects, plants and marine invertebrates and their control of the syntheses of novel metabolites with pharmaceutical potential. The review finishes with comments on the biodiversity programs that São Paulo State has put in place and how they are materially aiding in investigations of Brazilian flora and fauna but under conditions that are CBD-compliant. <![CDATA[Update: Biological and Chemical Aspects of <em>Senna spectabilis</em>]]> Senna spectabilis (syn Cassia spectabilis) is one of the most important species within the Fabaceae family, natively found in Central and South America, as well as parts of Asia and Africa. Due to the extensive geographical distribution, this fast-growing tree produces a wide variety of bioactive secondary metabolites, being of special interest for chemical and pharmacological studies. Phytochemical investigations have shown that S. spectabilis produces over 40 constituents from different biosynthetic pathways, including piperidine alkaloids, pentacyclic terpenoids and anthraquinones, displaying antiproliferative, antitumoral and antifungal activities. Moreover, studies have also been conducted to identify endophytic and rizhospheric microorganisms associated to S. spectabilis and their chemical composition, enabling further elucidation of cadinane sesquiterpenoids, cytochalasins, depsipeptides and dibenzopirones. This review aims to provide an updated summary of the main features of S. spectabilis, compiling all currently available information on the chemical and pharmacological composition of its parts and its associated microorganisms. <![CDATA[An UPLC-MS/MS Method for Determination of Vicenin-2 and Lychnopholic Acid in Rat Plasma and its Application to a Pharmacokinetic Study]]> Vicenin-2 (VIC) and lychnopholic acid (LA) are present in large amounts in hydroalcoholic extract from leaves of Lychnophora salicifolia, commonly known in the Brazilian Cerrado as "arnicão", a plant applied as topic anti-inflammatory and as a flavoring agent for the traditional spirit (cachaça). A new ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for quantification of LA and VIC in plasma samples in order to evaluate their pharmacokinetic profiles in rats. The method was linear in the range of 10-2500 ng mL-1, acceptable precision accuracies were obtained and no significant matrix effect was observed. The validated method was successfully applied to pharmacokinetic study. LA presented very low t1/2 (half-time), high Cl (serum clearance) and Vd (volume of distribution), and for VIC, the t1/2 value was slightly larger, but still rather low, whereas Cl and Vd values were slightly lower, indicating that both substances are instantaneous and well distributed in the body, and quickly eliminated. <![CDATA[Evaluation of Chemical Defense and Chemical Diversity in the Exotic Bryozoan <em>Amathia verticillata</em>]]> The present investigation tests the effects against feeding by fishes of crude extracts obtained from eleven distinct populations of the bryozoan Amathia verticillata, an invasive species found globally in tropical to warm-temperate waters. Investigation of extracts from 11 populations of A. verticillata led to the identification and quantification of the known indole alkaloid 2,5,6-tribromo-N-methylgramine and isolation and identification of the new indole alkaloid, 2,6-dibromo-N-methylgramine. One extract of A. verticillata from Brazil significantly deterred feeding, while other extracts of A. verticillata from Florida significantly stimulated feeding by fishes, in field assays performed in Brazil. The same extracts of Florida samples showed variable effects on feeding, ranging from attraction to deterrence, in assays carried out in Florida. The absence of broad chemical defenses against feeding by fish suggests that the establishment of A. verticillata as an invasive species into new areas may be due to reasons other than defensive chemistry. <![CDATA[Identification of Triterpenoids from <em>Schefflera systyla</em>, <em>Odontadenia puncticulosa</em> and <em>Conostegia speciosa</em> and In Depth Investigation of Their <em>in vitro</em> and <em>in vivo</em> Antifungal Activities]]> As a part of a broad screening of antifungal agents from plant origin, crude extracts from Panamanian plants having related types of constituents displayed significant activities in an agar overlay thin layer chromatography assay against a susceptible strain of Candida albicans. These were the methanolic extract of the leaves of Schefflera systyla and Odontadenia puncticulosa and of the stems of Conostegia speciosa, that are species not previously investigated from a phytochemical viewpoint. For all plants, high-performance liquid chromatography (HPLC) antifungal activity based profiling allowed the rapid localization of antifungal agents that were further obtained by targeted isolation procedure by semi-preparative HPLC or medium pressure liquid chromatography (MPLC) after LC gradient transfer. Different hederagenin saponins and one aglycone were found to be responsible for the antifungal activities of the extracts. Alpha-hederin was the antifungal of S. systyla, pulsatilla saponin D and 3β-O-[β-D-xylopyranosyl-(1→3)-α-L-rhamnopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-α-L-arabinopyranosylhederagenin of O. puncticulosa and arjunolic acid of C. speciosa. Their minimal inhibitory concentration (MIC) against planktonic and biofilm cells of C. albicans were determined. Alpha-hederin was the most potent compound with a MIC of 4 µg mL-1. Structurally related compounds (hederagenin, medicagenic acid 3-O-β-D-glucopyranoside and medicagenic acid) were used as standards and tested for comparison purposes. In order to better estimate the potential of these triterpenoids as antifungal agents, their cytological effects on C. albicans were determined by transmission electron microscopy (TEM) and the in vivo activity of alpha-hederin, medicagenic acid 3-O-β-D-glucopyranoside and medicagenic acid was evaluated for the first time in the Galleria mellonella larvae model. <![CDATA[Comparison of Standardized Dichloromethane with Aqueous <em>Pterodon pubescens</em> Benth. Fruit Extracts on Antinociceptive and Anti-Inflammatory Activity]]> Pterodon pubescens Benth., popularly known as "sucupira", is traditionally used as pain healing agent for many inflammatory diseases. The present study evaluated the in vivo antinociceptive and anti-inflammatory properties of sucupira's fruit dicloromethane extract (Pp) compared to the aqueous extract (Ppa) traditionally used in folk medicine. Extracts' chemical characterization was performed by gas chromatography coupled to mass spectra (GC-MS) detection. The standardized extracts were evaluated using antinociceptive and anti-inflammatory experimental models with mice. The results reported herein allowed establishing a relationship between the popular use of Pterodon pubescens fruit for pain relief and the activity of two major compounds isolated from this species which demonstrated antinociceptive activity. The experimental models corroborate activity of aqueous extract antinociceptive and anti-inflammatory activity, with lower potency compared to dichloromethane extract. Nevertheless the resulting data corroborates sucupira's folk use for pain relief. <![CDATA[Bioprospecting Anticancer Compounds from the Marine-Derived Actinobacteria <em>Actinomadura</em> sp. Collected at the Saint Peter and Saint Paul Archipelago (Brazil)]]> The actinomycete strain BRA 177 was recovered from sediment samples collected at the St. Peter and St. Paul Archipelago, Brazil. This work accessed the ability of this strain, identified as Actinomadura sp., to produce bioactive metabolites by exploring the genome and characterizing chemistry and cytotoxicity of isolated compounds. From the crude ethyl acetate extract, the pigments nonylprodigiosin, cyclononylprodigiosin and methylcyclooctilprodigiosin were isolated and displayed cytotoxicity against human tumor and non-tumor cell lines. Sequencing, assembling and prospection of BRA 177 draft genome led to identification of two contigs encoding enzymes with high homology to those from prodiginine biosynthetic gene clusters (BGC) in actinomycetes. Further, Actinomadura sp. BGC presented unique putatives RedJ thioesterase and RedL-like type I PKS, involved on selection of prodiginine biosynthetic fatty acyl precursor, and RedG-like Rieske oxygenase, key for cyclization of the prodiginines, suggesting that cyclononilprodigiosin and methylcyclooctylprodigiosin could actually be considered chemical signatures of Actinomadura spp. <![CDATA[Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration]]> Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC50 of 3.0 ± 1.0 µM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC50 of 1.5 ± 1 µM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4. <![CDATA[Steroids from the Brazilian Zoanthids <em>Palythoa caribaeorum</em> and <em>Palythoa variabilis</em>]]> Two unreported ergostane-type sterols 24(R)-7α-hydroperoxy-ergost-5-en-3β-ol and 6β-carboxyl-24(R)-(8→6)-abeo-ergostan-3β,5β-diol, along with seven known ones were isolated from the hexane and alcohol extracts from the zoanthids Palythoa caribaeorum and Palythoa variabilis. The structures of the new compounds were determined using spectroscopic techniques, including 1D and 2D nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), and comparison with data previously published. 6β-Carboxyl-24(R)-(8→6)-abeo-ergostan-3β,5β-diol showed moderate cytotoxicity against colon cancer cells (HCT-116) as previously described for others abeo-sterol derivatives. <![CDATA[Application of an Ionic Liquid in the Microwave Assisted Extraction of Cytotoxic Metabolites from Fruits of <em>Schinus terebinthifolius</em> Raddi (Anacardiaceae)]]> This work reports the application of an ionic liquid (1-butyl-3-methylimidazolium bromide, BMImBr) in the microwave assisted extraction (MAE) of metabolites from fruits of Schinus terebinthifolius. Dried fruits were individually extracted using BMImBr:H2O 1:1, v/v (experiment 1) and pure H2O (experiment 2) by MAE (10 min at 60 ºC). After partition using EtOAc, the yield to experiment 1 was about 23% while to experiment 2 was 0.1%. The EtOAc fraction obtained from experiment 1 was purified by chromatographic methods to afford 3-oxotirucalla-7,24Z-dien-27-oic acid, 3a-hydroxytirucalla-7,24Z-dien-27-oic acid, 3a-acetoxytirucalla-7,24Z-dien-27-oic acid, gallic acid, and ethyl gallate, being the first occurrence of the third compound as natural product. Cytotoxic activity was evaluated in vitro against cancer cell lines (A2058, HeLa, SiHa, HCT, SKBR-3, U87, and B16F2Nex2), being 3a-acetoxytirucalla-7,24Z-dien-27-oic acid the more active metabolite with IC50 ranging from 10.9 ± 1.3 to 17.3 ± 1.4 µg mL-1, lower than that determined to positive control cisplatin. <![CDATA[Multiple Monohydroxylation Products from rac-Camphor by Marine Fungus <em>Botryosphaeria</em> sp. Isolated from Marine Alga <em>Bostrychia radicans</em>]]> This manuscript describes the biooxidation of rac-camphor using whole cells of marine-derived fungus Botryosphaeria sp. CBMAI 1197. The main biotransformation products of this monoterpene were achieved via a hydroxylation reaction and occurred with 5 days of rac-camphor incubation. Products were identified by means of gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) data. The major hydroxylated products were 6-endo-hydroxycamphor, 6-exo-hydroxycamphor, 5-exo-hydroxycamphor, 5-endo-hydroxycamphor, 3-exo-hydroxycamphor and 8-hydroxycamphor. The 6-exo-hydroxycamphor was obtained through a retro-aldol reaction when 6-endo-hydroxycamphor was maintained in presence of CDCl3; this isomerization was confirmed by 1H NMR and GC-MS data. <![CDATA[Rosmarinic and Cinnamic Acid Derivatives of <em>in vitro</em> Tissue Culture of <em>Plectranthus ornatus</em>: Overproduction and Correlation with Antioxidant Activities]]> This work describes the tissue culture of Plectranthus ornatus Codd. (Lamiaceae) on Murashige and Skoog (MS) medium with naphthalene acetic acid (NAA) (1.0, 2.0 and 4.0 mg L-1) and 6-benzylaminopurine (BAP) (1.0, 2.0 and 4.0 mg L-1) as growth regulators to obtain the overproduction of rosmarinic acid. The content of rosmarinic acid and its biosynthetic precursors were determined by high performance liquid chromatography (HPLC). The antioxidant activities (AA) of the extracts were also evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The best growing condition was observed with the addition of 1.0 mg L-1 of both NAA and BAP in the culture medium yielded an increase of 94 times of rosmarinic acid comparing with the wild plant. All extracts diplayed antioxidant activity, as evidenced by the DPPH free radical scavenging assay. However, those with 2.0 mg L-1 NAA and, 1.0 mg L-1 NAA and BAP in culture medium showed the lowest EC50 (26.0 and 29.8 µg mL-1, respectively). At concentration higher than 10 µg mL-1 of rosmarinic acid it was not observed the correlation with AA, suggesting some other anti-oxidant mechanism acting. <![CDATA[Isolation of Tiliroside from <em>Spiranthera odoratissima</em> as Inhibitor of <em>Trypanosoma cruzi</em> Glyceraldehyde-3-phosphate Dehydrogenase by Using Bioactivity-Guided Fractionation]]> Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme involved in the Trypanosoma cruzi glycolytic pathway, parasite that causes Chagas' disease. There are only few drugs available to treat this disease, most of which present strong side effects. Natural products constitute a prime source for the discovery of new scaffolds potentially useful for the treatment of several diseases, including Chagas' disease. Bioactivity-guided fractionation of Spiranthera odoratissima extract using T. cruzi GAPDH (TcGAPDH) as a target led to the isolation of the flavonoid tiliroside (kaempferol-3-O-β-D-(6''-trans-p-coumaroyl)-glucopyranoside), identified as an excelent inhibitor of this enzyme and for the first time reported for this plant species. Mechanistic studies of tiliroside showed that it is a reversible non-competitive inhibitor of TcGAPDH. In additon, molecular modeling analysis indicated the binding mode of tiliroside to TcGAPDH. Therefore, the identification of tiliroside as TcGPADH inhibitor in a complex matrix such as the plant crude extract and the discovery of a new binding site may contribute to the opening of new paths in the search for natural product inhibitors of this enzyme.