Publications by authors named "Antonio G Ferreira"

72 Publications

A novel family of nonribosomal peptides modulate collective behavior in Pseudovibrio bacteria isolated from marine sponges.

Angew Chem Int Ed Engl 2021 May 7. Epub 2021 May 7.

University of Illinois at Chicago, Pharmaceutical Sciences, 900 S Ashland Ave, 60607, Chicago, UNITED STATES.

Although swarming motility and biofilms are opposed collective behaviors, both contribute to bacterial survival and host colonization. Pseudovibrio bacteria have attracted attention because they are part of the microbiome of healthy marine sponges. Two-thirds of Pseudovibrio genomes contain a member of a nonribosomal peptide synthetase-polyketide synthase gene cluster family, which is also found sporadically in Pseudomonas pathogens of insects and plants. After developing reverse genetics for Pseudovibrio, we isolated heptapeptides with an ureido linkage and related nonadepsipeptides we termed pseudovibriamides A and B, respectively. A combination of genetics and imaging mass spectrometry experiments showed heptapetides were excreted, promoting motility and reducing biofilm formation. In contrast to lipopeptides widely known to affect motility/biofilms, pseudovibriamides are not surfactants. Our results expand current knowledge on metabolites mediating bacterial collective behavior.
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http://dx.doi.org/10.1002/anie.202017320DOI Listing
May 2021

Influence of the seasonality and of urban variables in the BTEX and PM atmospheric levels and risks to human health in a tropical coastal city (Fortaleza, CE, Brazil).

Environ Sci Pollut Res Int 2021 Apr 5. Epub 2021 Apr 5.

Laboratory for Assessment of Organic Contaminants (LACOr), Institute of Marine Sciences, Federal University of Ceará, Fortaleza, Ceará, 60165-081, Brazil.

The International Agency for Research on Cancer (IARC) classifies benzene in group 1 (carcinogenic to humans). Particulate matter (PM) has recently also been classified in this category. This was an advance toward prioritizing the monitoring of particles in urban areas. The aim of the present study was to assess levels of PM and BTEX (benzene, toluene, ethylbenzene, and xylene), the influence of meteorological variables, the planetary boundary layer (PBL), and urban variables as well as risks to human health in the city of Fortaleza, Brazil, in the wet and dry periods. BTEX compounds were sampled using the 1501 method of NIOSH and determined by GC-HS-PID/FID. PM was monitored using an air sampling pump with a filter holder and determined by the gravimetric method. Average concentrations of BTEX ranged from 1.6 to 45.5 μg m, with higher values in the wet period, which may be explained by the fact that annual distribution is influenced by meteorological variables and the PBL. PM levels ranged from 4.12 to 33.0 μg m and 4.18 to 86.58 μg m in the dry and wet periods, respectively. No seasonal pattern was found for PM, probably due to the influence of meteorological variables, the PBL, and urban variables. Cancer risk ranged from 2.46E to 4.71E and 1.72E to 2.01E for benzene and from 3.07E to 7.04E and 3.08E to 2.85E for PM in the wet and dry periods, respectively. Cancer risk values for benzene were above the acceptable limit established by the international regulatory agency in both the dry and wet periods. The results obtained of the noncarcinogenic risks for the compounds toluene, ethylbenzene, and xylene were within the limits of acceptability. The findings also showed that the risk related to PM is always greater among smokers than nonsmokers.
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http://dx.doi.org/10.1007/s11356-021-13590-6DOI Listing
April 2021

Analytical and clinical performance of molecular assay used by the Brazilian public laboratory network to detect and discriminate Zika, Dengue and Chikungunya viruses in blood.

Braz J Infect Dis 2021 Mar-Apr;25(2):101542. Epub 2021 Feb 13.

Oswaldo Cruz Foundation/Fiocruz, Institute of Technology in Immunobiology Bio-Manguinhos, Rio de Janeiro, RJ, Brazil. Electronic address:

In response to the Zika epidemics in Brazil, the ZDC molecular assay (Bio-Manguinhos) was developed and registered at the Brazilian Regulatory Agency of Health Surveillance - ANVISA. The circulation of Zika (ZIKV) Dengue (DENV) and Chikungunya (CHIKV) viruses and their clinical similarities are challenges to correctly diagnose these viruses. The simultaneous detection of ZIKV, DENV and CHIKV is an important tool for diagnosis and surveillance. Here, we present the analytical and clinical performance evaluation of ZDC molecular assay (Bio-Manguinhos) at the public health laboratories three years after its registration at ANVISA. The clinical performance demonstrates the ZDC molecular assay (Bio-Manguinhos) has 100% sensitivity and 100% specificity to detect and discriminate ZIKV, CHIKV, and DENV from clinical plasma samples. The ZDC molecular assay (Bio-Manguinhos) results were highly reproducible and no cross-reactivity was seen during testing with a panel of other infectious agents. In conclusion, the ZDC molecular assay (Bio-Manguinhos) is an accurate and reliable tool to monitor Zika, dengue and chikungunya infections in countries like Brazil with simultaneous circulation of the three viruses.
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http://dx.doi.org/10.1016/j.bjid.2021.101542DOI Listing
May 2021

Blood plasma metabolomics of children and adolescents with sickle cell anaemia treated with hydroxycarbamide: a new tool for uncovering biochemical alterations.

Br J Haematol 2021 Mar 21;192(5):922-931. Epub 2021 Jan 21.

Bahiana School of Medicine and Public Health, Salvador, Bahia, Brasil.

Sickle cell anaemia (SCA) is a debilitating genetic haemoglobinopathy predominantly affecting the disenfranchised strata of society in Africa and the Americas. The most common pharmacological treatment for this disease is the administration of hydroxycarbamide (HC) for which questions remain regarding its mechanism of action, efficacy and long-term toxicity specifically in paediatric individuals. A multiplatform metabolomics approach was used to assess the metabolome of plasma samples from a population of children and adolescents with SCA with and without HC treatment along with non-SCA individuals. Fifty-three metabolites were identified by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) and H nuclear magnetic resonance (NMR) with a predominance of membrane lipids, amino acids and organic acids. The partial least-squares discriminant analysis (PLS-DA) analysis allowed a clear discrimination between the different studied groups, revealing clear effects of the HC treatment in the patients' metabolome including rescue of specific metabolites to control levels. Increased creatine/creatinine levels under HC treatment suggests a possible increase in the arginine pool and increased NO synthesis, supporting existing models for HC action in SCA. The metabolomics results extend the current knowledge on the models for SCA pathophysiology including impairment of Lands' cycle and increased synthesis of sphingosine 1-phosphate. Putative novel biomarkers are suggested.
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http://dx.doi.org/10.1111/bjh.17315DOI Listing
March 2021

Metabolomics Reveals Minor Tambjamines in a Marine Invertebrate Food Chain.

J Nat Prod 2021 03 29;84(3):790-796. Epub 2020 Dec 29.

Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP, São Carlos, SP 13560-970, Brazil.

Metabolomics analysis detected tambjamine alkaloids in aqueous and EtOAc extracts of the marine invertebrates , , , and . Among several tambjamines, the new amino acid derivatives tambjamines M-O (-) were identified by Marfey's advanced analysis, UPLC-MS/MS analyses, and total synthesis. The tambjamine diversity increased from the bryozoan to its nudibranch predators and and attained a higher diversity in , the nudibranch that preys upon and . The total tambjamine content also increases among the trophic levels, probably due to biomagnification. Tambjamines A (), C (), and D () are the major metabolites in the tissues of , , , and and are likely the main chemical defenses of these marine invertebrates.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01043DOI Listing
March 2021

Ruthenium(II) Phosphine/Mercapto Complexes: Their in Vitro Cytotoxicity Evaluation and Actions as Inhibitors of Topoisomerase and Proteasome Acting as Possible Triggers of Cell Death Induction.

Inorg Chem 2020 Oct 30;59(20):15004-15018. Epub 2020 Sep 30.

Departamento de Química, Universidade Federal de São Carlos, CEP 13565-905 São Carlos, São Paulo, Brazil.

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF (-), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, ), 2-mercaptopyrimidine (pySm, ), and 4,6-diamino-2-mercaptopyrimidine (damp, ), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by H-P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01835DOI Listing
October 2020

Development of a New Lateral Flow Assay Based on IBMP-8.1 and IBMP-8.4 Chimeric Antigens to Diagnose Chagas Disease.

Biomed Res Int 2020 17;2020:1803515. Epub 2020 Aug 17.

Gonçalo Moniz Institute (Fiocruz/BA), Salvador, Brazil.

Despite several available methodologies for Chagas disease (CD) serological screening, the main limitation of chronic CD diagnosis is the lack of effective tools for large-scale screening and point-of-care diagnosis to be used in different CD epidemiological scenarios. Taking into account that developing such a diagnostic tool will significantly improve the ability to identify CD carriers, we aimed at performing a proof-of-concept study (phase I study) to assess the use of these proteins in a point-of-care platform using serum samples from different geographical settings of Brazil and distinct clinical presentations. The diagnostic accuracy study was conducted on a panel of two WHO International Standards (IS) and 14 sera from -positive and 16 from -negative individuals. The results obtained with the test strips were converted to digital images, allowing quantitative comparison expressed as a relative band intensity ratio (RBI). The diagnostic potential and performance were also determined. Regardless of the geographical origin or clinical presentation, all sera with antibodies returned positive both for IBMP-8.1 and IBMP-8.4 chimeric antigens. The area under the ROC curve (AUC) values was 100% for both antigens, demonstrating an outstanding overall diagnostic accuracy (100%). Based on the data, we believe that the lateral flow assays based on these antigens are promising methodologies for screening CD.
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http://dx.doi.org/10.1155/2020/1803515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450325PMC
April 2021

Antiproliferative Flavanoid Dimers Isolated from Brazilian Red Propolis.

J Nat Prod 2020 06 11;83(6):1784-1793. Epub 2020 Jun 11.

Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP 13560-970, São Carlos, SP, Brazil.

Herein reported are results of the chemical and biological investigation of red propolis collected at the Brazilian Northeast coastline. New propolones A-D (-), with a 3-{3-[(2-phenylbenzofuran-3-yl)methyl]phenyl}chromane skeleton; propolonones A-C (-), with a 3-[3-(3-benzylbenzofuran-2-yl)phenyl]chromane skeleton; and propolol A (), with a 6-(3-benzylbenzofuran-2-yl)-3-phenylchromane skeleton, were isolated as constituents of Brazilian red propolis by cytotoxicity-guided assays and structurally identified by analysis of their spectroscopic data. Propolone B () and propolonone A () display significant cytotoxic activities against an ovarian cancer cell line expressing a multiple drug resistance phenotype when compared with doxorubicin.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01136DOI Listing
June 2020

Merulinic acid C overcomes gentamicin resistance in Enterococcus faecium.

Bioorg Chem 2020 07 12;100:103921. Epub 2020 May 12.

Brazilian Biosciences National Laboratory (LNBio), CNPEM, 13083-970 Campinas, SP, Brazil; Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS), Grenoble, France. Electronic address:

Enterococci are gram-positive, widespread nosocomial pathogens that in recent years have developed resistance to various commonly employed antibiotics. Since finding new infection-control agents based on secondary metabolites from organisms has proved successful for decades, natural products are potentially useful sources of compounds with activity against enterococci. Herein are reported the results of a natural product library screening based on a whole-cell assay against a gram-positive model organism, which led to the isolation of a series of anacardic acids identified by analysis of their spectroscopic data and by chemical derivatizations. Merulinic acid C was identified as the most active anacardic acid derivative obtained against antibiotic-resistant enterococci. Fluorescence microscopy analyses showed that merulinic acid C targets the bacterial membrane without affecting the peptidoglycan and causes rapid cellular ATP leakage from cells. Merulinic acid C was shown to be synergistic with gentamicin against Enterococcus faecium, indicating that this compound could inspire the development of new antibiotic combinations effective against drug-resistant pathogens.
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http://dx.doi.org/10.1016/j.bioorg.2020.103921DOI Listing
July 2020

Chronic Influence of Inspiratory Muscle Training at Different Intensities on the Serum Metabolome.

Metabolites 2020 Feb 21;10(2). Epub 2020 Feb 21.

Physical Therapy Department, Federal University of São Carlos, São Carlos, SP 13565-905, Brazil.

This study investigated the chronic effect of inspiratory muscle training (IMT) on the human serum metabolome in healthy male recreational cyclists. Using a randomized, parallel group design, twenty-eight participants were randomized to three IMT groups: low intensity (LI, = 7); moderate intensity (MI, = 10); and high intensity (HI, = 11). The IMT was performed for 11 weeks. Another group of participants under the same conditions, who did not perform the IMT but participated in all procedures, was included as controls (CG, = 6). Blood samples were collected one week before and after 11 weeks of IMT and analyzed for metabolite shifts using 1H NMR. Statistical analysis included a 4 (group) × 2 (time) repeated measures ANOVA using the general linear model (GLM), and multivariate principal component analysis (PCA). Untargeted metabolomics analysis of serum samples identified 22 metabolites, including amino acids, lipids, and tricarboxylic acid cycle intermediates. Metabolites shifts did not differ between groups, indicating that IMT at three intensity levels did not alter the serum metabolome relative to the control group. These results reveal novel insights into the metabolic effects of the IMT and are consistent with the results from other studies showing negligible chronic alterations in the serum metabolome in response to physical training.
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http://dx.doi.org/10.3390/metabo10020078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073856PMC
February 2020

Water-Soluble Glutamic Acid Derivatives Produced in Culture by IS1-A from King George Island, Maritime Antarctica.

J Nat Prod 2020 01 2;83(1):55-65. Epub 2020 Jan 2.

Instituto de Química de São Carlos , Universidade de São Paulo , CP 780, CEP 13560-970 , São Carlos , SP , Brazil.

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-, anti-, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of IS1-A provided the new glutamic acid derivatives solitumine A (), solitumine B (), and solitumidines A-D (-). The structures of compounds - have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds -, the new structures reported for - indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00635DOI Listing
January 2020

Green Extraction Approaches for Carotenoids and Esters: Characterization of Native Composition from Orange Peel.

Antioxidants (Basel) 2019 Dec 3;8(12). Epub 2019 Dec 3.

Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via Consolare Valeria, 98125 Messina, Italy.

Orange peel is a by-product produced in large amounts that acts as a source of natural pigments such as carotenoids. Xanthophylls, the main carotenoid class found in citrus fruit, can be present in its free form or esterified with fatty acids, forming esters. This esterification modifies the compound's chemical properties, affecting their bioavailability in the human body, and making it important to characterize the native carotenoid composition of food matrices. We aimed to evaluate the non-saponified carotenoid extracts of orange peel (cv. Pera) obtained using alternative green approaches: extraction with ionic liquid (IL), analyzed by high performance liquid chromatography coupled to a diode array detector with atmospheric pressure chemical ionization and mass spectrometry HPLC-DAD-APCI-MS, and supercritical fluid extraction (SFE), followed by supercritical fluid chromatography with atmospheric pressure chemical ionization and triple quadrupole mass spectrometry detection (SFC-APCI/QqQ/MS) in an online system. Both alternative green methods were successfully applied, allowing the total identification of five free carotenoids, one apocarotenoid, seven monoesters, and 11 diesters in the extract obtained with IL and analyzed by HPLC-DAD-APCI-MS, and nine free carotenoids, six carotenoids esters, 19 apocarotenoids, and eight apo-esters with the SFE-SFC-APCI/QqQ/MS approach, including several free apocarotenoids and apocarotenoid esters identified for the first time in oranges, and particularly in the Pera variety, which could be used as a fruit authenticity parameter.
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http://dx.doi.org/10.3390/antiox8120613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943544PMC
December 2019

Resistance mutations of NS3 and NS5b in treatment-naïve patients infected with hepatitis C virus in Santa Catarina and Rio Grande do Sul states, Brazil.

Genet Mol Biol 2020 17;43(1):e20180237. Epub 2020 Feb 17.

Fundação Oswaldo Cruz/Fiocruz, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Rio de Janeiro, RJ, Brazil.

Hepatitis C virus (HCV) infection is a worldwide health problem. Nowadays, direct-acting antiviral agents (DAAs) are the main treatment for HCV; however, the high level of virus variability leads to the development of resistance-associated variants (RAVs). Thus, assessing RAVs in infected patients is important for monitoring treatment efficacy. The aim of our study was to investigate the presence of naturally occurring resistance mutations in HCV NS3 and NS5 regions in treatment-naïve patients. Ninety-six anti-HCV positive serum samples from blood donors at the Center of Hematology and Hemotherapy of Santa Catarina State (HEMOSC) were collected retrospectively in 2013 and evaluated in this study. HCV 1a (37.9%), 1b (25.3%), and 3a (36.8%) subtypes were found. The frequency of patients with RAVs in our study was 6.9%. The HCV NS5b sequencing reveled 1 sample with L320F mutation and 4 samples with the C316N/R polymorphism. The analysis of the NS3 region revealed the D168A/G/T (3.45%), S122G (1.15%), and V55A (2.3%) mutations. All samples from genotype 3a (36.8%) presented the V170 I/V non-synonymous mutation. In conclusion, we have shown that mutations in NS3 and NS5b genes are present in Brazilian isolates from therapy-naïve HCV patients.
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http://dx.doi.org/10.1590/1678-4685-GMB-2018-0237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229887PMC
February 2020

In vitro cytotoxicity and in vivo zebrafish toxicity evaluation of Ru(ii)/2-mercaptopyrimidine complexes.

Dalton Trans 2019 May;48(18):6026-6039

Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goias-UFG, CEP 74690-900 Goiania, Goias, Brazil.

In this paper, four new ruthenium complexes, [Ru(N-S)(dppm)2]PF6 (1), [Ru(N-S)(dppe)2]PF6 (2), [Ru(N-S)2(dppp)] (3) and [Ru(N-S)2(PPh3)2] (4) [dppm = 1,1-bis(diphenylphosphino)methane, dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, PPh3 = triphenylphosphine and N-S = 2-mercaptopyrimidine anion] were synthesized and characterized using spectroscopy techniques, molar conductance, elemental analysis, electrochemical techniques and X-ray diffraction. The DNA binding studies were investigated using voltammetry and spectroscopy techniques. The results show that all complexes exhibit a weak interaction with DNA. HSA interaction with the complexes was studied using fluorescence emission spectroscopy, where the results indicate a spontaneous interaction between the species by a static quenching mechanism. The cytotoxicity of the complexes was evaluated against A549, MDA-MB-231 and HaCat cells by MTT assay. Complexes (1) and (2), which are very active against triple negative MDA-MB-231, were subjected to further biological tests with this cell line. The cytotoxic activity triggered by the complexes was confirmed by clonogenic assay. Cell cycle analyses demonstrated marked anti-proliferative effects, especially at the G0/G1 and S phases. The morphological detection of apoptosis and necrosis - HO/PI and Annexin V-FITC/PI assay, elucidated that the type of cell death triggered by these complexes was probably by apoptosis. The in vivo toxicological assessment performed on zebrafish embryos revealed that complexes (1) and (2) did not present embryotoxic or toxic effects during embryonic and larval development showing that they are promising new prototypes of safer and more effective drugs for triple negative breast cancer treatment.
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http://dx.doi.org/10.1039/c8dt03738hDOI Listing
May 2019

Bromopyrrole Alkaloid Inhibitors of the Proteasome Isolated from a Dictyonella sp. Marine Sponge Collected at the Amazon River Mouth.

J Nat Prod 2018 10 3;81(10):2296-2300. Epub 2018 Oct 3.

Instituto de Química de São Carlos , Universidade de São Paulo , CP 780 , CEP 13560-970 , São Carlos , SP , Brazil.

The new pyrrole-imidazole and pyrrole-guanidine alkaloids 4-debromooroidin (1), 4-debromougibohlin (2), 5-debromougibohlin (3), and 5-bromopalau'amine (4), along with the known hymenidin (5) and (+)-monobromoisophakellin (6), have been isolated from a Dictyonella sp. marine sponge, collected at the Amazon River mouth. The bromine-substitution pattern observed for compounds 1, 2 and 4 is unusual among bromopyrrole alkaloids isolated from marine sponges. The 20S proteasome inhibitory activities of compounds 1-6 have been recorded, with 5-bromopalau'amine (4) being the most active in this series.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00533DOI Listing
October 2018

One-step real-time PCR assay for detection and quantification of RNA HCV to monitor patients under treatment in Brazil.

Braz J Infect Dis 2018 Sep - Oct;22(5):418-423. Epub 2018 Sep 20.

Federal University of Rio de Janeiro - UFRJ, Brazil.

The Brazilian Public Health Service provides freely αPEG-IFN to treat patients infected with HCV. The primary goal of HCV therapy is the long-term elimination of HCV from the blood to reduce the risk of HCV associated complications and death. Patient viremia affects the treatment duration and response, thus influencing clinical decisions. We developed a high-throughput method to perform the quantification of RNA hepatitis C virus (HCV) virus load in plasma samples to monitor patients under treatment. The method is based on a duplex detection, in a one-step real-time RT-PCR assay and it has been validated according to the rules established by the official Brazilian regulatory agency (ANVISA). This new method was compared to a commercial kit (Cobas/Taqman HCV Test v2.0 - Roche), showing virus load results with significant correlation between them (p = 0,012) using commercial and clinical panels. In addition, 611 samples from patients treated with peguilated alfa-interferon (αPEG-IFN) from different regions of Brazil were analyzed. Our one-step real-time RT-PCR assay demonstrated good performance in viral load measurement and in treatment course monitoring, with acceptable sensitivity and specificity values.
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http://dx.doi.org/10.1016/j.bjid.2018.08.003DOI Listing
January 2019

Isolation, synthesis and bioactivity studies of phomactin terpenoids.

Nat Chem 2018 09 30;10(9):938-945. Epub 2018 Jul 30.

Department of Chemistry, University of California, Berkeley, CA, USA.

Studies of secondary metabolites (natural products) that cover their isolation, chemical synthesis and bioactivity investigation present myriad opportunities for discovery. For example, the isolation of novel secondary metabolites can inspire advances in chemical synthesis strategies to achieve their practical preparation for biological evaluation. In the process, chemical synthesis can also provide unambiguous structural characterization of the natural products. Although the isolation, chemical synthesis and bioactivity studies of natural products are mutually beneficial, they are often conducted independently. Here, we demonstrate the benefits of a collaborative study of the phomactins, diterpenoid fungal metabolites that serve as antagonists of the platelet activating factor receptor. Our isolation of novel phomactins has spurred the development of a bioinspired, unified approach that achieves the total syntheses of six congeners. We also demonstrate in vitro the beneficial effects of several phomactins in suppressing the rate of repopulation of tumour cells following gamma radiation therapy.
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http://dx.doi.org/10.1038/s41557-018-0084-xDOI Listing
September 2018

Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations.

J Mol Model 2018 Jul 14;24(8):207. Epub 2018 Jul 14.

Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemicals and Biological Sciences, University of Karachi, Karachi, 75210, Pakistan.

Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (K) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with K = 30 μM ,even greater than tacrine (K = 140 μM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.
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http://dx.doi.org/10.1007/s00894-018-3751-3DOI Listing
July 2018

Eucalyptus xylan: An in-house-produced substrate for xylanase evaluation to substitute birchwood xylan.

Carbohydr Polym 2018 Oct 31;197:167-173. Epub 2018 May 31.

Graduate Program in Chemical Engineering, Federal University of São Carlos, PO Box 676, São Carlos, São Paulo, Brazil; Chemical Engineering Department, Federal University of São Carlos, PO Box 676, São Carlos, São Paulo, Brazil. Electronic address:

Over the past decades, most studies with xylanases have used Birchwood xylan as the standard substrate for activity assays. However, recently, Birchwood xylan production was discontinued by major suppliers, creating an important demand for a substitute. Ongoing and future studies require a substrate with characteristics equivalent to the discontinued xylan, in order to enable the comparison of results. In this context, a protocol for the production of a substrate similar to the discontinued commercial Birchwood xylan is reported. Obtained from bleached Eucalyptus cellulose pulp, xylan was extracted using 4% w/v NaOH solution at 25 °C, precipitated with glacial acetic acid (HOAc), and freeze-dried. A thermal pretreatment in an autoclave for 15 min increased its solubility. The resulting xylan was characterized by infrared spectroscopy, thermogravimetry, and NMR. When assessing the activity of xylanases, the results were the same as those for commercial Birchwood xylan.
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http://dx.doi.org/10.1016/j.carbpol.2018.05.088DOI Listing
October 2018

Hydrolysis reaction promotes changes in coordination mode of Ru(II)/acylthiourea organometallic complexes with cytotoxicity against human lung tumor cell lines.

J Inorg Biochem 2018 09 18;186:147-156. Epub 2018 Jun 18.

Departamento de Química, Universidade Federal de São Carlos - UFSCar, Rodovia Washington Luís KM 235, CP 676, 13565-905 São Carlos, SP, Brazil. Electronic address:

In this study, Ru(II)-arene complexes with acylthiourea ligands of the type [Ru(η‑p‑cymene)(PPh)(T)Cl]PF(1-5) and [Ru(η‑p‑cymene)(PPh)(T)]PF(1a, 4a), where PPh = triphenylphosphine and T = N‑acyl‑N'(monosubstituted)thiourea, were synthesized and characterized, and their cytotoxic properties were also evaluated. 1a and 4a were obtained from the hydrolysis reaction of 1 and 4. All complexes showed unusual coordination modes for acylthiourea ligands, which are coordinated in a monodentate fashion (S) in 1-5, while they found to be bidentate (S,N), in 1a and 4a. To the best of our knowledge, 1a and 4a are the first crystallographically reported ruthenium compounds with acylthiourea coordinated via S and N(amide) atoms. The cytotoxicity of the compounds was evaluated in human lung cells, A549 and MRC-5. The IC values ranging from 0.25 to 0.61 μM after 48 h incubation in lung cancer cells indicate that the compounds showed high cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 μM). Interaction studies were carried out using human serum albumin (HSA) and DNA. All complexes showed similar cytotoxic activity, however complex 1a, which is the hydrolysis product of 1, presented the highest activity and selectivity among all seven compounds synthesized here. Complexes 1 and 1a inhibited the colony formation decreasing the colony size and inducing morphology changes in A549 cells. These complexes induced apoptosis cell death and promoted cell cycle arrest in the Sub-G1 phase with a decrease in the cell number at the S phase.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.06.007DOI Listing
September 2018

The potential of compounds isolated from Xylaria spp. as antifungal agents against anthracnose.

Braz J Microbiol 2018 Oct - Dec;49(4):840-847. Epub 2018 Mar 31.

Universidade de São Paulo, Escola Superior de Agricultura "Luiz de Queiroz", Departamento de Ciências Exatas, Piracicaba, SP, Brazil. Electronic address:

Anthracnose is a crop disease usually caused by fungi in the genus Colletotrichum or Gloeosporium. These are considered one of the main pathogens, causing significant economic losses, such as in peppers and guarana. The current forms of control include the use of resistant cultivars, sanitary pruning and fungicides. However, even with the use of some methods of controlling these cultures, the crops are not free of anthracnose. Additionally, excessive application of fungicides increases the resistance of pathogens to agrochemicals and cause harm to human health and the environment. In order to find natural antifungal agents against guarana anthracnose, endophytic fungi were isolated from Amazon guarana. The compounds piliformic acid and cytochalasin D were isolated by chromatographic techniques from two Xylaria spp., guided by assays with Colletotrichum gloeosporioides. The isolated compounds were identified by spectrometric techniques, as NMR and mass spectrometry. This is the first report that piliformic acid and cytochalasin D have antifungal activity against C. gloeosporioides with MIC 2.92 and 2.46μmolmL respectively. Captan and difenoconazole were included as positive controls (MIC 16.63 and 0.02μmolmL, respectively). Thus, Xylaria species presented a biotechnological potential and production of different active compounds which might be promising against anthracnose disease.
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http://dx.doi.org/10.1016/j.bjm.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175768PMC
December 2018

The Brazilian experience of nucleic acid testing to detect human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infections in blood donors.

Transfusion 2018 04 30;58(4):862-870. Epub 2018 Jan 30.

Institute of Technology in Immunobiology Bio-Manguinhos, Oswaldo Cruz Foundation/Fiocruz.

Background: The history of the development and implementation of the Brazilian nucleic acid testing (NAT) platform to detect and discriminate among human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections in blood donors is described here. The results for the sensitivity, reproducibility, and NAT yield of the platform since program implementation are provided.

Study Design And Methods: The Brazilian NAT HIV, HCV, and HBV kit was developed and evaluated with regard to analytical sensitivity, specificity, intralot and interlot reproducibility, interfering substances, and genotype and diagnostic sensitivity. Additionally, a sample of identified NAT-yield cases was characterized with regard to viral load.

Results: The 95% limits of detection for HIV, HCV, and HBV were 68.02, 102.35, and 9.08 IU/mL, respectively. All replicates were detected with reproducibility assays between the acceptable values. A total of 13,610,536 blood donors was screened from 2010 to 2016, and 63 HIV-yield cases and 28 HCV-yield cases were detected. Among 5,795,424 blood donors screened for HBV from 2014 to 2016, 42 yield cases were found.

Conclusion: The Brazilian NAT HIV, HCV, and HBV kit is an automated NAT system suitable for routine blood donor screening in a completely traceable process. The analytical sensitivity as well as the diagnostic sensitivity fulfilled all requirements set by the health ministry for blood donor screening. A significant number of transmission cases were prevented by the implementation of this important program.
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http://dx.doi.org/10.1111/trf.14478DOI Listing
April 2018

Isolation, Derivative Synthesis, and Structure-Activity Relationships of Antiparasitic Bromopyrrole Alkaloids from the Marine Sponge Tedania brasiliensis.

J Nat Prod 2018 01 3;81(1):188-202. Epub 2018 Jan 3.

Instituto de Química de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.

The isolation and identification of a series of new pseudoceratidine (1) derivatives from the sponge Tedania brasiliensis enabled the evaluation of their antiparasitic activity against Plasmodium falciparum, Leishmania (Leishmania) amazonensis, Leishmania (Leishmania) infantum, and Trypanosoma cruzi, the causative agents of malaria, cutaneous leishmaniasis, visceral leishmaniasis, and Chagas disease, respectively. The new 3-debromopseudoceratidine (4), 20-debromopseudoceratidine (5), 4-bromopseudoceratidine (6), 19-bromopseudoceratidine (7), and 4,19-dibromopseudoceratidine (8) are reported. New tedamides A-D (9-12), with an unprecedented 4-bromo-4-methoxy-5-oxo-4,5-dihydro-1H-pyrrole-2-carboxamide moiety, are also described. Compounds 4 and 5, 6 and 7, 9 and 10, and 11 and 12 have been isolated as pairs of inseparable structural isomers differing in their sites of bromination or oxidation. Tedamides 9+10 and 11+12 were obtained as optically active pairs, indicating an enzymatic formation rather than an artifactual origin. N-Acetylpseudoceratidine (2) and N-formylpseudoceratidine (3) were obtained by derivatization of pseudoceratidine (1). The antiparasitic activity of pseudoceratidine (1) led us to synthesize 23 derivatives (16, 17, 20, 21, 23, 25, 27-29, 31, 33, 35, 38, 39, 42, 43, 46, 47, 50, and 51) with variations in the polyamine chain and aromatic moiety in sufficient amounts for biological evaluation in antiparasitic assays. The measured antimalarial activity of pseudoceratidine (1) and derivatives 4, 5, 16, 23, 25, 31, and 50 provided an initial SAR evaluation of these compounds as potential leads for antiparasitics against Leishmania amastigotes and against P. falciparum. The results obtained indicate that pseudoceratidine represents a promising scaffold for the development of new antimalarial drugs.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989537PMC
January 2018

Mate extract as feed additive for improvement of beef quality.

Food Res Int 2017 09 30;99(Pt 1):336-347. Epub 2017 May 30.

Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador São-Carlense 400, CP 780, CEP 13560-970, São Carlos, SP, Brazil. Electronic address:

Mate (Ilex paraguariensis A.St.-Hil.) is generally recognized as safe (GRAS status) and has a high content of alkaloids, saponins, and phenolic acids. Addition of mate extract to broilers feed has been shown to increase the oxidative stability of chicken meat, however, its effect on beef quality from animals supplemented with mate extract has not been investigated so far. Addition of extract of mate to a standard maize/soy feed at a level of 0.5, 1.0 or 1.5% w/w to the diet of feedlot for cattle resulted in increased levels of inosine monophosphate, creatine and carnosine in the fresh meat. The content of total conjugated linoleic acid increased in the meat as mate extract concentration was increased in the feed. The tendency to radical formation in meat slurries as quantified by EPR spin-trapping decreased as increasing mate extract addition to feed, especially after storage of the meat, indicating higher oxidative stability. Mate supplementation in the diet did not affect animal performance and carcass characteristics, but meat from these animals was more tender and consequently more accepted by consumers. Mate extract is shown to be a promising additive to feedlot diets for cattle to improve the oxidative stability, nutritive value and sensory quality of beef.
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http://dx.doi.org/10.1016/j.foodres.2017.05.033DOI Listing
September 2017

Cultures of the Marine Bacterium Pseudovibrio denitrificans Ab134 Produce Bromotyrosine-Derived Alkaloids Previously Only Isolated from Marine Sponges.

J Nat Prod 2017 02 13;80(2):235-240. Epub 2017 Feb 13.

Instituto de Química de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.

Herein we report the isolation and spectroscopic identification of fistularin-3 (1), 11-hydroxyaerothionin (2), and verongidoic acid (3), as well as the UPLC-HRMS detection of aerothionin (4), homopurpuroceratic acid B (5), purealidin L (6), and aplysinamisine II (7), from cultures of the marine bacterium Pseudovibrio denitrificans Ab134, isolated from tissues of the marine sponge Arenosclera brasiliensis. These results unambiguously demonstrate for the first time that bromotyrosine-derived alkaloids that were previously isolated only from Verongida sponges can be biosynthesized by a marine bacterium.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00838DOI Listing
February 2017

Rearranged Terpenoids from the Marine Sponge Darwinella cf. oxeata and Its Predator, the Nudibranch Felimida grahami.

J Nat Prod 2017 03 13;80(3):720-725. Epub 2017 Feb 13.

Instituto de Química de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.

Marine sponges are a rich source of terpenoids with rearranged spongian carbon skeletons. Investigation of extracts from the sponge Darwinella cf. oxeata yielded four new rearranged diterpenoids, oxeatine (2) and oxeatamides H-J (3-5), as well as the known metabolites oxeatamide A (6), oxeatamide A methyl ester (7), and membranolide (1). Oxeatine (2) has a new heterocyclic skeleton, while oxeatamide J (5) has an N-methyl urea group included in a γ-lactam moiety. UPLC-QTOF analysis of the extract obtained from the mantle of the nudibranch Felimida grahami indicated the presence of 1 and 4.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01160DOI Listing
March 2017

A validated H NMR method for quantitative analysis of α-bisabolol in essential oils of Eremanthus erythropappus.

Talanta 2016 Dec 10;161:71-79. Epub 2016 Aug 10.

Laboratory of Nuclear Magnetic Resonance, Department of Chemistry, Universidade Federal de São Carlos, Via Washington Luís, Km 235, C.P. 676, São Carlos, SP, 13565-905 Brazil.

α-Bisabolol is a natural terpene produced by Eremanthus erythropappus and is widely used in cosmetics and pharmaceuticals due to its anti-inflammatory, antibacterial and antimycotic properties. Due to these applications, a control of composition and authenticity of commercial oils rich in this terpene is required, resulting in a demand for new methodologies for quality control. In this work a rapid and efficient method for quantification of α-bisabolol in the essential oil of E. erythropappus (candeia) using H NMR was developed, validated and compared to gas chromatography (GC) method. The quantification of α-bisabolol by H NMR was successfully achieved for most of the essential oil samples of E. erythropappus evaluated, except for those with a more complex composition. To circumvent this limitation a 2D NMR COSY contour map was used. This method proved to be a fast and efficient alternative, providing results with standard deviations SD<0.3%. All evaluated parameters (selectivity, linearity, accuracy/precision, repeatability, robustness and stability of analyte and internal standard in solution) gave satisfactory results. Using the H NMR signals at 5.36 and 5.13ppm, the limit of detection (LOD) and limit of quantification (LOQ) were 0.26 and 2.59mg, respectively. The results obtained by the H NMR method presented SD=0.59%, smaller than the value found for GC (SD=1.18%). Tukey tests have shown that the results obtained by H NMR and COSY methodology are similar to the obtained by the traditional GC-FID technique using external and internal standardization and normalization with 95% confidence.
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http://dx.doi.org/10.1016/j.talanta.2016.08.032DOI Listing
December 2016

Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway.

J Nat Prod 2016 06 26;79(6):1668-78. Epub 2016 May 26.

Instituto de Quimica de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived Penicillium sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins 6-8 and cyclosulfoxicurvularins 10 and 11, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, 3 and 4, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U-(13)C3(15)N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in 6-8 and the oxidized sulfoxide in 10 and 11. Cyclothiocurvularins A (6) and B (7) are formed by spontaneous reaction between 10,11-dehydrocurvularin (2) and mercaptopyruvate (12) obtained by transamination of cysteine. High ratios of [U-(13)C3(15)N]-l-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (7) and its methyl ester (8), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF2.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00295DOI Listing
June 2016

Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents.

Inorg Chem 2015 Dec 25;54(24):11709-20. Epub 2015 Nov 25.

Departamento de Química, Universidade Federal de São Carlos-UFSCar, CEP 13565-905, São Carlos-SP, Brazil.

Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl(P)2(CQ)]PF6 (where (P)2 = triphenylphosphine (PPh3) (5), 1,3-bis(diphenylphosphine)propane (dppp) (6), 1,4-bis(diphenylphosphine)butane (dppb) (7), 1,1'-bis(diphenylphosphine)ferrocene (dppf) (8), and CQ = chloroquine] and their precursors of the type [PtCl2(P)2] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet-visible (UV-vis) regions, multinuclear ((1)H, (13)C, (31)P, (15)N, and (195)Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum-chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB-231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs.
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http://dx.doi.org/10.1021/acs.inorgchem.5b01647DOI Listing
December 2015

Structure and Biogenesis of Roussoellatide, a Dichlorinated Polyketide from the Marine-Derived Fungus Roussoella sp. DLM33.

Org Lett 2015 Nov 7;17(21):5152-5. Epub 2015 Oct 7.

Instituto de Química de São Carlos, Universidade de São Paulo , CP 780, CEP 13560-970, São Carlos, SP, Brazil.

The structure of the fungal metabolite roussoellatide (1) has been established by spectroscopic and X-ray diffraction analyses. Results from feeding experiments with [1-(13)C]acetate, [2-(13)C]acetate, and [1,2-(13)C]acetate were consistent with a biosynthetic pathway to the unprecedented skeleton of 1 involving Favorskii rearrangements in separate pentaketides, subsequently joined via an intermolecular Diels-Alder reaction.
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http://dx.doi.org/10.1021/acs.orglett.5b02060DOI Listing
November 2015