RESUMEN
Polyunsaturated fatty acids and their metabolites have been reported in which their pathway has potential for the modulation of cancer cell growth. 13-(S)-HODE and 15-(S)-HETE, both of which are main metabolites of 15-LOXs, play an important role as endogenous ligands in biological systems. However, the modification of 13-(S)-HODE and 15-(S)-HETE in pharmaceutical applications has not been explored widely. Herein, we report the stereoselective syntheses of 13-(S)-HODE, 15-(S)-HETE, and its derivatives to enable the synthesis of bioactive fatty acid analogues.
Asunto(s)
Ácidos Grasos Insaturados , Ácidos Hidroxieicosatetraenoicos , Estereoisomerismo , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/síntesis química , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/síntesis química , Estructura Molecular , Ácidos Linoleicos/química , Ácidos Linoleicos/síntesis químicaRESUMEN
Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented.
Asunto(s)
Ácidos Grasos Insaturados , Humanos , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/síntesis química , Animales , Prostaglandina-Endoperóxido Sintasas/metabolismo , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Inflamación/tratamiento farmacológico , Inflamación/metabolismoRESUMEN
Besides its native biological function as a plant hormone, cis-(+)-12-oxo-phytodienoic acid (12-OPDA) serves as a metabolite for the cellular formation of (-)-jasmonic acid and has also been shown to have an influence on mammalian cells. In order to make this biologically active, but at the same time very expensive natural product 12-OPDA broadly accessible for further biological and medicinal research, we developed an efficient bioprocess based on the utilization of a tailor-made whole-cell catalyst by following the principles of its biosynthesis in nature. After process optimization, the three-step one-pot synthesis of 12-OPDA starting from readily accessible α-linolenic acid could be conducted at appropriate technically relevant substrate loadings in the range of 5-20 g L-1. The desired 12-OPDA was obtained with an excellent conversion efficiency, and by means of the developed, efficient downstream-processing, this emulsifying as well as stereochemically labile biosynthetic metabolite 12-OPDA was then obtained with very high chemical purity (>99%) and enantio- and diastereomeric excess (>99% ee, 96% de) as well as negligible side-product formation (<1%). With respect to future technical applications, we also demonstrated the scalability of the production of the whole cell-biocatalyst in a high cell-density fermentation process.
Asunto(s)
Ácidos Grasos Insaturados , Reguladores del Crecimiento de las Plantas , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Ácidos Grasos Insaturados/síntesis química , Reguladores del Crecimiento de las Plantas/síntesis química , Reguladores del Crecimiento de las Plantas/química , Reguladores del Crecimiento de las Plantas/metabolismo , Estereoisomerismo , Estructura MolecularRESUMEN
Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase-mediated oxidation of polyunsaturated fatty acids. Originally isolated and identified from brown seaweed (Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii), and later replicated on milligram scale through chemical synthesis, the full biological activities of these compounds remain to be elucidated. To bridge this gap in knowledge, we propose a unified methodology to synthesize the 14-membered macrocyclic structures of Ecklonialactones, Eiseniachlorides and analogs using a versatile and convergent approach. This study delineates the synthesis of Ecklonialactone A, B, C, D, and Eiseniachlorides A and B, as well as ent-Ecklonialactone B, 16-epi-Ecklonialactone B and 12,13-diepi-Ecklonialactone B.
Asunto(s)
Lactonas , Lactonas/química , Lactonas/síntesis química , Phaeophyceae/química , Oxidación-Reducción , Algas Marinas/química , Estereoisomerismo , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/síntesis química , Estructura MolecularRESUMEN
This manuscript describes our third generation, gram-scale synthesis of very long chain-polyunsaturated fatty acids (VLC-PUFAs), a unique and increasingly important class of lipids. Critical to this work and what makes it different from our previous approach to this family was the avoidance of oxidation sequences. Central to accomplishing this involved the use of a Negishi coupling reaction between the acid chloride derived from DHA and a saturated alkyl zinc reaction. Overall, the general approach required 6 synthetic transformations from DHA and was accomplished with an overall yield of 40%.
Asunto(s)
Ácidos Grasos Insaturados , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/síntesis química , Estructura Molecular , Zinc/química , Ácidos Docosahexaenoicos/química , Ácidos Docosahexaenoicos/síntesis químicaRESUMEN
Jasmonic acid (JA) is a plant hormone involved in the defense response against insects and fungi. JA is synthesized from α-linolenic acid (LA) by the octadecanoid pathway in plants. 12-oxo-Phytodienoic acid (OPDA) is one of the biosynthetic intermediates in this pathway. The reported stereo selective total synthesis of cis-(+)-OPDA is not very efficient due to the many steps involved in the reaction as well as the use of water sensitive reactions. Therefore, we developed an enzymatic method for the synthesis of OPDA using acetone powder of flax seed and allene oxide cyclase (PpAOC2) from Physcomitrella patens. From this method, natural cis-(+)-OPDA can be synthesized in the high yield of approximately 40%. In this study, we investigated the substrate specificity of the enzymatic synthesis of other OPDA analogs with successions to afford OPDA amino acid conjugates, dinor-OPDA (dn-OPDA), and OPDA monoglyceride, and it was suggested that the biosynthetic pathway of arabidopsides could occur via MGDG.
Asunto(s)
Ácidos Grasos Insaturados/síntesis química , Oxidorreductasas Intramoleculares/química , Proteínas de Plantas/química , Bryopsida/enzimología , Lino/enzimología , Semillas/enzimología , EstereoisomerismoRESUMEN
The first total synthesis of marine natural product, (-)-majusculoic acid (1) and its seven analogs (9-15), was accomplished in three to ten steps with a yield of 3% to 28%. The strategy featured the application of the conformational controlled establishment of the trans-cyclopropane and stereochemical controlled bromo-olefination or olefination by Horner-Wadsworth-Emmons (HWE) reaction. The potential anti-inflammatory activity of the eight compounds (1 and 9-15) was evaluated by determining the nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7. (-)-Majusculoic acid (1), methyl majusculoate (9), and (1R,2R)-2-((3E,5Z)-6-bromonona-3,5-dien-1-yl)cyclopropane-1-carboxylic acid (12) showed significant effect with inhibition rates of 33.68%, 35.75%, and 43.01%, respectively. Moreover, they did not show cytotoxicity against RAW264.7 cells, indicating that they might be potential anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/síntesis química , Ácidos Grasos Insaturados/síntesis química , Hidrocarburos Bromados/síntesis química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Proliferación Celular/efectos de los fármacos , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Hidrocarburos Bromados/química , Hidrocarburos Bromados/farmacología , Lipopolisacáridos/toxicidad , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Óxido Nítrico/metabolismo , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
A set of 12 analogues of piperine was designed, replacing the amide functional group of the molecule with different aliphatic and aromatic ester functional groups. Molecular docking studies of these molecules with FDA-approved target proteins for anti-bacterial drugs were done. The binding energy of the proteins and the ligands were low and the analogues were found to be drug-like based on the ADME results; hence, the molecules were synthesized. The synthesized compounds were tested for their anti-bacterial property against six bacterial species via Agar well-diffusion method. Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis were the strains tested. The overall susceptibility is higher in gram-positive. The analogues showed better activity than piperine. The analogues, propyl piperic ester (P3) and 2-fluorophenyl piperic ester (P9) and 4-fluorophenyl piperic ester (P10) showed comparatively bigger inhibition zones for all the strains.
Asunto(s)
Alcaloides/síntesis química , Antibacterianos/síntesis química , Benzodioxoles/síntesis química , Ácidos Grasos Insaturados/síntesis química , Piperidinas/síntesis química , Alcamidas Poliinsaturadas/síntesis química , Alcaloides/farmacología , Antibacterianos/farmacología , Benzodioxoles/farmacología , Ácidos Grasos Insaturados/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Relación Estructura-ActividadRESUMEN
In this work, three series of ω-3 polyunsaturated fatty acid-alkanolamine derivatives (PUFA-AAs) were synthesized, characterized and their anti-inflammatory activity in vivo was evaluated. Compounds 4a, 4f, and 4k exhibited marked anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. The most promising compound 4k dose-dependently suppressed the cytokines with IC50 values in the low micromolar range. Further, 4k exhibited potential in vitro Nur77-binding affinity (Kd = 6.99 × 10-6 M) which is consistent with the result of docking studies. Next, the anti-inflammatory mechanism of 4k was found to be through NF-κB signal pathway in a Nur77-dependent manner. Moreover, we also observed 4k significantly inhibited LPS-induced expression of cytokines (IL-6, TNF-α, and IL-1ß) through suppressing NF-κB activation and attenuated LPS-induced inflammation in mouse acute lung injury (ALI) model. In conclusion, the study strongly suggests that the PUFA-AA derivatives can be particularly as new Nur77 mediators for further treatment in inflammatory diseases.
Asunto(s)
Aminas/química , Antiinflamatorios/síntesis química , Ácidos Grasos Insaturados/síntesis química , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Ácidos Grasos Insaturados/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de SeñalRESUMEN
A stereoselective method was developed for the synthesis of synthetic analogues of natural 5Z,9Z-dienoic acids by esterification of aliphatic and aromatic alcohols and carboxylic acids with (5Z,9Z)-1,14-tetradeca-5,9-dienedioic acid and (5Z,9Z)-1,14-tetradeca-5,9-dienediol, synthesized by Ti-catalyzed homo-cyclomagnesiation of the tetrahydropyran ether of hepta-5,6-dien-1-ol with Grignard reagents. In order to establish the effect of molecular structure on the antitumor activity, the obtained 5Z,9Z-dienoic acids were tested for the inhibitory activity against human topoisomerase I, the cytotoxic activity in vitro against several cancer and normal cell lines (Jurkat, HL-60, K562, U937, fibroblasts), the effect on the cell cycle, and apoptosis-inducing ability using flow cytofluorometry. In addition, the effect of the synthesized acids on the cancer cell production of some phosphorylated and unphosphorylated proteins responsible for proliferation and apoptosis was studied by a new multiplex assay technology, MAGPIX.
Asunto(s)
Antineoplásicos/farmacología , Productos Biológicos/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Ácidos Grasos Insaturados/farmacología , Inhibidores de Topoisomerasa I/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/química , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/químicaRESUMEN
The kalimantacins make up a family of hybrid polyketide-nonribosomal peptide-derived natural products that display potent and selective antibiotic activity against multidrug resistant strains of Staphylococcus aureus. Herein, we report the first total synthesis of kalimantacin A, in which three fragments are prepared and then united via Sonogashira and amide couplings. The enantioselective synthetic approach is convergent, unlocking routes to further kalimantacins and analogues for structure-activity relationship studies and clinical evaluation.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/química , Productos Biológicos , Carbamatos/síntesis química , Ácidos Grasos Insaturados/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The resolution of inflammation is governed by the active biosynthesis of specialized pro-resolving mediators using ω-6 and ω-3 polyunsaturated fatty acids as substrates. These mediators act as resolution agonists and display several interesting bioactivities. PD2n-3 DPA is an oxygenated polyunsaturated fatty acid biosynthesized from n-3 docosapentaenoic acid belonging to the specialized pro-resolving lipid mediator family named protectins. The protectins exhibit anti-inflammatory properties and pro-resolving bioactivities. These endogenously produced compounds are of interest as leads in resolution pharmacology and drug development. Herein, together with its NMR, MS, and UV data, a stereoselective total synthesis of PD2n-3 DPA is presented.
Asunto(s)
Ácidos Grasos Insaturados/síntesis química , Animales , Ácidos Grasos Insaturados/química , Humanos , Estructura Molecular , Análisis Espectral/métodos , Especificidad por SustratoRESUMEN
The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.
Asunto(s)
Antiinflamatorios , Apoptosis/efectos de los fármacos , Ácidos Grasos Insaturados , Macrófagos/inmunología , Neutrófilos/inmunología , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Apoptosis/inmunología , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunologíaRESUMEN
Seven piperic acid amides along with their lower homologs (12) were synthesized using HATU-DIPEA coupling reagent. All the synthesized derivatives were evaluated for their antibacterial activities against Staphylococcus aureus, Pseudomonas aeruginosa, and vancomycin-resistant P. aeruginosa. They were found to be more active on P. aeruginosa than on S. aureus. However, they did not exhibit potent activity on Vancomycin resistant P. aeruginosa. Among the tested compounds, methylenedioxycinnamic acid amide of anthranilic acid (MDCA-AA, 2a) was found to be most active against S. aureus with MIC of 3.125 µg/ml. The PAS and INH amides of piperic acid were screened against Mycobacterium tuberculosis H37Ra strain. They were found to be most active among all the tested compounds but were found to be less active than the standard drug, isoniazid.
Asunto(s)
Amidas/farmacología , Antibacterianos/farmacología , Ácidos Grasos Insaturados/farmacología , Amidas/síntesis química , Amidas/química , Antibacterianos/síntesis química , Antibacterianos/química , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/química , Isoniazida/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
In this study, a combined targeted/untargeted UHPLC-ESI-QTOF-MS/MS method for the targeted quantitative analysis of the primary platelet lipid mediators thromboxane B2 (TXB2), 12S-hydroxy-5Z,8E,10E-heptadecatrienoic acid (HHT) and its oxidation product 12-keto-5Z,8E,10E-heptadecatrienoic acid (KHT) was developed, which allowed simultaneous untargeted profiling for the detection of other lipid biomarkers such as other oxylipins and fatty acids (FAs) in platelet releasates. A general procedure for the synthesis of keto-analogs from hydroxylated polyunsaturated FAs (PUFAs) using Dess-Martin periodinane oxidation reagent was proposed for the preparation of KHT standard. MS detection was performed in data independent acquisition (DIA) mode with sequential window acquisition of all theoretical fragment ion mass spectra (SWATH) in the range of 50-500â¯Da with variable window sizes. The LC-MS/MS assay was validated for the targeted analytes and applied for analysis of supernatants derived from resting platelets and from platelets treated with thrombin. The targeted analytes KHT, HHT and TXB2 were found at highly elevated levels in the activated platelet releasates. On average, 13⯱â¯7, 15⯱â¯9, and 0.6⯱â¯0.2 attomols per platelet were released upon thrombin-activation. Furthermore, the simultaneous untargeted profiling (nâ¯=â¯8 in each group) revealed that these oxylipins are released with a pool of other (significantly upregulated) oxidized (12-HETE, 12-HEPE) and non-oxidized PUFAs. All these compounds can be considered additional biomarkers of platelet activation complementing the primary platelet activation marker thromboxane B2. The other lipids may support platelet activation or trigger other biological actions with some potential implications in thromboinflammation.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Ácidos Grasos/sangre , Activación Plaquetaria/efectos de los fármacos , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Trombina/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Ácidos Grasos Insaturados/sangre , Ácidos Grasos Insaturados/síntesis química , Humanos , Límite de Detección , Tromboxano B2/sangreRESUMEN
BACKGROUND: Piperine or piperic acid was isolated from fruits of Piper nigrum and had been reported as pharmacological valuable bioactive constituents. Keeping in view, a series of piperic acid-based N heterocyclic's derivatives were synthesized and evaluated for antibacterial activity. All these prepared ligands were docked to study the molecular interactions and binding affinities against the protein PDB ID: 5 CDP. OBJECTIVE: To meet the real need of newer antibacterials, we designed and synthesized scaffolds with good antibacterial activity. The obtained antibacterials have been validated in terms of ligand-protein interaction and thus prove to build up as good drug candidates. METHODS: Antibacterial activity of the compounds were carried out against bacterial strains; three Grampositive and three Gram-negative bacterial strains using agar well diffusion method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrödinger molecular modeling package by Maestro 11.0. RESULTS: Compounds BC 28, BC 32, and BC 33 exhibits antibacterial activity along with Glide docking score of -8.580, -9.753 kcal/mol, and -8.813 kcal/mol, respectively. Docking studies explained hydrogen bonding, pi-pi, and hydrophobic interactions with amino acid residues which explain the binding affinity of the most docked ligand with protein. CONCLUSION: In the present study, substituted piperic acid was synthesized and evaluated as antibacterial compared with standard drug ciprofloxacin and results interpret that having nitrogen as heteroatom in the heterocyclic nucleus found to be more potent than the standard drug ciprofloxacin. On comparing, substitution with electron-donating groups generates excellent antibacterial potential against the bacterial strains. It was also proved that having substitution with electron-donating groups on meta and para position with triazoline ring system exhibits greater potential while compounds which have a meta- electron-donating substituent showed lesser activity with thiazole nucleus. In addition, structure-based activities of the prepared analogs were discussed under Structure-Activity Relationship (SAR) section.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/síntesis química , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Infecciones Bacterianas/tratamiento farmacológico , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Girasa de ADN/metabolismo , Ácidos Grasos Insaturados/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Topoisomerasa II/síntesis químicaRESUMEN
Amino-acid-derived phthalazine catalysts have been designed and synthesized for enantioselective halolactonization of prochiral dienoic acids. The scope of the reaction is evidenced by 17 examples of spiro α-exo-methylene-halolactones with up to 99.8% enantiomeric excess. The resulting enantio-enriched spiro halolactone products are found to exhibit potent antitumor effects. In addition, both antipodes of products with equally excellent enantioselevity could be obtained since a pair of enantiomeric catalysts is guaranteed.
Asunto(s)
Aminoácidos/química , Ácidos Grasos Insaturados/síntesis química , Lactonas/química , Ftalazinas/química , Catálisis , Ácidos Grasos Insaturados/química , Estructura Molecular , Ftalazinas/síntesis química , EstereoisomerismoRESUMEN
In this study, co-functionalization with phosphate and carboxylate on polydiacetylene (PDA) was proposed to detect calcium ions in serum, inspired by biologically abundant phosphate-calcium ion and carboxylate-calcium ion binding. The cooperative interaction of calcium ions with phosphate and carboxylate in PDA induced the change of electronic properties in the backbone without aggregation of liposomes, accompanied by blue-to-purple color transition. The cooperative effect through the introduction of mixed ligands facilitated the selective detection of calcium ions over magnesium ions, which was a source of major interference in many calcium ion probes, and in the presence of major serum metal ions. The sensor system exhibited highly sensitive detection of calcium ions with an estimated limit of detection of 0.97 µM. In addition, the detection method was employed to determine the concentration of calcium ions in various serums.
Asunto(s)
Calcio/sangre , Ácidos Grasos Insaturados/química , Organofosfatos/química , Polímero Poliacetilénico/química , Animales , Bovinos , Colorimetría/métodos , Equidae , Ácidos Grasos Insaturados/síntesis química , Caballos , Límite de Detección , Liposomas/síntesis química , Liposomas/química , Ratones , Organofosfatos/síntesis química , Polímero Poliacetilénico/síntesis química , RatasRESUMEN
Covalent conjugates of multiple nutrients often exhibit greater biological activities than each individual nutrient and more predictable safety profiles than completely unnatural chemical entities. Here, we report the construction and application of a focused chemical library of 308 covalent conjugates of a variety of small-molecule nutrients. Screening of the library with a reporter gene of sterol regulatory element-binding protein (SREBP), a master regulator of mammalian lipogenesis, led to the discovery of a conjugate of docosahexaenoic acid (DHA), glucosamine, and amino acids as an inhibitor of SREBP (molecule 1, DHG). Mechanistic analyses indicate that molecule 1 impairs the SREBP activity by inhibiting glucose transporters and thereby activating AMP-activated protein kinase (AMPK). Oral administration of molecule 1 suppressed the intestinal absorption of glucose in mice. These results suggest that such synthetic libraries of nutrient conjugates serve as a source of novel chemical tools and pharmaceutical seeds that modulate energy metabolism.
Asunto(s)
Nutrientes/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Aminoácidos/síntesis química , Aminoácidos/farmacología , Animales , Células CACO-2 , Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/farmacología , Genes Reporteros , Glucosamina/síntesis química , Glucosamina/farmacología , Glucosa/metabolismo , Humanos , Absorción Intestinal/efectos de los fármacos , Masculino , Ratones Endogámicos ICR , Nutrientes/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Proteínas de Unión a los Elementos Reguladores de Esteroles/genética , Vitaminas/síntesis química , Vitaminas/farmacologíaRESUMEN
Stereoselective synthesis of Z-configured double bonds is central in organic synthesis due to the presence of such motifs in polyunsaturated fatty acids and many natural products. Traditionally, reductions of internal alkynes or Wittig, Ando or Still-Gennari reactions, are often used for preparing such compounds. The substrate scope is limited for both the Ando and the Still-Gennari reactions, while the Wittig reaction often gives low Z-selectivity for the synthesis of polyunsaturated Z-configured methylene interrupted (skipped) double bonds. Reductions of internal alkynes are challenging due to diminished Z-selectivity, poor catalyst reproducibility and over-reductions. An alternative and highly attractive approach is to employ naturally occurring and commercially available polyunsaturated fatty acids as starting materials. The main advantage of this strategy is the conservation of the multiple Z-configured double bonds present in the starting material, allowing a precise incorporation of the desired double bonds into the final product. In particular, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid have been used for the stereoselective synthesis of polyunsaturated fatty acids, their derivatives and other polyunsaturated natural products. Herein, such efforts are reviewed.