144 results on '"Néstor M. Carballeira"'
Search Results
2. Synthesis of Marine α-Methoxylated Fatty Acid Analogs that Effectively Inhibit the Topoisomerase IB from Leishmania donovani with a Mechanism Different from that of Camptothecin
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Rosa M. Reguera, Christopher F. Prada, Raquel Alvarez-Velilla, Nashbly Montano, Néstor M. Carballeira, and Rafael Balaña-Fouce
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methoxylated fatty acids ,leishmania donovani ,2-methoxy-5,9-eicosadienoic acid ,topoisomerase IB ,Biology (General) ,QH301-705.5 - Abstract
Sponges biosynthesize α-methoxylated fatty acids with unusual biophysical and biological properties and in some cases they display enhanced anticancer activities. However, the antiprotozoal properties of the α-methoxylated fatty acids have been less studied. In this work, we describe the total synthesis of (5Z,9Z)-(±)-2-methoxy-5, 9-eicosadienoic acid (1) and its acetylenic analog (±)-2-methoxy-5,9-eicosadiynoic acid (2), and report that they inhibit (EC50 values between 31 and 22 µM) the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB). The inhibition of LdTopIB (EC50 = 53 µM) by the acid (±)-2-methoxy-6-icosynoic acid (12) was studied as well. The potency of LdTopIB inhibition followed the trend 2 > 1 > 12, indicating that the effectiveness of inhibition depends on the degree of unsaturation. All of the studied α-methoxylated fatty acids failed to inhibit the human topoisomerase IB enzyme (hTopIB) at 100 µM. However, the α-methoxylated fatty acids were capable of inhibiting an active but truncated LdTopIB with which camptothecin (CPT) cannot interact suggesting that the methoxylated fatty acids inhibit LdTopIB with a mechanism different from that of CPT. The diunsaturated fatty acids displayed low cytotoxicity towards Leishmania infantum promastigotes (EC50 values between 260 and 240 µM), but 12 displayed a better cytotoxicity towards Leishmania donovani promastigotes (EC50 = 100 µM) and a better therapeutic index.
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- 2013
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3. Synthetic Fatty Acids Prevent Plasmid-Mediated Horizontal Gene Transfer
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María Getino, David J. Sanabria-Ríos, Raúl Fernández-López, Javier Campos-Gómez, José M. Sánchez-López, Antonio Fernández, Néstor M. Carballeira, and Fernando de la Cruz
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Microbiology ,QR1-502 - Abstract
ABSTRACT Bacterial conjugation constitutes a major horizontal gene transfer mechanism for the dissemination of antibiotic resistance genes among human pathogens. Antibiotic resistance spread could be halted or diminished by molecules that interfere with the conjugation process. In this work, synthetic 2-alkynoic fatty acids were identified as a novel class of conjugation inhibitors. Their chemical properties were investigated by using the prototype 2-hexadecynoic acid and its derivatives. Essential features of effective inhibitors were the carboxylic group, an optimal long aliphatic chain of 16 carbon atoms, and one unsaturation. Chemical modification of these groups led to inactive or less-active derivatives. Conjugation inhibitors were found to act on the donor cell, affecting a wide number of pathogenic bacterial hosts, including Escherichia, Salmonella, Pseudomonas, and Acinetobacter spp. Conjugation inhibitors were active in inhibiting transfer of IncF, IncW, and IncH plasmids, moderately active against IncI, IncL/M, and IncX plasmids, and inactive against IncP and IncN plasmids. Importantly, the use of 2-hexadecynoic acid avoided the spread of a derepressed IncF plasmid into a recipient population, demonstrating the feasibility of abolishing the dissemination of antimicrobial resistances by blocking bacterial conjugation. IMPORTANCE Diseases caused by multidrug-resistant bacteria are taking an important toll with respect to human morbidity and mortality. The most relevant antibiotic resistance genes come to human pathogens carried by plasmids, mainly using conjugation as a transmission mechanism. Here, we identified and characterized a series of compounds that were active against several plasmid groups of clinical relevance, in a wide variety of bacterial hosts. These inhibitors might be used for fighting antibiotic-resistance dissemination by inhibiting conjugation. Potential inhibitors could be used in specific settings (e.g., farm, fish factory, or even clinical settings) to investigate their effect in the eradication of undesired resistances.
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- 2015
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4. An improved synthesis for the (Z)-14-methyl-9-pentadecenoic acid and its topoisomerase I inhibitory activity
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Néstor M. Carballeira, David Sanabria, and Delise Oyola
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Organic chemistry ,QD241-441 - Published
- 2006
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5. Vinyl halogenated fatty acids display antibacterial activity against clinical isolates of methicillin-resistant
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David J, Sanabria-Rios, Denisse, Alequin-Torres, Alenis, De Jesus, Giovanni, Cortes, and Néstor M, Carballeira
- Abstract
Methicillin-resistant
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- 2022
6. Antibacterial Activity of Hexadecynoic Acid Isomers toward Clinical Isolates of Multidrug‐Resistant <scp> Staphylococcus aureus </scp>
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Néstor M. Carballeira, David J. Sanabria-Ríos, Ashley Rivera‐Román, Joseph Mooney, Tomás Pereles‐De‐León, Solymar Medina, Damarith Díaz, Christian Morales-Guzman, Carlimar Ocasio-Malavé, and Nataliya E. Chorna
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Methicillin-Resistant Staphylococcus aureus ,0301 basic medicine ,Stereochemistry ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,DNA gyrase ,Article ,Gas Chromatography-Mass Spectrometry ,Structure-Activity Relationship ,03 medical and health sciences ,Bacterial Proteins ,Ciprofloxacin ,Drug Resistance, Multiple, Bacterial ,medicine ,Humans ,Antibacterial agent ,Microbial Viability ,030109 nutrition & dietetics ,biology ,Chemistry ,Organic Chemistry ,Cell Biology ,Staphylococcal Infections ,biology.organism_classification ,Triple bond ,Anti-Bacterial Agents ,Multiple drug resistance ,030104 developmental biology ,DNA Gyrase ,Staphylococcus aureus ,Alkynes ,Fatty Acids, Unsaturated ,Antibacterial activity ,Bacteria ,medicine.drug - Abstract
In the present study, the structural characteristics that impart antibacterial activity to C16 alkynoic fatty acids (aFA) were further investigated. The syntheses of hexadecynoic acids (HDA) containing triple bonds at C-3, C-6, C-8, C-9, C-10, and C-12 were carried out in four steps and with an overall yield of 34-78%. In addition, HDA analogs containing a sulfur atom at either C-4 or C-5 were also prepared in 69-77% overall yields, respectively. Results from this study revealed that the triple bond at C-2 is pivotal for the antibacterial activity displayed by 2-HDA, while the farther the position of the triple bond from the carbonyl group, the lower its bactericidal activity against gram-positive bacteria, including clinical isolates of methicillin-resistant Staphylococcus aureus (CIMRSA) strains. The potential of 2-HDA as an antibacterial agent was also assessed in five CIMRSA strains that were resistant to Ciprofloxacin (Cipro) demonstrating that 2-HDA was the most effective treatment in inhibiting their growth when compared with either Cipro alone or equimolar combinations of Cipro and 2-HDA. Moreover, it was proved that the inhibition of S. aureus DNA gyrase can be linked to the antibacterial activity displayed by 2-HDA. Finally, it was determined that the ability of HDA analogs to form micelles can be linked to their decreased activity against gram-positive bacteria, since critical micellar concentrations (CMC) between 50 and 300 μg/mL were obtained.
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- 2020
7. 2-Hexadecynoic acid targets Methicillin-Resistant Staphylococcus aureus plasma membrane and fatty acid synthesis
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David J. Sanabria-Ríos, Néstor M. Carballeira, Giancarlo Casillas-Vargas, and Carlimar Ocasio-Malavé
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chemistry.chemical_compound ,Membrane ,chemistry ,2-hexadecynoic acid ,medicine ,medicine.disease_cause ,Methicillin-resistant Staphylococcus aureus ,Fatty acid synthesis ,Microbiology - Published
- 2021
8. Synthesis of a novel brominated vinylic fatty acid with antileishmanial activity that effectively inhibits the Leishmania topoisomerase IB enzyme mediated by halogen bond formation
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Victorio Jauregui Matos, Adriano D. Andricopulo, Néstor M. Carballeira, Rafael Balaña-Fouce, Leonardo L. G. Ferreira, Leilani M. Lotti Diaz, Denisse Alequín, Rosa M. Reguera, Yolanda Pérez-Pertejo, and Mikhail Y. Golovko
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chemistry.chemical_classification ,0303 health sciences ,Halogen bond ,biology ,010405 organic chemistry ,Stereochemistry ,Chemistry ,General Chemical Engineering ,Topoisomerase ,Fatty acid ,Leishmaniasis ,General Chemistry ,biology.organism_classification ,Leishmania ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,Enzyme ,biology.protein ,medicine ,Leishmania infantum ,030304 developmental biology - Abstract
Many marine derived fatty acids, mainly from sponges, possess vinylic halogenated moieties (bromine or iodine) but their assessment as antileishmanial candidates remains elusive. In this work, we undertook the first total synthesis of a novel series of 2-allyl-3-halo-2-nonadecenoic acids, which preferentially inhibit the Leishmania DNA topoisomerase IB enzyme (LTopIB) over the human topoisomerase IB enzyme (hTopIB). The synthesis of 2-allyl-3-bromo-2E-nonadecenoic acid (1a) and 2-allyl-3-chloro-2E-nonadecenoic acid (2a) was achieved through a palladium catalyzed haloallylation of 2-nonadecynoic acid (2-NDA) using either allyl bromide or allyl chloride in the presence of PdCl2(PhCN)2 in 57–83 % overall yields. Among the new halogenated synthetic compounds, 1a was the most inhibitory of LTopIB with an EC50 = 7 μM, while the shorter chain analogs 2-allyl-3-bromo-2E-dodecenoic acid (1b) and 2-allyl-3-chloro-2E-dodecenoic acid (2b), synthesized from 2-dodecynoic acid, were not inhibitory of LTopIB (EC50 > 100 μM) resulting in the overall order of inhibition 1a > 2-NDA > 2a > > 1b ≅ 2b. The acids 1a and 2a inhibit LTopIB by a Gimatecan-independent mechanism. The enhanced LTopIB inhibition of 1a was computationally rationalized in terms of a halogen bond between the bromine in 1a and a DNA phosphate (binding energy = − 4.85 kcal/mol). Acid 1a also displayed preferential cytotoxicity towards Leishmania infantum amastigotes (EC50 = 2.5 μM) over L. infantum promastigotes (EC50 > 25 μM).
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- 2019
9. Antibacterial fatty acids: An update of possible mechanisms of action and implications in the development of the next-generation of antibacterial agents
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David J. Sanabria-Ríos, Giancarlo Casillas-Vargas, Carlimar Ocasio-Malavé, Christian Morales-Guzman, Néstor M. Carballeira, Solymar Medina, and René García Del Valle
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0106 biological sciences ,0301 basic medicine ,biology ,Multidrug-resistant bacteria ,Fatty Acids ,Cell Biology ,biology.organism_classification ,01 natural sciences ,Biochemistry ,Article ,Anti-Bacterial Agents ,Non-traditional antibacterial ,03 medical and health sciences ,Broad spectrum ,030104 developmental biology ,Multidrug resistant bacteria ,Antibacterial agents ,Antibacterial activity ,FA mechanisms ,Bacteria ,010606 plant biology & botany - Abstract
The antibacterial activity of fatty acids (FA) is well known in the literature and represents a promising option for developing the next-generation of antibacterial agents to treat a broad spectrum of bacterial infections. FA are highly involved in living organisms' defense system against numerous pathogens, including multidrug-resistant bacteria. When combined with other antibacterial agents, the remarkable ability of FA to enhance their bactericidal properties is a critical feature that is not commonly observed in other naturally-occurring compounds. More reviews focusing on FA antibacterial activity, traditional and non-traditional mechanisms and biomedical applications are needed. This review is intended to update the reader on the antibacterial properties of recent FA and how their chemical structures influence their antibacterial activity. This review also aims to better understand both traditional and non-traditional mechanisms involved in these recently explored FA antibacterial activities.
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- 2020
10. Antibacterial and antiparasitic activity of novel brominated vinylic fatty acids
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Carlimar Ocasio, Solymar Medina, Damarith Díaz, Tomás Pereles, David J. Sanabria Ríos, Rafael Balaña-Fouce, Néstor M. Carballeira, Denisse Alequín Torres, and Victorio Jauregui Matos
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- 2020
11. Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria
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María Álvarez-Bardón, Rosa M. Reguera, María Martínez-Valladares, Rafael Balaña-Fouce, Yolanda Pérez-Pertejo, Sankaranarayanan Murugesan, Daniel Sepúlveda-Crespo, Carlos García-Estrada, C. Ordóñez, Néstor M. Carballeira, Babu L. Tekwani, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Universidad de León, and Martínez Valladares, María
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Drug ,Aquatic Organisms ,media_common.quotation_subject ,Plasmodium falciparum ,malaria ,Antiprotozoal Agents ,Drug Resistance ,Pharmaceutical Science ,trypanosomatids ,Disease ,Drug resistance ,Review ,chloroquine derivatives ,Euglenozoa Infections ,high-throughput screening ,marine pharmacology ,03 medical and health sciences ,Plasmodium malariae ,Environmental health ,Drug Discovery ,medicine ,Animals ,Humans ,Malaria, Falciparum ,neglected tropical diseases ,lcsh:QH301-705.5 ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Repurposing ,030304 developmental biology ,media_common ,Pharmaceutical industry ,0303 health sciences ,Biological Products ,030306 microbiology ,Drug discovery ,business.industry ,phenotypic screening ,Neglected Diseases ,medicine.disease ,High-Throughput Screening Assays ,lcsh:Biology (General) ,target-based screening ,Neglected tropical diseases ,Trypanosomatina ,business ,Malaria - Abstract
42 páginas, 15 figuras, 1 tabla., Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin., Financial support from the Ministerio de Economía y Competitividad (MINECO, AEI, FEDER, UE)[MINECO: AGL2016-79813-C2-1R and SAF2017-83575-R], the Junta de Castilla y León co-financed by FEDER, UE[LE020P17] to RBF and DBT, New Delhi [BT/IN/Spain/39/SM/2017-18] to MS are gratefully acknowledged. MAB(LE051-18) and DSC (LE020P17) are supported by a scholarship from the Junta de Castilla y León co-financed byFSE. MMV is supported by the Spanish “Ramon y Cajal” Programme Ministry of Economy and Competitiveness(Ministerio de Economia y Competitividad; MMV, RYC-2015-18368). We thank University of Leon for providingfunding to cover publication expenses.
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- 2020
12. Biological and structural effects of the conjugation of an antimicrobial decapeptide with saturated, unsaturated, methoxylated and branched fatty acids
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Georgina Tonarelli, María Carolina Rey, María Verónica Húmpola, Arturo Carlos Simonetta, and Néstor M. Carballeira
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0301 basic medicine ,medicine.drug_class ,030106 microbiology ,Antibiotics ,Peptide ,Conjugated system ,Biochemistry ,03 medical and health sciences ,Structural Biology ,Drug Discovery ,Amphiphile ,medicine ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,biology ,Chemistry ,Organic Chemistry ,Fatty acid ,General Medicine ,Antimicrobial ,biology.organism_classification ,Yeast ,030104 developmental biology ,Molecular Medicine ,Bacteria - Abstract
The increasing bacterial resistance against conventional antibiotics has led to the search for new antimicrobial drugs with different modes of action. Cationic antimicrobial peptides (AMPs) and lipopeptides are promising candidates to treat infections because they act on bacterial membranes causing rapid destruction of sensitive bacteria. In this study, a decapeptide named A2 (IKQVKKLFKK) was conjugated at the N-terminus with saturated, unsaturated, methoxylated and methyl -branched fatty acids of different chain lengths (C8 - C20), the antimicrobial and structural properties of the lipopeptides being then investigated. The attachment of the fatty acid chain significantly improved the antimicrobial activity of A2 against bacteria, and so, endowed it with moderated antifungal activity against yeast strains belonging to genus Candida. Lipopeptides containing hydrocarbon chain lengths between C8 and C14 were the best antibacterial compounds (MIC = 0.7 to 5.8 μM), while the most active compounds against yeast were A2 conjugated with methoxylated and enoic fatty acids (11.1 to 83.3 μM). The improvement in antimicrobial activity was mainly related to the amphipathic secondary structure adopted by A2 lipopeptides in the presence of vesicles that mimic bacterial membranes. Peptide conjugation with long hydrocarbon chains (C12 or more), regardless of their structure, significantly increased toxicity towards eukaryotic cells, resulting in a loss of selectivity. These findings suggest that A2-derived lipopeptides are potential good candidates for the treatment of infectious diseases caused by bacteria and opportunistic pathogenic yeast belonging to genus Candida. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
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- 2016
13. Novel Very Long-Chain α-Methoxylated Δ5,9 Fatty Acids from the SpongeAsteropus nigerAre Effective Inhibitors of Topoisomerases IB
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Abimael D. Rodríguez, Raquel Álvarez-Velilla, Luis A. Amador, Svetlana A. Golovko, Rafael Balaña-Fouce, Rosa M. Reguera, Mikhail Y. Golovko, Nashbly Montano, and Néstor M. Carballeira
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0301 basic medicine ,Circular dichroism ,Magnetic Resonance Spectroscopy ,Topoisomerase Inhibitors ,medicine.drug_class ,01 natural sciences ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Glycosphingolipids ,Article ,Mice ,03 medical and health sciences ,Column chromatography ,medicine ,Animals ,Humans ,Leishmania infantum ,Cytotoxicity ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Topoisomerase ,Organic Chemistry ,Hep G2 Cells ,Cell Biology ,biology.organism_classification ,Porifera ,0104 chemical sciences ,030104 developmental biology ,Enzyme ,chemistry ,Fatty Acids, Unsaturated ,biology.protein ,Leishmaniasis, Visceral ,DNA Topoisomerases ,Camptothecin ,Topoisomerase inhibitor ,medicine.drug - Abstract
The novel fatty acids (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic acid (1a) and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid (1b) were isolated in 80 % purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography-mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP-1 and HepG2 cells with EC50's between 41 and 35 μg/mL. Apoptosis was not the preferred mode of cell death induced by 1a-1b in the THP-1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC50 = 1.8 μg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC(50) = 0.17 mg/mL) and free living promastigotes (IC(50) = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC(50) = 5.1 μg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.
- Published
- 2015
14. Review of Biology and Ecology of Pharmaceutical Marine Sponges
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Néstor M. Carballeira
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Pharmacology ,Marine sponges ,Complementary and alternative medicine ,Ecology ,Ecology (disciplines) ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Biology ,Analytical Chemistry - Published
- 2020
15. First Total Synthesis of ω-Phenyl Δ6 Fatty Acids and their Leishmanicidal and Anticancer Properties
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Rafael Balaña-Fouce, Zally Torres-Martinez, Yolanda Pérez-Pertejo, Arthur D. Tinoco, Ester Alvarez-Benedicto, Rosa M. Reguera, Yamixa Delgado, Ruben Carbajo-Andres, Kai Griebenow, Christian Morales-Guzman, and Néstor M. Carballeira
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0301 basic medicine ,Stereochemistry ,Cell Survival ,Leishmania donovani ,Antiprotozoal Agents ,Antineoplastic Agents ,01 natural sciences ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,Cell Line, Tumor ,Fatty Acids, Omega-6 ,Drug Discovery ,Humans ,Leishmania infantum ,Cytotoxicity ,Amastigote ,IC50 ,EC50 ,Cell Proliferation ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Acetylide ,Topoisomerase ,Total synthesis ,General Medicine ,030108 mycology & parasitology ,biology.organism_classification ,Recombinant Proteins ,0104 chemical sciences ,DNA Topoisomerases, Type I ,biology.protein ,Drug Screening Assays, Antitumor ,Topoisomerase I Inhibitors - Abstract
Introduction: The first total synthesis of ω-phenyl Δ6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16-phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6-decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6-decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z-decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the ω-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 ± 1 μM. On the other hand, among the C10 acids, the ω-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 ± 2 μM) towards A549. Results: Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death. Conclusion: The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 μM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 μM) and L. infantum promastigotes (IC50 = 60- 70 μM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum ω- phenylated acid of the series.
- Published
- 2018
16. Conjugation inhibitors compete with palmitic acid for binding to the conjugative traffic ATPaseTrwD, providing a mechanism to inhibit bacterial conjugation
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Néstor M. Carballeira, María Getino, Fernando de la Cruz, Ignacio Arechaga, David J. Sanabria-Ríos, Elena Cabezón, Yolanda García-Cazorla, Universidad de Cantabria, Ministerio de Economía y Competitividad (España), National Institutes of Health (US), National Center for Research Resources (US), Getino, María [0000-0002-2937-3420], and Getino, María
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0301 basic medicine ,ATPase ,Palmitic Acid ,Bacterial Conjugation ,Crystallography, X-Ray ,medicine.disease_cause ,Microbiology ,Biochemistry ,Palmitic acid ,03 medical and health sciences ,chemistry.chemical_compound ,Plasmid ,Escherichia coli ,medicine ,Secretion ,Binding site ,Molecular Biology ,Adenosine Triphosphatases ,ATPase Inhibitors ,Binding Sites ,biology ,Escherichia coli Proteins ,Bacterial conjugation ,Cell Biology ,Type IV Secretion System ,biology.organism_classification ,Anti-Bacterial Agents ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Alkynes ,Conjugation, Genetic ,Antibiotic Resistance ,Drug Design ,Fatty Acids, Unsaturated ,biology.protein ,Bacteria - Abstract
Bacterial conjugation is a key mechanism by which bacteria acquire antibiotic resistance. Therefore, conjugation inhibitors (COINs) are promising compounds in the fight against the spread of antibiotic resistance genes among bacteria. Unsaturated fatty acids (uFAs) and alkynoic fatty acid derivatives, such as 2-hexadecanoic acid (2-HDA), have been reported previously as being effective COINs. The traffic ATPase TrwD, a VirB11 homolog in plasmid R388, is the molecular target of these compounds, which likely affect binding of TrwD to bacterial membranes. In this work, we demonstrate that COINs are abundantly incorporated into Escherichia coli membranes, replacing palmitic acid as the major component of the membrane. We also show that TrwD binds palmitic acid, thus facilitating its interaction with the membrane. Our findings also suggest that COINs bind TrwD at a site that is otherwise occupied by palmitic acid. Accordingly, molecular docking predictions with palmitic acid indicated that it shares the same binding site as uFAs and 2-HDA, although it differs in the contacts involved in this interaction. We also identified 2-bromopalmitic acid, a palmitate analog that inhibits many membrane-associated enzymes, as a compound that effectively reduces TrwD ATPase activity and bacterial conjugation. Moreover, we demonstrate that 2-bromopalmitic and palmitic acids both compete for the same binding site in TrwD. Altogether, these detailed findings open up a new avenue in the search for effective synthetic inhibitors of bacterial conjugation, which may be pivotal for combating multidrug-resistant bacteria., This work was supported by Spanish Ministerio de Economia y Competitividad (MINECO) Grants BFU2016-78521-R (to E. C. and I. A.) and BFU2014-55534 (to F. d. l. C.) and by Grant P20GM103475-16 from the National Center for Research Resources and NIGMS, National Institutes of Health (to D. S. R.).
- Published
- 2018
17. Papers from the 2nd International Conference on Global Challenges in Neglected Tropical Diseases (NTD2018)
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Néstor M. Carballeira
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Global challenges ,Chemistry ,General Chemical Engineering ,Regional science ,Neglected tropical diseases ,General Chemistry - Published
- 2019
18. The (5Z)-5-Pentacosenoic and 5-Pentacosynoic Acids Inhibit the HIV-1 Reverse Transcriptase
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Lizabeth Giménez Moreira, José W. Rodríguez, Gabriela Ortiz Soto, Karolyna Rosado, Néstor M. Carballeira, Elsie A. Orellano, Rafael Victorio Carvalho Guido, Adriano D. Andricopulo, and David J. Sanabria-Ríos
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Models, Molecular ,chemistry.chemical_classification ,Fatty Acids ,Organic Chemistry ,Fatty acid ,Biological activity ,Cell Biology ,Biochemistry ,HIV Reverse Transcriptase ,Article ,Reverse transcriptase ,Structure-Activity Relationship ,chemistry.chemical_compound ,Enzyme ,chemistry ,Fatty Acids, Unsaturated ,Leukocytes, Mononuclear ,Free fatty acid receptor ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,IC50 ,Cells, Cultured ,Nervonic acid - Abstract
The natural fatty acids (5Z)-5-pentacosenoic and (9Z)-9-pentacosenoic acids were synthesized for the first time in eight steps starting from either 4-bromo-1-butanol or 8-bromo-1-butanol and in 20-58% overall yields, while the novel fatty acids 5-pentacosynoic and 9-pentacosynoic acids were also synthesized in six steps and in 34-43% overall yields. The ∆(5) acids displayed the best IC50's (24-38 µM) against the HIV-1 reverse transcriptase (RT) enzyme, comparable to nervonic acid (IC50 = 12 µM). The ∆(9) acids were not as effective towards HIV-RT with the (9Z)-9-pentacosenoic acid displaying an IC50 = 54 µM and the 9-pentacosynoic acid not inhibiting the enzyme at all. Fatty acid chain length and position of the unsaturation was important for the observed inhibition. None of the synthesized fatty acids were toxic (IC50 > 500 µM) towards peripheral blood mononuclear cells. Molecular modeling studies indicated the structural determinants underlying the biological activity of the most potent compounds. These results provide new insights into the structural requirements that must be present in fatty acids so as to enhance their inhibitory potential towards HIV-RT.
- Published
- 2015
19. Synthesis of novel C5-curcuminoid-fatty acid conjugates and mechanistic investigation of their anticancer activity
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Christian Velez, Gabriela Ortiz-Soto, David J. Sanabria-Ríos, Beatriz Zayas, Néstor M. Carballeira, Joanne S. Altieri-Rivera, Félix Álvarez-Colón, Eddy Ríos-Olivares, Camille Ríos, Victor Serrano, José W. Rodríguez, R. Gutiérrez, Joshua Rosario, and Yaritza Rivera-Torres
- Subjects
Curcumin ,Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Biochemistry ,Article ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Molecular Biology ,Caspase ,biology ,Chemistry ,Cell growth ,Topoisomerase ,Fatty Acids ,Organic Chemistry ,Decanoic acid ,medicine.anatomical_structure ,Cell culture ,Cancer cell ,biology.protein ,Molecular Medicine - Abstract
The first synthesis of C5-curcumin-fatty acid (C5-Curc-FA) conjugates was successfully performed. Through a two-step synthetic route, 10 analogs were synthesized for a structure–activity relationship (SAR) study. It was found that C5-Curc-FA conjugates containing either decanoic acid or palmitic acid moieties were cytotoxic against colorectal adenocarcinoma cell (CCL-229) at IC50s ranging from 22.5 to 56.1 μg/mL, being 5c the most active C5-Curc-FA conjugate. Our results strongly suggests that a decanoic acid moiety at the meta position in C5-Curc-FA conjugates is important for their anticancer activity effect. Possible mechanisms for the anticancer activity of C5-Curc-FA conjugates were also investigated including apoptosis induction, mitochondrial damage and caspases activation. It was shown that 5c inhibited the luminescence activity of NFκB, a key signaling molecule involved in cell apoptosis and cell proliferation, at IC50 = 18.2 μg/mL. In addition, it was demonstrated that 5c displayed significant apoptotic effect at GI50 = 46.0 μg/mL in colorectal adenocarcinoma cell line (ATCC CCL-222), which can be explained by the significant mitochondrial membrane permeabilization and caspases 3 and 7 activation effect of 5c. Finally, it was investigated that C5-Curc-FA conjugates can affect the replication process of cancer cells, since compounds 5c, 5e, and 6c inhibited the relaxing activity of the human DNA topoisomerase I at minimum inhibitory concentrations (MICs) that range from 50 to 250 μg/mL. Our results strongly support the hypothesis that the inhibition of both NFκB and DNA topoisomerase I by C5-Curc-FA conjugates is associated with their anticancer activity.
- Published
- 2015
20. 2-Methoxylated FA Display Unusual Antibacterial Activity Towards Clinical Isolates of Methicillin-Resistant Staphylococcus aureus (CIMRSA) and Escherichia coli
- Author
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Xiomara Torres, Joseph Mooney, Christian Morales, David J. Sanabria-Ríos, Nashbly Montano, Dakeishla Díaz, and Néstor M. Carballeira
- Subjects
0301 basic medicine ,Methicillin-Resistant Staphylococcus aureus ,Stereochemistry ,030106 microbiology ,Biology ,medicine.disease_cause ,Biochemistry ,Micelle ,DNA gyrase ,Article ,Fatty Acids, Monounsaturated ,03 medical and health sciences ,medicine ,Escherichia coli ,Humans ,IC50 ,Escherichia coli Infections ,Degree of unsaturation ,Organic Chemistry ,Cell Biology ,Staphylococcal Infections ,Methicillin-resistant Staphylococcus aureus ,Anti-Bacterial Agents ,030104 developmental biology ,Staphylococcus aureus ,Antibacterial activity - Abstract
The naturally occurring (6Z)-(±)-2-methoxy-6-hexadecenoic acid (1) and (6Z)-(±)-2-methoxy-6-octadecenoic acid (2) were synthesized in 7–8 steps with 38 and 13% overall yields, respectively, by using an acetylide coupling approach, which made it possible to obtain a 100% cis-stereochemistry for the double bonds. In a similar fashion, the acetylenic analogs (±)-2-methoxy-6-hexadecynoic acid (3) and (±)-2-methoxy-6-octadecynoic acid (4) were also synthesized in 6–7 steps with 48 and 16% overall yields, respectively. The antibacterial activity of acids 1–4 was determined against clinical isolates of methicillin-resistant Staphylococcus aureus (ClMRSA) and Escherichia coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17 and 37 μg/mL, in sharp contrast to the 6-octadecynoic acid, which was not bactericidal at all. On the other hand, acids 1 and 3 were the only acids that displayed antibacterial activity towards E. coli, but 1 stood out as the best candidate with an IC50 of 21 μg/mL. The critical micelle concentrations (CMCs) of acids 1–4 were also determined. The C18 acids 2 and 4 displayed a five-fold lower CMC (15–20 μg/mL) than the C16 analogs 1 and 3 (70–100 μg/mL), indicating that 4 exerts its antibacterial activity in a micellar state. None of the studied acids were inhibitory towards S. aureus DNA gyrase discounting this type of enzyme inhibition as a possible antibacterial mechanism. It was concluded that the combination of α-methoxylation and C-6 unsaturation increases the bactericidal activity of the C16 and C18 FA towards the studied bacterial strains. Acids 1 and 4 stand out as viable candidates to be used against E. coli and CIMRSA, respectively.
- Published
- 2017
21. Antibacterial activity of 2-alkynoic fatty acids against multidrug-resistant bacteria
- Author
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Camille Ríos, José W. Rodríguez, Gabriel A. Cintrón, Gamalier Maldonado-Domínguez, Eddy Ríos-Olivares, Idializ Domínguez, Nashbly Montano, Joanne S. Altieri-Rivera, Néstor M. Carballeira, Damarith Díaz, David J. Sanabria-Ríos, and Yaritza Rivera-Torres
- Subjects
Methicillin-Resistant Staphylococcus aureus ,Klebsiella pneumoniae ,Carboxylic acid ,Gram-positive bacteria ,Bacillus cereus ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,medicine.disease_cause ,Biochemistry ,Article ,Microbiology ,Gram-Negative Bacteria ,medicine ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Staphylococcus saprophyticus ,biology ,Pseudomonas aeruginosa ,Organic Chemistry ,Cell Biology ,biology.organism_classification ,Drug Resistance, Multiple ,Anti-Bacterial Agents ,chemistry ,Staphylococcus aureus ,Fatty Acids, Unsaturated ,Leukocytes, Mononuclear ,Antibacterial activity - Abstract
The first study aimed at determining the structural characteristics needed to prepare antibacterial 2-alkynoic fatty acids (2-AFAs) was accomplished by synthesizing several 2-AFAs and other analogues in 18-76% overall yields. Among all the compounds tested, the 2-hexadecynoic acid (2-HDA) displayed the best overall antibacterial activity against Gram-positive Staphylococcus aureus (MIC = 15.6 μg/mL), Staphylococcus saprophyticus (MIC = 15.5 μg/mL), and Bacillus cereus (MIC = 31.3 μg/mL), as well as against the Gram-negative Klebsiella pneumoniae (7.8 μg/mL) and Pseudomonas aeruginosa (MIC = 125 μg/mL). In addition, 2-HDA displayed significant antibacterial activity against methicillin-resistant S. aureus (MRSA) ATCC 43300 (MIC = 15.6 μg/mL) and clinical isolates of MRSA (MIC = 3.9 μg/mL). No direct relationship was found between the antibacterial activity of 2-AFAs and their critical micelle concentration (CMC) suggesting that the antibacterial properties of these fatty acids are not mediated by micelle formation. It was demonstrated that the presence of a triple bond at C-2 as well as the carboxylic acid moiety in 2-AFAs are important for their antibacterial activity. 2-HDA has the potential to be further evaluated for use in antibacterial formulations.
- Published
- 2014
22. Synthesis of the novel (±)-2-methoxy-6-icosynoic acid—A fatty acid that induces death of neuroblastoma cells
- Author
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Elsie A. Orellano, Michelle M. Cartagena, Karolyna Rosado, and Néstor M. Carballeira
- Subjects
Apoptosis ,Biochemistry ,Micelle ,Article ,HeLa ,Neuroblastoma ,Cell Line, Tumor ,medicine ,Humans ,Cytotoxicity ,Molecular Biology ,Micelles ,chemistry.chemical_classification ,biology ,Chemistry ,Fatty Acids ,Organic Chemistry ,Total synthesis ,Fatty acid ,Stereoisomerism ,Cell Biology ,biology.organism_classification ,medicine.disease ,Cell culture ,Critical micelle concentration ,Fatty Acids, Unsaturated ,HeLa Cells - Abstract
The first total synthesis for the novel fatty acid (±)-2-methoxy-6-icosynoic acid was accomplished in seven steps and in a 14% overall yield starting from 2-(4-bromobutoxy)-tetrahydro-2H-pyran. The title compound displayed an EC50 = 23 ± 1 μM against the human SH-SY5Y neuroblastoma cell line and an EC50 = 26 ± 1 μM against the human adenocarcinoma cervix cell line (HeLa) after 48 h of exposure. The corresponding non-methoxylated analog 6-icosynoic acid did not display cytotoxicity (EC50 > 500 μM) toward the studied cell lines as well as the 2-methoxyicosanoic acid (EC50 > 300 μM). The critical micelle concentration (CMC = 20–30 μM) for the (±)-2-methoxy-6-icosynoic acid was also determined. It was found that α-methoxylation decreases the CMC of a fatty acid.
- Published
- 2013
23. First total synthesis of the (±)-2-methoxy-6-heptadecynoic acid and related 2-methoxylated analogs as effective inhibitors of the Leishmania topoisomerase IB enzyme
- Author
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Rosa M. Reguera, Michelle M. Cartagena, Zhongfang Chen, Néstor M. Carballeira, Rafael Balaña-Fouce, Fengyu Li, Estefanía Calvo-Álvarez, and Christopher F. Prada
- Subjects
chemistry.chemical_classification ,Degree of unsaturation ,biology ,Stereochemistry ,General Chemical Engineering ,Topoisomerase ,Leishmania donovani ,Active site ,Fatty acid ,Total synthesis ,General Chemistry ,biology.organism_classification ,Article ,Enzyme ,chemistry ,Yield (chemistry) ,biology.protein - Abstract
The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid, (±)-2-methoxy-6-hepta-decynoic acid, and (±)-2-methoxyheptadecanoic acid were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Both 2-OMe-17:1 fatty acids were synthesized from 4-bromo-1-pentanol, the olefinic fatty acid in 10 steps and in 7 % overall yield, while the acetylenic fatty acid in 7 steps and in 14 % overall yield. The 2-OMe-17:0 acid was prepared in 6 steps and in 42 % yield from 1-hexa-decanol. The 2-OMe-17:1 acids inhibited LdTopIB, with the acetylenic acid displaying an EC50 = 16.6 ± 1.1 μM, but the 2-OMe-17:0 acid did not inhibit LdTopIB. The (±)-2-methoxy-6Z-heptadecenoic acid preferentially inhibited LdTopIB over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity toward Leishmania donovani promastigotes was also investigated, resulting in the order acetylenic > olefinic > saturated with the (±)-2-methoxy-6-heptadecynoic acid displaying an EC50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C17:1 fatty acids toward L. donovani promastigotes, but improves their selectivity index.
- Published
- 2012
24. Antiprotozoal activity of Melampyrum arvense and its metabolites
- Author
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Néstor M. Carballeira, Marcel Kaiser, Deniz Tasdemir, Michelle M. Cartagena, Reto Brun, Irem Atay, Hasan Kırmızıbekmez, Erdem Yesilada, Department of Pharmacognosy, Yeditepe University, Faculty of Pharmacy, Medical Parasitology and Infection Biology [Basel, Suisse] (MPI), Swiss Tropical and Public Health Institute [Basel], Department of Chemistry, University of Puerto Rico (UPR), Centre for Pharmacognosy and Phytotherapy, and University of London, School of Pharmacy
- Subjects
medicine.drug_class ,Stereochemistry ,Trypanosoma brucei brucei ,Antiprotozoal Agents ,Plasmodium gallinaceum ,Iridoid Glucosides ,Biology ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Inhibitory Concentration 50 ,03 medical and health sciences ,chemistry.chemical_compound ,Melampyrum ,Orobanchaceae ,medicine ,Luteolin ,Nuclear Magnetic Resonance, Biomolecular ,Aucubin ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,Lignan ,0303 health sciences ,Plant Extracts ,Life Sciences ,Glycoside ,biology.organism_classification ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Antiprotozoal ,Melampyrum arvense ,Leishmania donovani - Abstract
International audience; An activity guided isolation of the H2O subextract of the crude extract of Melampyrum arvense L. afforded iridoid glucosides aucubin (1), melampyroside (2), mussaenoside (3), mussaenosidic acid (4), 8-epi-loganin (5); flavonoids, apigenin (6), luteolin (7), luteolin 7-O--glucopyranoside (8); a lignan glycoside dehydrodiconiferyl alcohol 9-O--glucopyranoside (9); and benzoic acid (10). -Sitosterol (11) and a fatty acid mixture (12) were identified as the active principles of the CHCl3 subextract. The structures of the isolates were elucidated by spectroscopic methods, while the composition of 12 was identified by GC-MS after methylation. Luteolin (7) appeared as the most active compound against Trypanosoma brucei rhodesiense and Leishmania donovani (IC50 values 3.8 and 3.0 mg/ml). Luteolin 7-O--glucopyranoside (8) displayed the best antiplasmodial activity against Plasmodium falciparum (IC50 value 2.9 mg/ml). This is the first detailed phytochemical study on Turkish M. arvense and the first report of the antiprotozoal effect of Melampyrum species and its constituents.
- Published
- 2010
25. 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections
- Author
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Deniz Tasdemir, Remo Perozzo, Reto Brun, Stefan H. I. Kappe, Mire Zloh, Alice S. Tarun, Ina L. Lauinger, David Sanabria, Rob W. Herman, and Néstor M. Carballeira
- Subjects
Erythrocytes ,Plasmodium falciparum ,Clinical Biochemistry ,Protozoan Proteins ,Leishmania donovani ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Article ,Antimalarials ,Cell Line, Tumor ,parasitic diseases ,Drug Discovery ,Fatty Acid Synthase, Type II ,medicine ,Humans ,Computer Simulation ,Malaria, Falciparum ,Trypanosoma cruzi ,Molecular Biology ,chemistry.chemical_classification ,Binding Sites ,biology ,Organic Chemistry ,biology.organism_classification ,In vitro ,Kinetics ,Fatty acid synthase ,Enzyme ,Liver ,chemistry ,Alkynes ,Fatty Acids, Unsaturated ,biology.protein ,Molecular Medicine ,Plasmodium yoelii ,Atovaquone ,medicine.drug - Abstract
Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.
- Published
- 2010
26. First total synthesis of (5Z,9Z)-(±)-2-methoxy-5,9-octadecadienoic acid, a marine derived methoxylated analog of taxoleic acid
- Author
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Néstor M. Carballeira, Diana Silva, and Rosann O’Neill
- Subjects
chemistry.chemical_classification ,Esterification ,Double bond ,Organic Chemistry ,Total synthesis ,Stereoisomerism ,Cell Biology ,Biochemistry ,Article ,Porifera ,Sodium hydride ,chemistry.chemical_compound ,chemistry ,Octadecadienoic Acid ,Fatty Acids, Unsaturated ,Animals ,Organic chemistry ,Acid hydrolysis ,Furans ,Trimethylsilyl cyanide ,Molecular Biology ,Triethylamine ,Stearic Acids ,Methyl iodide - Abstract
The first total synthesis for the sponge derived (5Z,9Z)-(+/-)-2-methoxy-5,9-octadecadienoic acid, an analog of taxoleic acid, was accomplished in seven steps and in a 10% overall yield. It was again corroborated that the best strategy to prepare these cis,cis dimethylene interrupted double bonds is the double-alkyne bromide coupling reaction of 1,5-hexadiyne, which provides the advantage of achieving a 100% cis stereochemical purity for both double bonds after hydrogenation under Lindlar conditions. The alpha-methoxy functionality was best prepared via the Mukaiyama reaction of (4Z,8Z)-heptadecadienal with trimethylsilyl cyanide and triethylamine followed by acid hydrolysis. Selective methylation of the hydroxyl group of (5Z,9Z)-(+/-)-2-hydroxy-5,9-octadecadienoic acid was achieved with sodium hydride/methyl iodide when tetrahydrofuran was used as solvent. Complete spectral data is presented, for the first time, for this unusual marine alpha-methoxylated fatty acid.
- Published
- 2008
27. Tracing 13C-enriched dissolved and particulate organic carbon in the bacteria-containing coral reef sponge Halisarca caerulea: Evidence for DOM-feeding
- Author
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Leon Moodley, Fleur C. van Duyl, Néstor M. Carballeira, Marco Houtekamer, Jasper M. de Goeij, Ecosystems Studies, and Support Staff
- Subjects
chemistry.chemical_classification ,geography ,geography.geographical_feature_category ,biology ,Coral ,fungi ,technology, industry, and agriculture ,Assimilation (biology) ,Coral reef ,biochemical phenomena, metabolism, and nutrition ,Aquatic Science ,Oceanography ,biology.organism_classification ,Sponge ,chemistry ,Botany ,natural sciences ,Organic matter ,Caerulea ,Reef ,geographic locations ,Bacteria - Abstract
Here we report on the trophodynamics of the bacteria-containing coral reef sponge Halisarca caerulea. The assimilation and respiration of the 13C-enriched substrates glucose, algal-derived dissolved and particulate organic matter (diatom-DOM and -POM), and bacteria were followed in 1- and 6-h incubations. Except for glucose, all substrates were readily processed by the sponge, with assimilation being the major fate. 13C-Enrichment patterns in fatty acid biomarkers revealed that sponge dissolved organic 13C assimilation was both direct and bacteria mediated as tracer carbon was recovered both in bacteria-specific and nonbacterial fatty acid. This is the first direct evidence of DOM incorporation by sponges. The present study demonstrates that the encrusting sponge H. caerulea feeds on both DOM and POM and given their dominant coverage of the largest coral reef habitat (coral cavities) it is proposed that organic matter assimilation by cryptic reef sponges may represent an important, largely overlooked ecological function. Quantitatively significant DOM processing may not be the exclusive function of the microbial world on coral reefs; sponges transform DOM to biomass, and thus retain and store organic matter in the reef system.
- Published
- 2008
28. New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents
- Author
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Néstor M. Carballeira
- Subjects
Antifungal ,Antifungal Agents ,biology ,INHA ,medicine.drug_class ,Fatty Acids ,Plasmodium falciparum ,Antitubercular Agents ,Cell Biology ,Reductase ,biology.organism_classification ,Antimycobacterial ,Biochemistry ,Article ,Mycobacterium tuberculosis ,Antimalarials ,Enzyme inhibition ,medicine ,Animals ,Humans ,Tuberculosis ,Antimalarial Agent ,Malaria, Falciparum - Abstract
This review deals with the most recent findings on the antimalarial, antimycobacterial, and antifungal properties of fatty acids, with particular emphasis on novel marine fatty acids. The first section deals with the most recent and some background literature on what has been the latest developments with respect to fatty acids as antimalarial agents and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (FabI) of Plasmodium falciparum, the principal agent responsible for malaria. This section of the review also emphasizes the latest antimalarial research with the very long-chain Delta5,9 fatty acids from sponges. The second section of the review deals with the recent literature on the antimycobacterial activity of fatty acids and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP reductase (InhA) of Mycobacterium tuberculosis for antimycobacterial activity. The inhibitory activities of the Delta5,9 fatty acids against InhA as well as that of the alpha-methoxylated fatty acids are also discussed. The importance of Delta5,9 fatty acids as topoisomerase I inhibitors and its connection to cancer is also reviewed. The last part of the review, the antifungal section, also emphasizes the most recent research with antifungal fatty acids and the importance of enzyme inhibition, in particular N-myristoyltransferase (NMT) inhibition, for antifungal activity. This last section of the review emphasizes the latest research with the alpha-methoxylated fatty acids but the importance of acetylenic fatty acids is also considered.
- Published
- 2008
29. First total syntheses of (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid
- Author
-
Nashbly Montano, Néstor M. Carballeira, and Luis Padilla
- Subjects
Trimethylsilyl Compounds ,Double bond ,Trimethylsilyl ,Stereochemistry ,Myristic acid ,Palmitic Acids ,Biochemistry ,Article ,Tetradecenoic Acid ,Fatty Acids, Monounsaturated ,chemistry.chemical_compound ,Enzyme Inhibitors ,Bifunctional ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,Spectrum Analysis ,Acetylide ,Organic Chemistry ,Stereoisomerism ,Cell Biology ,chemistry ,Acetylene ,Hexadecenoic Acid ,Topoisomerase I Inhibitors ,Myristic Acids ,Biomarkers - Abstract
The first total syntheses for the (Z)-15-methyl-10-hexadecenoic acid and the (Z)-13-methyl-8-tetradecenoic acid were accomplished in seven steps and in 31-32% overall yields. The (trimethylsilyl)acetylene was the key reagent in both syntheses. It is proposed that the best synthetic strategy towards monounsaturated iso methyl-branched fatty acids with double bonds close to the omega end of the acyl chain is first acetylide coupling of (trimethylsilyl)acetylene to a long-chain bifunctional bromoalkane followed by a second acetylide coupling to a short-chain iso bromoalkane, since higher yields are thus obtained. Spectral data is also presented for the first time for these two unusual fatty acids with potential as biomarkers and as topoisomerase I inhibitors.
- Published
- 2007
30. Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria
- Author
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José W. Rodríguez, Nashbly Montano, Yeireliz Torres-García, Joshua Rosario, R. Gutiérrez, Eddy Ríos-Olivares, Yaritza Rivera-Torres, David J. Sanabria-Ríos, Gabriela Ortiz-Soto, and Néstor M. Carballeira
- Subjects
Methicillin-Resistant Staphylococcus aureus ,Staphylococcus aureus ,Curcumin ,Multi drug resistant bacteria ,Clinical Biochemistry ,Pharmaceutical Science ,medicine.disease_cause ,Biochemistry ,DNA gyrase ,Article ,Microbiology ,Drug Discovery ,Chlorocebus aethiops ,medicine ,Escherichia coli ,Animals ,Humans ,Topoisomerase II Inhibitors ,Molecular Biology ,Vero Cells ,biology ,Chemistry ,DNA, Superhelical ,Organic Chemistry ,biology.organism_classification ,Methicillin-resistant Staphylococcus aureus ,Anti-Bacterial Agents ,DNA Gyrase ,Alkynes ,Fatty Acids, Unsaturated ,Leukocytes, Mononuclear ,Molecular Medicine ,Antibacterial activity ,Bacteria ,Conjugate - Abstract
The first total synthesis of a C5-Curcumin-2-Hexadecynoic Acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13 % overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 μg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-Curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 μg/mL (IC50 = 100.2 ± 13.9 μg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.
- Published
- 2015
31. Racemic and optically active 2-methoxy-4-oxatetradecanoic acids: novel synthetic fatty acids with selective antifungal properties
- Author
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Keykavous Parang, Rosann O’Neill, and Néstor M. Carballeira
- Subjects
Cryptococcus neoformans ,Antifungal ,Antifungal Agents ,biology ,Chemistry ,Stereochemistry ,medicine.drug_class ,Organic Chemistry ,Significant difference ,Aspergillus niger ,Stereoisomerism ,Cell Biology ,Fatty Acids, Nonesterified ,Optically active ,biology.organism_classification ,2-methoxy-4-oxatetradecanoic ,Biochemistry ,Corpus albicans ,Candida albicans ,medicine ,Molecular Biology - Abstract
The unprecedented (±)-2-methoxy-4-oxatetradecanoic acid and the optically pure (S)-2-methoxy-4-oxatetradecanoic acid were synthesized in six steps and in 11–14% overall yields starting with either 1,2-O-isopropylidene-rac-glycerol or 1,2-O-isopropylidene-(S)-glycerol. The key step in the synthesis was the selective monosilylation of a dibutylstannylene intermediate. The title compounds displayed selective fungitoxicity in the range of 0.08–0.22 mM against Cryptococcus neoformans ATCC 66031 and Aspergillus niger ATCC 16404, but no significant activity against C. albicans ATCC 14053 and ATCC 60193 (>2.6 mM). Albeit being good substrates for N-myristoyltransferases (NMTs), the racemic and the S-enantiomer of the oxygenated 2-methoxylated compounds showed no significant difference in antifungal activity. This finding suggests an alternative mechanism of fungitoxicity other than NMT inhibition.
- Published
- 2005
32. 2-Methoxylated fatty acids in marine sponges: Defense mechanism against mycobacteria?
- Author
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Heindyleen Cruz, Néstor M. Carballeira, Baojie Wan, Cecil D. Kwong, and Scott G. Franzblau
- Subjects
Marine sponges ,Molecular Structure ,Extramural ,Fatty Acids ,Organic Chemistry ,Mycobacterium tuberculosis ,Cell Biology ,Biology ,biology.organism_classification ,Antimicrobial ,Biochemistry ,Anti-Bacterial Agents ,Porifera ,Alamar blue ,Green fluorescent protein ,Minimum inhibitory concentration ,Animals ,Symbiotic bacteria - Abstract
A series of saturated 2-methoxylated FA having even-numbered chains with 8-14 carbons were synthesized, and their spectroscopic data are presented for the first time. The 2-methoxylated C10-C14 acids were prepared from the corresponding 2-hydroxylated FA, whereas the 2-methoxyoctanoic acid was synthesized starting with heptaldehyde. All of the methoxylated FA displayed some degree of inhibition (between 2 and 99%) of Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL. The most inhibitory FA was 2-methoxydecanoic acid, with a minimum inhibitory concentration of 200-239 microM against M. tuberculosis H(37)Rv as determined by both the microplate Alamar Blue assay and the green fluorescent protein microplate assay. These results are discussed in terms of the possible role of the 2-methoxylated FA as antimicrobial lipids produced either by marine sponges, or the associated marine symbiotic bacteria, as a defense mechanism in a highly competitive environment.
- Published
- 2004
33. Total Synthesis andin Vitro-Antifungal Activity of (±)-2-Methoxytetradecanoic Acid
- Author
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Néstor M. Carballeira, Soroush Sardari, Denisse Ortiz, and Keykavous Parang
- Subjects
Antifungal Agents ,Stereochemistry ,Pharmaceutical Science ,Myristic acid ,In Vitro Techniques ,chemistry.chemical_compound ,Minimum inhibitory concentration ,Amphotericin B ,Candida albicans ,Drug Discovery ,chemistry.chemical_classification ,Cryptococcus neoformans ,Myristates ,biology ,Fatty Acids ,Aspergillus niger ,Fatty acid ,biology.organism_classification ,Corpus albicans ,chemistry ,Capric Acid ,Myristic Acids ,Acyltransferases ,Nuclear chemistry - Abstract
The marine fatty acid (+/-)-2-methoxytetradecanoic acid was synthesized in two steps (71% overall yield) starting from commercially available methyl-2-hydroxy-tetradecanoate. The title compound was antifungal against Candida albicans (ATCC 14053) in RPMI medium and Aspergillus niger (ATCC 16404) and Cryptococcus neoformans (ATCC 66031) in SDB medium at the minimum inhibitory concentration (MIC) of 100 mM, which compares to the fungitoxicity of a 2-iodotetradecanoic acid against the same fungi. The title compound was also five to ten times more cytotoxic than capric acid to C. albicans and A. niger in the tested medium but comparable in cytotoxicity to either capric acid and its 2-methoxylated analog to C. neoformans. The antifungal activity of (+/-)-2-methoxytetradecanoic acid is explained in terms of inhibition of N-myristoyltransferase.
- Published
- 2004
34. The first total synthesis of the marine fatty acid (±)-2-methoxy-13-methyltetradecanoic acid: a cytotoxic fatty acid to leukemia cells
- Author
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Néstor M. Carballeira, Fernando A. González, Elsie A. Orellano, and Heidyleen Cruz
- Subjects
Stereochemistry ,Antineoplastic Agents ,HL-60 Cells ,Biochemistry ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Cytotoxicity ,Trimethylsilyl cyanide ,Molecular Biology ,Triethylamine ,chemistry.chemical_classification ,Fatty Acids ,Organic Chemistry ,Total synthesis ,Fatty acid ,Stereoisomerism ,U937 Cells ,Cell Biology ,medicine.disease ,Porifera ,Leukemia ,chemistry ,13-Methyltetradecanoic acid ,Drug Screening Assays, Antitumor ,K562 Cells ,Chronic myelogenous leukemia - Abstract
The recently discovered marine fatty acid (±)-2-methoxy-13-methyltetradecanoic acid was synthesized for the first time in six steps (26% overall yield) starting from commercially available methyl 12-methyltridecanoate. The synthetic approach provided enough material to corroborate the structure of the acid, which was recently identified in the sponge Amphimedon complanata from Aguadilla, Puerto Rico, and to test its cytotoxicity to three leukemia cell lines. The key step in the synthesis was the addition of trimethylsilyl cyanide to 12-methyltridecanal under triethylamine catalysis. Nuclear magnetic resonance data are provided for the first time for this methoxylated fatty acid and the synthetic approach utilized is of general applicability since it can be used in the synthesis of other methyl-branched 2-methoxylated fatty acids. We also report that the acid (±)-2-methoxy-13-methyltetradecanoic acid is cytotoxic to human chronic myelogenous leukemia K-562 (EC 50 =238 μM), histiocytic lymphoma U-937 (EC 50 =250 μM), and promielocytic leukemia HL-60 (EC 50 =476 μM) in RPMI 1640 medium.
- Published
- 2003
35. Fatty acids bound to Fasciola hepatica 12 kDa fatty acid-binding protein, a candidate vaccine, differ from fatty acids in extracts of adult flukes
- Author
-
Néstor M. Carballeira, Heidyleen Cruz, and George V. Hillyer
- Subjects
chemistry.chemical_classification ,Vaccines ,biology ,Cholesterol ,Fatty Acids ,Organic Chemistry ,Helminth Proteins ,Cell Biology ,Fasciola hepatica ,Fatty Acid-Binding Proteins ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Fatty acid-binding protein ,Molecular Weight ,chemistry.chemical_compound ,chemistry ,Hepatica ,Animals ,Composition (visual arts) ,Carrier Proteins ,Fucosterol ,Polyunsaturated fatty acid - Abstract
The FA composition of Fasciola hepatica 12 kDA purified native FA-binding protein (nFh12), a candidate vaccine against fascioliasis, is described. The FA chain lengths ranged between 12 and 24 carbons. The principal FA were 16:0, 18:1n-9, 18:0, 20:4n-6, and 20:1n-9. The acids 16:0, 18:1n-9, and 18:0 comprised over half the FA that were bound to the whole FA-binding protein. Small amounts (1.0-2.8%) of iso-anteiso methyl-branched FA also were characterized. Forty-one different FA were identified in extracts of the adult flukes, with the three most abundant FA also being 16:0, 18:1n-9, and 18:0. A similar proportion of saturated vs. unsaturated FA was observed between the whole extract from F. hepatica and the nFh12 protein. However, the n-3/n-6 ratio of PUFA was significantly different, being 1.2 in the whole extract vs. 9.6 in the nFh12 protein complex. The nFh12 protein binds more n-5, n-6, and n-7 PUFA and less n-3 and n-9 PUFA than the whole extract. In addition, cholesterol (56%), sitosterol (36%), and fucosterol (8%) also were bound to the nFh12 protein complex.
- Published
- 2003
36. Total synthesis of 2-methoxy-14-methylpentadecanoic acid and the novel 2-methoxy-14-methylhexadecanoic acid identified in the sponge agelas dispar
- Author
-
Norma L. Ayala, Néstor M. Carballeira, and Heidyleen Cruz
- Subjects
Molecular Structure ,biology ,Stereochemistry ,Dispar ,Fatty Acids ,Organic Chemistry ,Phospholipid ,Total synthesis ,Palmitic Acids ,Cell Biology ,Agelas dispar ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Porifera ,Palmitic acid ,chemistry.chemical_compound ,Sponge ,chemistry ,2-methoxy-14-methylhexadecanoic acid ,Animals - Abstract
The phospholipid FA composition of the Caribbean sponge Agelas dispar was revisited and 40 different FA were identified. Among these a novel 2-methoxylated FA, namely, the anteiso methyl-branched 2-methoxy-14-methylhexadecanoic acid, was identified together with the recently discovered iso methyl-branched 2-methoxy-14-methylpentadecanoic acid and the normal-chain 2-methoxytetradecanoic acid. The structures of the iso and anteiso methyl-branched 2-methoxylated FA were confirmed by total syntheses, which were accomplished in seven steps and in 45-48% overall yields. Other phospholipid FA identified in A. dispar include the unusual methyl-branched 10,13-dimethyltetradecanoic acid, 3,7,11,15-tetramethylhexadecanoic (phytanic) acid, and the 11-methyloctadecanoic acid. In addition, the delta5,9 FA (5Z,9Z)-15-methyl-5,9-hexadecadienoic acid and (5Z,9Z)-5,9-octadecadienoic acid were characterized. These findings establish alternative FA biosynthetic possibilities for these marine organisms.
- Published
- 2002
37. New advances in the chemistry of methoxylated lipids
- Author
-
Néstor M. Carballeira
- Subjects
Glycerol ,Antifungal ,Antifungal Agents ,Antimetabolites ,medicine.drug_class ,Microbial metabolism ,Antineoplastic Agents ,Glycerol metabolism ,Biochemistry ,medicine ,Animals ,Organic chemistry ,Alkyl ,chemistry.chemical_classification ,Bacteria ,Fatty Acids ,Biological activity ,Lipid metabolism ,Cell Biology ,Lipid Metabolism ,Lipids ,Anti-Bacterial Agents ,Porifera ,chemistry ,Rhodophyta ,Polyunsaturated fatty acid - Abstract
Methoxylated lipids have been reviewed emphasizing the alkylglycerol ethers and fatty acids bearing the methoxy group in the alkyl chain. The literature on methoxylated lipids and their derivatives has been divided into four main groups, namely 2-methoxylated alkyl glycerols, omega-methoxylated fatty acids, mid-chain methoxylated fatty acids, and alpha-methoxylated fatty acids. The natural occurrence, biological activity, and synthesis of this interesting group of lipids are discussed. Most of these compounds have been isolated from either bacterial or marine sources, but others are mainly of synthetic origin. Among the interesting biological activities displayed by these compounds the most important are antibacterial, antifungal, antitumor, and antiviral.
- Published
- 2002
38. Novel methoxylated FA from the Caribbean sponge Spheciospongia cuspidifera
- Author
-
Johanna Alicea and Néstor M. Carballeira
- Subjects
biology ,Fatty Acids ,Organic Chemistry ,Cell Biology ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Porifera ,Sponge ,Spheciospongia ,Animals ,Stearic Acids ,Bacteria - Abstract
The delta6 monoenoic methoxylated FA (6Z)-2-methoxy-6-heptadecenoic acid and (6Z)-2-methoxy-6-octadecenoic acid were identified for the first time in nature in the phospholipids from the uncommon Caribbean sponge Spheciospongia cuspidifera. These findings expand the occurrence of A6 2-methoxylated FA to C17-C18 chain lengths and establish a new FA biosynthetic possibility for these marine organisms. The novel methoxylated FA also could have originated from the phospholipids of a bacterium in symbiosis with the sponge.
- Published
- 2002
39. Phospholipid fatty acid composition of Gorgonia mariae and Gorgonia ventalina
- Author
-
Carlos Miranda, Abimael D. Rodríguez, and Néstor M. Carballeira
- Subjects
chemistry.chemical_classification ,Phosphatidylethanolamine ,food.ingredient ,Physiology ,Fatty Acids ,Phospholipid ,Phosphatidylserine ,Biology ,Gorgonia ventalina ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Cnidaria ,chemistry.chemical_compound ,food ,Caribbean Region ,chemistry ,Genus ,Phosphatidylcholine ,Botany ,Animals ,Molecular Biology ,Phospholipids ,Gorgonia ,Polyunsaturated fatty acid - Abstract
The phospholipid fatty acid composition of the Caribbean gorgonians Gorgonia mariae (Bayer) and Gorgonia ventalina (Linnaeus) is described for the first time. The main phospholipids identified were phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine. The main fatty acids were 14:0, 16:0, 18:3(n-6), 18:4(n-3), 18:2(n-6), 20:4(n-6), 22:6(n-3), and 24:5(n-6). In both G. mariae and G. ventalina n-6 polyunsaturated fatty acids predominated over the n-3 family. In addition, the 7-methyl-6(E)-hexadecenoic acid was identified in both gorgonians. The occurrence of tetracosapolyenoic fatty acids in the genus Gorgonia is also reported for the first time.
- Published
- 2002
40. Total synthesis of the novel bacterial fatty acid 16-methyl-8(Z)-heptadecenoic acid
- Author
-
Mayra Pagán and Néstor M. Carballeira
- Subjects
chemistry.chemical_classification ,biology ,Stereochemistry ,Organic Chemistry ,Fatty acid ,Total synthesis ,Micrococcus ,Dioxolanes ,Stereoisomerism ,Cell Biology ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Capillary gas chromatography ,Fatty Acids, Monounsaturated ,chemistry ,Heptadecenoic Acid ,Yield (chemistry) ,Organic chemistry ,Molecular Biology ,Bacteria ,Polyunsaturated fatty acid - Abstract
The recently discovered bacterial fatty acid 16-methyl-8(Z)-heptadecenoic acid was synthesized for the first time in four steps (22% overall yield) starting from commercially available 8-methylnonanoic acid. The synthetic approach provided enough material to corroborate the structure and stereochemistry of the acid, which was recently identified in a Micrococcus bacterium from Lake Pomorie in Bulgaria. Reference equivalent-chain length values in nonpolar capillary gas chromatography for methyl 16-methyl-8(Z)-heptadecenoate and methyl 16-methyl-8(E)-heptadecenoate are also reported. This information will be helpful in subsequent characterizations of these fatty acids, as well as in the total identification of the fatty acid profile of bacteria producing these compounds.
- Published
- 2001
41. Identification and Total Synthesis of Novel Fatty Acids from the Siphonarid Limpet Siphonaria denticulata
- Author
-
Mary J. Garson, J. J. De Voss, H. Cruz, C. A. Hill, and Néstor M. Carballeira
- Subjects
Delta ,Stereochemistry ,Palmitic Acid ,Pharmaceutical Science ,Stereoisomerism ,Chemical synthesis ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,Fatty Acids, Monounsaturated ,Palmitic acid ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Dimethyl disulfide ,Derivatization ,Pharmacology ,Molecular Structure ,biology ,Limpet ,Organic Chemistry ,Australia ,Total synthesis ,biology.organism_classification ,Complementary and alternative medicine ,chemistry ,Mollusca ,Molecular Medicine ,Stearic Acids - Abstract
The novel fatty acids 17-methyl-6(Z)-octadecenoic acid and 17-methyl-7(Z)-octadecenoic acid were identified for the first time in nature in the mollusk Siphonaria denticulata from Queensland, Australia. The principal fatty acids in the limpet were hexadecanoic acid, octadecanoic acid, and (Z)-9-octadecenoic acid, while the most interesting series of monounsaturated fatty acids was a family of five nonadecenoic acids with double bonds at either Delta (7), Delta (9), Delta (11), Delta (12), or Delta (13). The novel compounds were characterized using a combination of GC-MS and chemical transformations, such as dimethyl disulfide derivatization. The first total syntheses for the two novel methyl-branched nonadecenoic acids are also described, and these were accomplished in four to five steps and in high yields.
- Published
- 2001
42. New Methoxylated Fatty Acids from the Caribbean Sponge Callyspongia fallax
- Author
-
Néstor M. Carballeira and Mayra Pagán
- Subjects
Stereochemistry ,Pharmaceutical Science ,Ether ,Animal origin ,Gas Chromatography-Mass Spectrometry ,Mass Spectrometry ,Analytical Chemistry ,Callyspongia fallax ,chemistry.chemical_compound ,Symbiosis ,Drug Discovery ,Animals ,Monounsaturated fatty acid ,Phospholipids ,Pharmacology ,chemistry.chemical_classification ,biology ,Fatty Acids ,Organic Chemistry ,Fatty acid ,biology.organism_classification ,Porifera ,Sponge ,Complementary and alternative medicine ,Biochemistry ,chemistry ,Molecular Medicine ,Bacteria - Abstract
The saturated 2-methoxylated fatty acids 2-methoxytetradecanoic acid (1), 2-methoxypentadecanoic acid (2), and 2-methoxyoctadecanoic acid (3) as well as the Delta6 monoenoic methoxylated fatty acids (6Z)-2-methoxy-6-tetradecenoic acid (4), (6Z)-2-methoxy-6-pentadecenoic acid (5), and (6Z)-2-methoxy-13-methyl-6-tetradecenoic acid (7) were identified for the first time in nature in the phospholipids from the Caribbean sponge Callyspongia fallax. These findings expand the occurrence of 2-methoxylated fatty acids to C14-C15 chain lengths and establish new fatty acid biosynthetic possibilities for marine organisms. The novel methoxylated fatty acids could have originated from the phospholipids of a bacterium in symbiosis with the sponge.
- Published
- 2001
43. Characterization of Novel Methyl-Branched Chain Fatty Acids from a Halophilic Bacillus Species
- Author
-
César M. Lozano, Carlos Miranda, Kamen Stefanov, Iva Tzvetkova, Jordan Nechev, Mirolyuba Ilieva, Albena Ivanova, and Néstor M. Carballeira
- Subjects
Pharmaceutical Science ,Bacillus ,Gas Chromatography-Mass Spectrometry ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Bulgaria ,Fatty acid methyl ester ,Pharmacology ,chemistry.chemical_classification ,Chromatography ,biology ,Fatty Acids ,Organic Chemistry ,Fatty acid ,biology.organism_classification ,Halophile ,Enzyme ,Complementary and alternative medicine ,chemistry ,Biochemistry ,Saturated fatty acid ,Molecular Medicine ,Gas chromatography–mass spectrometry ,Bacteria ,Polyunsaturated fatty acid - Abstract
The 4-methylated fatty acids 4,9-dimethyldecanoic, 4,11-dimethyldodecanoic, 4,10-dimethyldodecanoic, and 4,13-dimethyltetradecanoic acid as well as the 2-methylated fatty acids 2,13-dimethyltetradecanoic and 2,12-dimethyltetradecanoic acid were identified for the first time in nature in the halophilic bacterium Bacillus sp. isolated from the salt pans of Burgas in Bulgaria. The principal fatty acids in this bacterium were a series of iso-anteiso fatty acids with chain lengths between C11 and C19, but an interesting series of linear alkylbenzene fatty acids with chain lengths between C10 and C14, such as 12-phenyldodecanoic acid, were also identified. The novel 4-methylated fatty acids were characterized using a combination of GC-MS and chemical transformations such as N-acylpyrrolidide derivatization. The 2-methylated fatty acids were also identified by GC-MS and gas chromatographic coelution with synthetic samples. The novel methyl-branched fatty acids probably originated from the selective incorporation of methylmalonyl-CoA by one of the fatty acid-synthesizing enzymes of the bacterium.
- Published
- 2001
44. Expression of dehydratase domains from a polyunsaturated fatty acid synthase increases the production of fatty acids in Escherichia coli
- Author
-
Delise Oyola-Robles, Abel Baerga-Ortiz, Néstor M. Carballeira, and Carlos Rullán-Lind
- Subjects
Glycerol ,Fatty Acid Synthases ,Recombinant Fusion Proteins ,Bioengineering ,Biology ,Applied Microbiology and Biotechnology ,Biochemistry ,Article ,Bacterial Proteins ,Escherichia coli ,Unsaturated fatty acid ,chemistry.chemical_classification ,Photobacterium ,Fatty Acids ,Temperature ,Fatty acid ,Carbon ,Peptide Fragments ,Culture Media ,Protein Structure, Tertiary ,Fatty acid synthase ,chemistry ,Biofuels ,Saturated fatty acid ,Fermentation ,Free fatty acid receptor ,biology.protein ,Biocatalysis ,Fatty Acids, Unsaturated ,Beta-ketoacyl-ACP synthase ,Biotechnology ,Polyunsaturated fatty acid - Abstract
Increasing the production of fatty acids by microbial fermentation remains an important step towards the generation of biodiesel and other portable liquid fuels. In this work, we report an Escherichia coli strain engineered to overexpress a fragment consisting of four dehydratase domains from the polyunsaturated fatty acid (PUFA) synthase enzyme complex from the deep-sea bacterium, Photobacterium profundum. The DH1-DH2-UMA enzyme fragment was excised from its natural context within a multi-enzyme PKS and expressed as a stand-alone protein. Fatty acids were extracted from the cell pellet, esterified with methanol and quantified by GC-MS analysis. Results show that the E. coli strain expressing the DH tetradomain fragment was capable of producing up to a 5-fold increase (80.31 mg total FA/L culture) in total fatty acids over the negative control strain lacking the recombinant enzyme. The enhancement in production was observed across the board for all the fatty acids that are typically made by E. coli. The overexpression of the DH tetradomain did not affect E. coli cell growth, thus showing that the observed enhancement in fatty acid production was not a result of effects associated with cell density. The observed enhancement was more pronounced at lower temperatures (3.8-fold at 16 °C, 3.5-fold at 22 °C and 1.5-fold at 30 °C) and supplementation of the media with 0.4% glycerol did not result in an increase in fatty acid production. All these results taken together suggest that either the dehydration of fatty acid intermediates are a limiting step in the E. coli fatty acid biosynthesis machinery, or that the recombinant dehydratase domains used in this study are also capable of catalyzing thioester hydrolysis of the final products. The enzyme in this report is a new tool which could be incorporated into other existing strategies aimed at improving fatty acid production in bacterial fermentations towards accessible biodiesel precursors.
- Published
- 2013
45. The use of (S)-(−)-1-(1-naphthyl)ethylamine as a resolving agent for α-methoxy fatty acids
- Author
-
Roberto Colón and Néstor M. Carballeira
- Subjects
Chromatography ,Resolution (mass spectrometry) ,Silica gel ,Organic Chemistry ,1-(1-naphthyl)ethylamine ,Diastereomer ,Catalysis ,Capillary gas chromatography ,Inorganic Chemistry ,chemistry.chemical_compound ,Column chromatography ,chemistry ,Organic chemistry ,Physical and Theoretical Chemistry ,Enantiomer ,Ethylamine - Abstract
A general method was developed for the diastereoselective resolution of α-methoxy fatty acids utilizing ( S )-(−)-1-(1-naphthyl)ethylamine as resolving agent. The diastereomeric amides can be easily separated by silica gel column chromatography and/or capillary gas chromatography, thus allowing for a preparative and analytical method for determining the enantiomeric purity of naturally occurring and/or synthetic α-methoxy fatty acids. The first synthesis of the naturally occurring ( R )-2-methoxyhexadecanoic acid was also accomplished in four steps starting from commercially available (±)-2-hydroxyhexadecanoic acid.
- Published
- 1999
46. Synthesis of racemic 9-methyl-10-hexadecenoic acid
- Author
-
Anthony Sostre, José A. Restituyo, and Néstor M. Carballeira
- Subjects
chemistry.chemical_classification ,Magnetic Resonance Spectroscopy ,Chromatography ,Double bond ,biology ,Organic Chemistry ,Fatty acid ,Stereoisomerism ,Cell Biology ,biology.organism_classification ,Biochemistry ,Gas Chromatography-Mass Spectrometry ,Fatty Acids, Monounsaturated ,chemistry ,Hexadecenoic Acid ,Yield (chemistry) ,Organic chemistry ,Molecular Biology ,Bacteria ,Vibrio - Abstract
The marine bacterial fatty acid 9-methyl-10-hexadecenoic acid was conveniently prepared in 6 steps and in a 22% overall yield, starting from commercially available methyl 10-hydroxydecanoate. The naturally occurring fatty acid has the E double bond configuration as confirmed by gas chromatographic co-elution experiments.
- Published
- 1999
47. 5,9-Nonadecadienoic acids in malvaviscus arboreus and allamanda cathartica
- Author
-
Clarisa Cruz and Néstor M. Carballeira
- Subjects
biology ,Apocynaceae ,Chemistry ,Allamanda cathartica ,Phospholipid ,Plant Science ,General Medicine ,Horticulture ,biology.organism_classification ,Biochemistry ,Malvaviscus ,chemistry.chemical_compound ,Phosphatidylcholine ,Ornamental plant ,Botany ,Allamanda ,Molecular Biology ,Malvaceae - Abstract
The phospholipid fatty acid composition of Malvaviscus arboreus DC. (Malvaceae) and Allamanda cathartica L. (Apocynaceae) was studied. The fatty acids, 17-methyl-5,9-octadecadienoic acid, 16-methyl-5,9-octadecadienoic acid, and 5,9-nonadecadienoic acid were identified in the phospholipid (mainly phosphatidylcholine) extract of M. arboreus by GC-MS. 17-Methyl-5,9-octadecadienoic acid was also identified in A. cathartica . This is the first report of iso - anteiso branched Δ5,9 fatty acids from a plant source.
- Published
- 1998
48. Fatty acid composition of bacteria associated with the toxic dinoflagellate Ostreopsis lenticularis and with caribbean Palythoa species
- Author
-
Anastacio Emiliano, Néstor M. Carballeira, Gretchen M. Colon, Ileana M. González, José A. Restituyo, Thomas R. Tosteson, Anthony Sostre, and Carmen G. Tosteson
- Subjects
food.ingredient ,Ciguatoxin ,Ciguatera ,Biochemistry ,Microbiology ,Ciguatoxins ,Cnidaria ,Cnidarian Venoms ,food ,Pseudomonas ,medicine ,Animals ,Alteromonas ,Symbiosis ,chemistry.chemical_classification ,Acrylamides ,biology ,Fatty Acids ,Organic Chemistry ,Dinoflagellate ,Fatty acid ,Cell Biology ,biology.organism_classification ,medicine.disease ,chemistry ,Dinoflagellida ,Palythoa ,Bacteria - Abstract
The fatty acid composition of a Pseudomonas sp. (Alteromonas) and its host, the dinoflagellate Ostreopsis lenticularis, vectors in ciguatera fish poisoning, has been studied. The major fatty acids in O. lenticularis were 16:0, 20:5n-3, and 22:6n-3, but 18:2n-6, 18:3n-3, and 18:n-3 were also identified. In contrast to other dinoflagellates, 1 8:5n-3 was not detected in O. lenticularis. Even-chain fatty acids such as 9-16:1, 11-18:1, and 13-20:1 predominated in the Pseudomonas sp. from O. lenticularis, but 1 6-20% of (E)-11-methyl-12-octadecenoic acid was also identified. The chirality of the latter was confirmed by total synthesis (28% overall yield) starting from oxacyclotridecan-2-one. The fatty acid compositions of two other Pseudomonas species, from the palytoxin-producing zoanthids Palythoa mamillosa and P. caribdea, were also studied and were similar to that of the Pseudomonas sp. from O. lenticularis. The possibility of using some of these fatty acids as chemotaxonomic lipids in identifying marine animals that consume toxic dinoflagellates or zoanthids is discussed.
- Published
- 1998
49. Phospholipid Fatty Acid Composition of Gorgonians of the Genus Eunicea: Further Identification of Tetracosapolyenoic Acids
- Author
-
Anthony Sostre, Abimael D. Rodríguez, and Néstor M. Carballeira
- Subjects
Phosphatidylethanolamine ,chemistry.chemical_classification ,biology ,Physiology ,Stereochemistry ,Phospholipid ,biology.organism_classification ,Biochemistry ,Succinea ,chemistry.chemical_compound ,Gorgonian ,chemistry ,Genus ,Phosphatidylcholine ,Organic chemistry ,Fatty acid composition ,Molecular Biology ,Polyunsaturated fatty acid - Abstract
The phospholipid fatty acid composition of the Caribbean gorgonian corals Eunicea fusca (Duchassaing and Michelotti), Eunicea laciniata (Duchassaing and Michelotti), Eunicea mammosa (Lamouroux), Eunicea succinea (Pallas), and Eunicea sp. is described for the first time. The main phospholipids identified were phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine. All five gorgonians presented a similar phospholipid fatty acid composition. The main fatty acids were 16:0, 18:3 (n − 6), 18:4 (n − 3), 20:4 (n − 6), 22:6 (n − 3), 24:5 (n − 6), and 24:6 (n − 3). In all of the studied Eunicea gorgonians, the tetracosapolyenoic fatty acids 24:5 (n − 6) and 24:6 (n − 3), as well as the (Z) and (E) isomers of 7-methyl-6-hexadecenoic acid, were identified. On the other hand, E. fusca and E. laciniata contained, in trace amounts, the unusual 19:4 (n − 3) acid, while E. succinea contained the recently reported 14-methyl-5,9-pentadecadienoic acid. In all of the five studied gorgonians n − 6 polyunsaturated fatty acids predominated. These findings expand the occurrence of tetracosapolyenoic fatty acids to the Eunicea.
- Published
- 1997
50. Total Synthesis of the Antimicrobial Fatty Acid (5Z,9Z)-14-Methylpentadeca-5,9-dienoic Acid and its Longer-Chain Analog (5Z,9Z)-24-Methylpentacosa-5,9-dienoic Acid
- Author
-
Elba D. Reyes and Néstor M. Carballeira
- Subjects
chemistry.chemical_classification ,Chain (algebraic topology) ,chemistry ,Stereochemistry ,Organic Chemistry ,Fatty acid ,Total synthesis ,Antimicrobial ,Catalysis - Published
- 1997
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