Scielo RSS <![CDATA[Journal of the Brazilian Chemical Society]]> vol. 27 num. 8 lang. es <![CDATA[SciELO Logo]]> <![CDATA[5<sup>th</sup> BCNP and XXXI RESEM: a Tribute to Biodiversity]]> <![CDATA[Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides]]> This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) that would not have been synthesized in the absence of knowledge of bioactive arabinose nucleosides. <![CDATA[Turning Metabolomics into Drug Discovery]]> Metabolomics is the "omics" that studies the whole metabolome. It has a wide range of applications, inter alia chemotaxonomy, environmental influences, agriculture, etc. Here we review the application of metabolomics in natural product research. The importance of physicochemical properties to drug delivery are discussed in relation to turning metabolomic studies towards drug discovery. We believe that coupling metabolomic studies with standards of known physicochemical properties in order to calibrate the chromatographic columns can be beneficial in identifying compounds of candidate drug quality. <![CDATA[Developing Commercial Production of Semi-Synthetic Artemisinin, and of β-Farnesene, an Isoprenoid Produced by Fermentation of Brazilian Sugar]]> The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast. Development of commercially viable yeast strains was a substantial challenge that was addressed by creation and implementation of an industrial synthetic biology pipeline. Using the engineered strains, production of β-farnesene from Brazilian sugarcane offers several environmental advantages. Among the many commercial applications of β-farnesene, its use as a feedstock for making biodegradable lubricants is highlighted. This example, along with others, highlight a powerful new suite of technologies that will become increasingly important for production of chemicals, spanning from pharmaceuticals through commodity chemicals. <![CDATA[Elucidating the Mode of Action of Marine Natural Products through an Immunoaffinity Fluorescent (IAF) Approach]]> Understanding the target and mode of action (MOA) of small molecules activity has become a critical feature in guiding the transition between drug discovery and clinical evaluation. While classically placed at the latter stages of a discovery program, we now describe how addressing the mode of action of natural products at the early stages of a program provides an important vehicle to inform the drug discovery process. In this review, we outline a streamlined cellular and molecular biological system and explore its utility through a series of four cases studies. We believe that this approach offers critical lessons to guide future drug discovery programs. <![CDATA[The Genus Psychotria: Phytochemistry, Chemotaxonomy, Ethnopharmacology and Biological Properties]]> Psychotria genus (Rubiaceae) is featured into the angiosperm, being the most speciose genus comprising approximately 1600 species. The available references demonstrate that Psychotria has several uses on traditional medicine including spiritual and cultural purposes, and presents great potential on pharmacological properties, especially the one related to neurodegenerative diseases. Despite its wide biological properties, this genus has shown complex phylogenetic analysis due to lack of chemotaxonomic information. In recent years, the interest in these plants has increased considerably and many active compounds have been isolated. Phytochemical investigations described in the literature confirmed the indole alkaloids as the major compounds and besides that, another particular chemical constituent are cyclic peptides, known as cyclotides. This present review will cover the relevant literature from 1962 until 2015, and outlines the current data on taxonomy, chemotaxonomy, traditional uses, pharmacological properties, chemical composition and ecological approach from Psychotria genus. <![CDATA[Benzoxazinoids: Reactivity and Modes of Action of a Versatile Class of Plant Chemical Defenses]]> In order to protect themselves from biotic stresses, including enemies and competitors, many plants recruit defensive secondary metabolites. Compounds containing a 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one skeleton and their derivatives, collectively known as benzoxazinoids, are common secondary metabolites in many grasses, including important cereal crops such as maize, wheat, and rye, as well as several dicot species. This diverse class of compounds is known for its broad range of antifeedant, insecticidal, antimicrobial, and allelopathic activities. However, the mechanisms underlying such biological activities are not yet completely understood. The present review aims to summarize the current knowledge on the chemical reactivity of benzoxazinoids in biological systems and associate it to their proposed modes of action. Structure-activity relationships for a wide spectrum of biological effects are critically discussed and directions for future research are addressed. <![CDATA[Synthesis, in vitro Antiproliferative and Anti-Mycobacterium tuberculosis Activities of Novel β-Carboline Derivatives]]> A series of β-carboline derivatives with amino or guanidinium were synthesized and evaluated in vitro against anti-Mycobacterium tuberculosis and for antiproliferative activities against nine human cancer cell lines. The compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline (24.9 µg mL-1) and 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline (26.9 µg mL-1) were the most active against M. Tuberculosis (MTB). Compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline and 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline, which had the same substituted groups, inhibited the growth of all human tumor cell lines with growth inhibitory activity (GI50) values from 1.37 to 9.20 mmol L-1. Also in this series, compounds 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline demonstrated significant activity against NCI/ADR cells. Among compounds with a terminal guanidine group, compounds 1-(4-hydroxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (27.8 µg mL-1) and 1-(3-nitrophenyl)-3-carboxamide(ethyl)guanidine β-carboline (37.4 µg mL-1) demonstrated the greatest activity against MTB. Additionally, compounds 1-(4-methoxyphenyl)-3-carboxamide(ethyl)guanidine β-carboline (GI50 = 0.45 mmol L-1) effectively inhibited growth and was highly selective against NCI/ADR. The in silico study revealed that 1-(4-hydroxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(ethylamine) β-carboline, 1-(4-hydroxyphenyl)-3-carboxamide(propylamine) β-carboline, 1-(4-methoxyphenyl)-3-carboxamide(propylamine) β-carboline and 1-(3-nitrophenyl)-3-carboxamide(propylamine) β-carboline compounds follow the rules established by Lipinski, suggesting that this compound has no problems with oral bioavailability. <![CDATA[Development of HPLC Analytical Techniques for Diterpene Glycosides from Stevia rebaudiana (Bertoni) Bertoni: Strategies to Scale-Up]]> Stevia rebaudiana is a plant well-known as a source of dozens of high potency non-caloric natural sweeteners, many of them still uncharacterized. Herein, we describe the development of several routine HPLC (high performance liquid chromatography) analytical techniques to better separate steviol glycosides. Different stationary phases/columns were used: reverse phase C-18, amino, HILIC (hydrophilic interaction chromatography), Sepaxdiol and Synergi. The advantages and disadvantages of each method for resolving the very polar and less polar elution regions are demonstrated. Strategies for scale up of the purification process of steviol glycosides to make it more economic are also summarized, emphasizing the advantages of using high efficiency normal phase chromatography in relation with reverse phase. Additionally, we also developed an easy and useful way for predicting yields and composition of the pools resulting from the preparative chromatography. The development of these analytical and preparative liquid chromatography techniques allowed the isolation of several steviol glycosides in gram quantities at relatively low cost. <![CDATA[An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains of <em>Burkholderia thailandensis</em> spp.]]> The present study aimed to investigate the intraspecific variation of biosynthetic gene clusters (BGCs) in different strains of Burkholderia thailandensis in order to guide natural products (NPs) discovery process. Species from the genus Burkholderia are emerging as promising species due to their biosynthetic potential. Through genome-mining strategies, it was able to identify that B. thailandensis strains present major genome variation between chromosomes I and II and the standard. The positioning of BGCs also differs when comparing each chromosome. Classical pathways as well as terpene and bacteriocins were commonly identified to all of them and BGCs related to the production of nonribosomal peptides and polyketides compounds are often noticed. In addition, hybrids BGCs were identified as using large amount of replicon information. Among all species studied, the strain MSMB121 showed greater potential for biosynthesizing novel natural products and after phylogenetic analysis, the likelihood of recognizing sites of novelties was assigned. <![CDATA[New Dereplication Method Applied to NMR-Based Metabolomics on Different <em>Fusarium</em> Species Isolated from Rhizosphere of <em>Senna spectabilis</em>]]> The search for new sources of natural products steadily increased the use of bioinformatic tools that enabled efficient analysis of complex matrices. In this context, dereplication methods emerged as a fast way of identifying known compounds, accelerating the identification of bioactive chemotypes. Although 1H NMR is widely used as an analytical technique, few studies have been reported using it as a dereplication tool, primarily because of the spectral complexity. This work aims to create a new computational method that analyses 1H NMR data from Fusarium solani and F. oxysporum isolated from Senna spectabilis's rhizosphere through principal component analysis (PCA). The algorithm uses loading values to select important peaks that distinguish both species in PCA, allowing compound dereplication, even in highly similar profiles. As a result, the method, associated with other NMR experiments and information from an in-house Fusarium's metabolite library was able to distinguish different mycotoxins produced by both fungi, identifying fusaric acid and beauvericin for F. oxysporum and the depsipeptide HA23 from F. solani. <![CDATA[Annularins I and J: New Metabolites Isolated from Endophytic Fungus <em>Exserohilum rostratum</em>]]> The paper describes the isolation of ergosterol peroxide, monocerin, annularin I and annularin J compounds of Exserohilum rostratum biomass extracts. Compounds were isolated by silica gel column chromatography in polarity gradient and the structures were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS) methods. Monocerin, annularin I and annularin J compounds were tested against Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis bacteria and showed moderate activity. Annularin I and annularin J compounds are new natural products. <![CDATA[Pyrrolizidine Alkaloids in the Pericopine Moth <em>Scearctia figulina</em> (Erebidae: Arctiinae): Metabolism and Chemical Defense]]> Pyrrolizidine alkaloids (PAs) are defensive compounds present in several plant families. However, some specialist herbivore insects have overcome these toxic compounds and sequester PAs converted to N-oxide as a defense against predators and a precursor of male sexual pheromones. In this context, we investigated PA sequestration by the specialist pericopine moth Scearctia figulina (Erebidae: Arctiinae), which feeds on leaves of Heliotropium transalpinum (Boraginaceae) as larvae. Additionally, we examined the role of PAs against different predators. The PAs sequestered from the host plant were metabolized by larvae and transferred to adults via two main pathways: (i) rinderine and its acetyl derivative (7S,3'R) were epimerized to intermedine (7R,3'R) and lycopsamine (7R,3'S), and (ii) insect PAs were biosynthesized from necine bases obtained from plant-acquired PAs, with necic acids of insect origin. Both metabolic products may be related to the biosynthesis of 7R male pheromone and to chemical defense. Larvae and adults were chemically protected against the spiders Nephila clavipes and Lycosa erythrognatha and the chick Gallus gallus, and this defense may be associated to PAs. <![CDATA[Copper and Manganese Cations Alter Secondary Metabolism in the Fungus <em>Penicillium brasilianum</em>]]> The fungus Penicillium brasilianum LaBioMMi 136 was isolated as an endophyte from Melia azedarach and has shown to be a prominent producer of great diversity of secondary metabolites, although it does not express some biosynthetic routes to other natural compounds found in Penicillium genera. The present study aimed at the diversification of P. brasilianum secondary metabolism by varying the chemical composition used for its growth. Medium composition supplemented with CuSO4 and MnSO4 locked verruculogen biosynthesis and addressed proline to the production of a series of cyclodepsipeptides identified as JBIR 113, JBIR 114 and JBIR 115, never described for this species so far. The induced cyclodepsipeptide JBIR 113 was isolated by the use of combined chromatographic procedures and identified by spectroscopic methods. The unique structure with three neighboring cyclic amino acids proline and twice pipecolinic acid is rare as natural products and has been described for the first time in terrestrial organism. Verruculogen and JBIR 113 exhibited weak antiparasitary activity against Leishmania amazonensis. <![CDATA[Generation of Volatile Compounds from Carotenoids of <em>Dunaliella bardawil</em> Algae by Water Bath Heating and Microwave Irradiation]]> The volatile compounds formed by thermal degradation of the carotenoids present in Dunaliella bardawil were investigated by microwave irradiation (MW) and water bath heating (WB) in different conditions of temperature and time using central composite design. Volatiles extraction by solid phase microextraction (SPME) was optimized and performed at 40 °C for 15 minutes, and those in greater amount were quantified by a validated method of gas chromatography coupled to a quadrupole mass spectrometer (GC-qMS). Employing WB, 10, 12 and 120 ng mL-1 of β-cyclocitral, α-ionone e β-ionone, respectively, were obtained between 60 and 87 °C for 30-75 min, while by MW, 5, 5, 50 ng mL-1 were obtained between 75-107 °C for 1.5-2.8 min. Considering the shorter time of MW, it can be concluded that if the time necessary to obtain the best yield by WB is employed in multiple MW cycles, an amount 10 times greater of those compounds would be obtained by MW than by WB. The results suggest a new biotechnology application for the carotenoids of the microalgae of the Dunaliella genus. <![CDATA[(E)-4-Oxo-2-hexenal Dimers in the Scent Glands of the Bark Bug <em>Phloea subquadrata</em> (Heteroptera, Phloeidae)]]> Bark bugs belonging to the family Phloeidae are known for their camouflage on tree trunks. The nymphs store in dorsal abdominal glands defensive secretions with a pungent odor mainly constituted of (E)-2-hexenal, (E)-2-octenal, and (E)-4-oxo-2-hexenal. The metathoracic glands of adults (male and female) store (E)-2-hexen-1-ol and (E)-2-hexenyl acetate, which are less irritating than their corresponding aldehydes. Additional compounds of m/z 224 were detected in the scent glands of these insects and were previously suggested to be dimers of the (E)-4-oxo-2-hexenal. Thus, the aim of this study was to elucidate the details of the chemical structure of the dimers found in the scent glands of Phloea subquadrata. These dimers were obtained by synthesis and were compared with the natural products, confirming the dimeric structures of the latter. These (E)-4-oxo-2-hexenal dimeric compounds are novel and have not been reported before. <![CDATA[Genome Mining of Endophytic <em>Streptomyces wadayamensis</em> Reveals High Antibiotic Production Capability]]> The actinobacteria Streptomyces wadayamensis A23, an endophitic strain, was recently sequenced and previous work showed qualitatively that the strain inhibits the growth of some pathogens. Herein we report the genome analysis of S. wadayamensis which reveals several antibiotic biosynthetic pathways. Using mass spectrometry, we were able to identify desferoxamines, several antimycins and candicidin, as predicted. Additionally, it was possible to confirm that the biosynthetic machinery of the strain when compared to identified known metabolites is far underestimated. As suggested by biochemical qualitative tests, genome encoded information reveals that the strain A23 has high capability to produce antibiotics. <![CDATA[Chemical Profiling of Ginseng Species and Ginseng Herbal Products Using UPLC/QTOF-MS]]> The chemical profiles of four ginseng roots samples from three species of ginseng (Panax quinquefolius, Panax ginseng and Panax notoginseng) and two commercial ginseng products containing P. quinquefolius and red P. ginseng were compared using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC/QTOF-MS). Principal component analysis allowed a holistic approach in showing distinct chemical differences between the three ginseng species and correct classification of the two commercial products to their respective species. Further investigation of the chemical profile variations yielded ten main markers that were distinct for the three species. This study shows the potential of chemical profiling for the classification of complex natural product samples, such as ginseng, and application to commercial products sold in the market. This methodology can assist the industry in authenticating the various species of ginseng and providing a quick assessment of the quality of commercial ginseng products. <![CDATA[Diurnal Pattern of Leaf, Flower and Fruit Specific Ambient Volatiles above an Oil Palm Plantation in Pará State, Brazil]]> Oil palm plantations are rapidly expanding in the tropics because of insatiable global demand for fruit oil to be used in food, biofuels and cosmetics. Here we show that three tissue-specific volatiles can be quantified in ambient air above an African-American hybrid oil palm plantation in Brazil and linked photosynthesis (isoprene), floral scent (estragole), and for the first time, fruit oil processing (6-methyl-5-hepten-2-one, MHO). Plant enclosure techniques verified their tissue specific emission sources with ambient concentrations displaying distinct diurnal patterns above the canopy. Isoprene concentrations were near zero at night, but dramatically increased during the day while estragole showed elevated concentrations at night suggesting a light-independent, temperature-driven emission pattern from flowers. MHO also showed elevated concentrations at night and both estragole and MHO increased during the day. Our observations demonstrate that the African-American oil palm hybrid is strong isoprene emitter and suggest that MHO is a specific oxidation product of lycopene released during the industrial processing of palm oil. This study highlights the potential value of quantifying volatile oil palm signals in the atmosphere as a novel, non-invasive method to better understand biological functioning and its interactions with the environment including carbon assimilation, floral-insect interactions, and fruit oil production/processing. <![CDATA[Rapid Detection of ACTG- and AK-Toxins in <em>Alternaria alternata</em> by LC-ESI-MS/MS Analysis and Antifungal Properties of Citrus Compounds]]> A methanol-soluble fraction of the dichloromethane extract from the culture broth of A. alternata AT4303 strain afforded the following five known mycotoxins: alternariol, alternariol monomethyl ether, altenusin, altenuene and altertoxin I. A hexane-soluble fraction of the dichloromethane extract yielded the steroids ergosterol and ergosterol peroxide, and alternariol monomethyl ether. The concentrated ethyl acetate extract afforded the nucleoside uridine, uracil and inosine. The micro-extracts obtained from this strain in solid media were analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), and the following five known toxins were identified: ACTG-C, D, E and F and AK-toxin II. The major toxins produced by the tangerine pathotype ACT-toxins appear to be absent in strain AT4303. However, the low concentration of ACT-toxins appears to be responsible for their lack of detection in this study. Some compounds isolated from citrus plants were tested for in vitro activity against this strain. The results indicated that 17.3 µM apigenin-7-O-rutinoside inhibited by 80% conidial germination and appressorium development. <![CDATA[Identification and Synthesis of the Male-Produced Sex Pheromone of the Soldier Beetle <em>Chauliognathus fallax</em> (Coleoptera: Cantharidae)]]> Chauliognathus fallax Germar 1824 (Coleoptera: Cantharidae) occurs in North and South America and Australia. Gas chromatographic (GC) analyses of volatiles released by adults showed the presence of a male specific compound. GC coupled with electroantennographic detection (GC-EAD) showed that this compound is exclusively bioactive on female antennae, suggesting it to be a sex pheromone. GC coupled with mass spectrometry (GC-MS) and Fourier transform infrared spectroscopy (GC-FTIR), as well as dimethyl disulfide (DMDS) derivatization and hydrogenation, suggested the target compound to be (Z)-tricos-11-ene. Unambiguous structural proof was achieved by independent synthesis, whereas the biological significance of the compound as a sex pheromone was confirmed by field bioassays. <![CDATA[Urease Inhibitors of Agricultural Interest Inspired by Structures of Plant Phenolic Aldehydes]]> The plant phenolic natural products (PNPs) protocatechuic aldehyde, syringaldehyde and vanillin were used as platforms for obtaining four urease inhibitors. Urea (urease substrate) or thiourea (urease inhibitor) core was added to the structure of newly synthesized compounds to provide inhibitors up to 230-fold more active than the PNPs they originated from. The PNP derivatives are mixed inhibitors with higher affinity to urease active site. Two compounds were as efficient as N-(butyl)thiophosphoric triamide (NBPT) toward soil. Overall, PNPs derivatives are promising urease inhibitors for use as additive in urea-based fertilizers formulations.