RESUMEN
The first concise and efficient synthesis of some fluorine-containing morpholino nucleosides has been developed. One synthetic strategy was based on the oxidative ring cleavage of the vicinal diol unit of uridine, cytidine adenosine and guanosine derivatives, followed by cyclisation of the dialdehyde intermediates by double reductive amination with fluorinated primary amines to obtain various N-fluoroalkylated morpholinos. Another approach involved cyclisation of the diformyl intermediates with ammonia source, followed by dithiocarbamate formation and desulfurization-fluorination with diethylaminosulfur trifluoride yielding the corresponding morpholine-based nucleoside analogues with a N-CF3 element in their structure.
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Herein, we report a stereoselective synthesis of a novel type of conformationally constrained nucleoside analogue in which the sugar part is replaced by a new symmetrical tricycle consisting of a morpholine ring condensed with two imidazolidines. 1,5-Dialdehydes obtained from trityl- and dimethoxytrityl-protected uridine, ribothymidine, inosine, cytidine, adenosine and guanosine by metaperiodate oxidation were reacted with N1,N3-dibenzyl-1,2,3-triaminopropane; the latter reactant was produced using a new method that avoids explosive intermediates. Reactions of dialdehydes with propane-triamine via cascade tricyclization resulted in the corresponding triaza-tricyclic derivatives bearing three new stereogenic centers in high yields. Out of the eight possible diastereoisomers, one stereoisomer was formed in each case due to the chiral control of the starting nucleoside-dialdehydes and the steric constraint of the condensed ring system. The absolute configuration of the new stereotriad was determined by X-ray diffraction and NMR experiments. A mechanistic study performed under reductive conditions to trap the presumed bicyclic intermediate showed that the triamine reactant first attacks the 2'-aldehyde group, followed by a rapid bicyclization to form the imidazolidino-morpholine unit.
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In the shadow of SARS-CoV-2, influenza seems to be an innocent virus, although new zoonotic influenza viruses evolved by mutations may lead to severe pandemics. According to WHO, there is an urgent need for better antiviral drugs. Blocking viral hemagglutinin with multivalent N-acetylneuraminic acid derivatives is a promising approach to prevent influenza infection. Moreover, dual inhibition of both hemagglutinin and neuraminidase may result in a more powerful effect. Since both viral glycoproteins can bind to neuraminic acid, we have prepared three series of amphiphilic self-assembling 2-thio-neuraminic acid derivatives constituting aggregates in aqueous medium to take advantage of their multivalent effect. One of the series was prepared by the azide-alkyne click reaction, and the other two by the thio-click reaction to yield neuraminic acid derivatives containing lipophilic tails of different sizes and an enzymatically stable thioglycosidic bond. Two of the three bis-octyl derivatives produced proved to be active against influenza viruses, while all three octyl derivatives bound to hemagglutinin and neuraminidase from H1N1 and H3N2 influenza types.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Humanos , Gripe Humana/tratamiento farmacológico , Ácido N-Acetilneuramínico/farmacología , Ácido N-Acetilneuramínico/metabolismo , Hemaglutininas/farmacología , Neuraminidasa/metabolismo , Subtipo H3N2 del Virus de la Influenza A , Ácidos Neuramínicos , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismoRESUMEN
The polyanionic phosphodiester backbone of nucleic acids contributes to high nuclease sensitivity and low cellular uptake and is therefore a major obstacle to the biological application of native oligonucleotides. Backbone modifications, particularly charge alterations is a proven strategy to provide artificial oligonucleotides with improved properties. Here, we describe the synthesis of a new type of oligonucleotide analogues consisting of a morpholino and a ribo- or deoxyribonucleoside in which the 5'-amino group of the nucleoside unit provides the nitrogen of the morpholine ring. The synthetic protocol is compatible with trityl and dimethoxytrityl protecting groups and azido functionality, and was extended to the synthesis of higher oligomers. The chimeras are positively charged in aqueous medium, due to the N-alkylated tertiary amine structure of the morpholino unit.
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OligonucleótidosRESUMEN
BACKGROUND: Cardioprotective effects of H2S are being suggested by numerous studies. Furthermore, H2S plays a role in relaxation of vascular smooth muscle, protects against oxidative stress, and modulates inflammation. Long-term high-dose use of NSAIDs, such as ibuprofen, have been associated with enhanced cardiovascular risk. The goal of the present work is the synthesis and basic pharmacological characterization of a newly designed H2S-releasing ibuprofen derivative. METHODS: Following the synthesis of EV-34, a new H2S-releasing derivative of ibuprofen, oxidative stability assays were performed (Fenton and porphyrin assays). Furthermore, stability of the molecule was studied in rat serum and liver lysates. H2S-releasing ability of the EC-34 was studied with a hydrogen sulfide sensor. MTT (3-(4,5-dimethylthiazol 2-yl)-2,5-(diphenyltetrazolium bromide)) assay was carried out to monitor the possible cytotoxic effect of the compound. Cyclooxygenase (COX) inhibitory property of EV-34 was also evaluated. Carrageenan assay was carried out to compare the anti-inflammatory effect of EV-34 to ibuprofen in rat paws. RESULTS: The results revealed that the molecule is stable under oxidative condition of Fenton reaction. However, EV-34 undergoes biodegradation in rat serum and liver lysates. In cell culture medium H2S is being released from EV-34. No cytotoxic effect was observed at concentrations of 10, 100, 500 µM. The COX-1 and COX-2 inhibitory effects of the molecule are comparable to those of ibuprofen. Furthermore, based on the carrageenan assay, EV-34 exhibits the same anti-inflammatory effect to that of equimolar amount of ibuprofen (100 mg/bwkg). CONCLUSION: The results indicate that EV-34 is a safe H2S releasing ibuprofen derivative bearing anti-inflammatory properties.
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Sulfuro de Hidrógeno/química , Ibuprofeno/química , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Ibuprofeno/farmacología , Inflamación/tratamiento farmacológico , Masculino , Estrés Oxidativo/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Nucleoside and nucleic acid analogues are known to possess a considerable therapeutic potential. In this work, by coupling cysteine to nucleosides, we successfully synthesized compounds that may not only have interesting biological properties in their monomeric form, but can be used beyond that, for oligomerization, in order to produce new types of synthetic nucleic acids. We elaborated different strategies for the synthesis of cysteinyl nucleosides as monomers of cysteinyl nucleic acids using nucleophilic substitution or thiol-ene coupling as a synthetic tool, and utilised on two complementary nucleosides, uridine and adenosine. Dipeptidyl dinucleosides and pentameric cysteinyl uridine were prepared from the monomeric building blocks, which are the first members of a new class of peptide nucleic acids containing the entire ribofuranosyl nucleoside units bound to the peptide backbone.
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NucleósidosRESUMEN
A comprehensive optimization and mechanistic study on the photoinduced hydrothiolation of different d- and l- hexo- and pentoglycals with various thiols was performed, at the temperature range of RT to -120 °C. Addition of thiols onto 2-substituted hexoglycals proceeded with complete 1,2-cis-α-stereoselectivity in all cases. Hydrothiolation of 2-substituted pentoglycals resulted in mixtures of 1,2-cis-α- and -ß-thioglycosides of varying ratio depending on the configuration of the reactants. Hydrothiolation of unsubstituted glycals at -80 °C proceeded with excellent yields and, except for galactal, provided the axially C2-S-linked isomers with high selectivity. Cooling was always beneficial to the efficacy, increased the yields and in most cases significantly raised the stereoselectivity. The suggested mechanism explains the different conformational preferences of the intermediate carbon-centered radicals, which is a crucial factor in the stereoselectivity of the reactions.
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A small library of 3'-deoxy-C3'-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3'-exomethylene derivatives of 2',5'-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.
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Citostáticos/síntesis química , Citostáticos/farmacología , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/farmacología , Xilosa/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dimetilsulfóxido/farmacología , Humanos , Concentración 50 Inhibidora , Espectroscopía de Protones por Resonancia Magnética , Compuestos de Sulfhidrilo/químicaRESUMEN
The photoinitiated thiol-ene coupling reactions of 2-substituted glycals were studied as a generally applicable strategy for stereoselective 1,2-cis-α-thioconjugation. Although all glycals reacted with full α-selectivity, the efficacy of the reactions varied in a broad range depending on their configuration and glycals bearing axial acetoxy substituents reacted with very low efficacy at room temperature. The study revealed that the reaction progress could be promoted by cooling and inhibited by heating. At -80 °C, the equilibrium of the rapidly reversible addition of the thiyl radical to alkenes is shifted almost completely toward products, leading to efficient addition reactions. By exploiting this unique temperature effect a series of α-thio-l-fucosides, -d-galactosides, and d-GlcNAc derivatives were prepared with high efficacy and complete stereoselectivity.
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Compuestos de Sulfhidrilo/química , Estereoisomerismo , TemperaturaRESUMEN
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.05,11]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl2, Et3SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.
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Sugar-modified nucleosides are prime synthetic targets in anticancer and antiviral drug development. Radical mediated thiol-ene coupling was applied for the first time on nucleoside enofuranoside derivatives to produce a broad range of thio-substituted d-ribo, -arabino, -xylo and l-lyxo configured pyrimidine nucleosides. In contrast to the analogous reactions of simple sugar exomethylenes, surprisingly, hydrothiolation of nucleoside alkenes under the standard conditions of various initiation methods showed low to moderate yields and very low stereoselectivity. Optimizing the reaction conditions, we have found that cooling the reaction mixture has a significant beneficial effect on both the conversion and the stereoselectivity, and UV-light initiated hydrothiolation of C2'-, C3'- and C4'-exomethylene derivatives of nucleosides at -80 °C proceeded in good to high yields, and, in most cases, in excellent diastereoselectivity. Beyond the temperature, the solvent, the protecting groups on nucleosides and, in some cases, the configuration of the thiols also affected the stereochemical outcome of the additions. The anomalous l-lyxo diastereoselectivity observed upon the addition of 1-thio-ß-d-gluco- and galactopyranose derivatives onto C4',5'-unsaturated uridines is attributed to steric mismatch between the d-ribo C4'-radical intermediates and the ß-configured 1-thiosugars.
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Alquenos/química , Nucleósidos/química , Nucleósidos/síntesis química , Procesos Fotoquímicos , Azúcares/química , Compuestos de Sulfhidrilo/química , Temperatura , Técnicas de Química Sintética , Química ClicRESUMEN
A new reagent system consisting of a Lewis acid such as BF3·Et2O or Cu(OTf)2, the mild protic acid hexafluoroisopropanol and the reducing quenching agent triethylsilane was elaborated for O-, N- and S-detritylation of nucleoside, carbohydrate and amino acid derivatives. The method is compatible with acetyl, silyl, acetal and Fmoc groups.
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In order to obtain self assembling, multivalent ligand for influenza virus hemagglutinin α-N-acetylneuraminyl-(2-6)-D-galactopyranose has been synthesized and bonded to a water soluble fullerene derivative using 1,3-dipolar cycloaddition click reaction. The aggregating amphiphilic compound did not inhibit the influenza virus hemagglutinin, but it proved to be an inhibitor of its neuraminidase with a 50% inhibitory concentration of 81 µM.
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Hidrocarburos Aromáticos con Puentes/farmacología , Disacáridos/farmacología , Fulerenos/farmacología , Hemaglutininas/metabolismo , Neuraminidasa/antagonistas & inhibidores , Orthomyxoviridae/metabolismo , Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Disacáridos/síntesis química , Disacáridos/química , Relación Dosis-Respuesta a Droga , Fulerenos/química , Ligandos , Estructura Molecular , Neuraminidasa/metabolismo , Orthomyxoviridae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
In order to obtain new, cluster-forming antibiotic compounds, teicoplanin pseudoaglycone derivatives containing two lipophilic n-octyl chains have been synthesized. The compounds proved to be poor antibacterials, but, surprisingly, they exhibited potent anti-influenza virus activity against influenza A strains. This antiviral action was related to inhibition of the binding interaction between the virus and the host cell. Related analogs bearing methyl substituents in lieu of the octyl chains, displayed no anti-influenza virus activity. Hence, an interaction between the active, dually n-octylated compounds and the lipid bilayer of the host cell can be postulated, to explain the observed inhibition of influenza virus attachment.
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Antivirales/farmacología , Orthomyxoviridae/efectos de los fármacos , Teicoplanina/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Sitios de Unión/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Membrana Dobles de Lípidos/metabolismo , Células de Riñón Canino Madin Darby/efectos de los fármacos , Células de Riñón Canino Madin Darby/metabolismo , Células de Riñón Canino Madin Darby/virología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Teicoplanina/síntesis química , Teicoplanina/químicaRESUMEN
Hydrogen sulfide (H2S), a gasotransmitter, plays a crucial role in vasorelaxation, anti-inflammatory processes and mitigating myocardial ischemia/reperfusion-induced injury by regulating various signaling processes. We designed a water soluble H2S-releasing ascorbic acid derivative, BM-164, to combine the beneficial cardiovascular and anti-inflammatory effects of H2S with the excellent water solubility and antioxidant properties of ascorbic acid. DPPH antioxidant assay revealed that the antioxidant activity of BM-164 in the presence of a myocardial tissue homogenate (extract) increased continuously over the 120 min test interval due to the continuous release of H2S from BM-164. The cytotoxicity of BM-164 was tested by MTT assay on H9c2 cells, which resulted in no cytotoxic effect at concentrations of 10 to 30 µM. The possible beneficial effects of BM-164 (30 µM) was examined in isolated 'Langendorff' rat hearts. The incidence of ventricular fibrillation (VF) was significantly reduced from its control value of 79 % to 31 % in the BM-164 treated group, and the infarct size was also diminished from the control value of 28 % to 14 % in the BM-164 treated group. However, coronary flow (CF) and heart rate (HR) values in the BM-164 treated group did not show significantly different levels in comparison with the drug-free control, although a non-significant recovery in both CF and HR was observed at each time point. We attempted to reveal the mechanism of action of BM-164, focusing on the processes of autophagy and apoptosis. The expression of key autophagic and apoptotic markers in isolated rat hearts were detected by Western blot analysis. All the examined autophagy-related proteins showed increased expression levels in the BM-164 treated group in comparison to the drug-free control and/or ascorbic acid treated groups, while the changes in the expression of apoptotic markers were not obvious. In conclusion, the designed water soluble H2S releasing ascorbic acid derivative, BM-164, showed better cardiac protection against ischemia/reperfusion-induced injury compared to the untreated and ascorbic acid treated hearts, respectively.
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Sulfuro de Hidrógeno , Daño por Reperfusión Miocárdica , Ratas , Animales , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Antioxidantes/farmacología , Ratas Wistar , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Isquemia , Antiinflamatorios/uso terapéutico , Agua , Reperfusión , Sulfuro de Hidrógeno/metabolismo , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/uso terapéuticoRESUMEN
We report on a new anti-influenza virus agent, SA-19, a lipophilic glycopeptide derivative consisting of aglycoristocetin coupled to a phenylbenzyl-substituted cyclobutenedione. In Madin-Darby canine kidney cells infected with influenza A/H1N1, A/H3N2, or B virus, SA-19 displayed a 50% antivirally effective concentration of 0.60 µM and a selectivity index (ratio of cytotoxic versus antiviral concentration) of 112. SA-19 was 11-fold more potent than unsubstituted aglycoristocetin and was active in human and nonhuman cell lines. Virus yield at 72 h p.i. was reduced by 3.6 logs at 0.8 µM SA-19. In contrast to amantadine and oseltamivir, SA-19 did not select for resistance upon prolonged virus exposure. SA-19 was shown to inhibit an early postbinding step in virus replication. The compound had no effect on hemagglutinin (HA)-mediated membrane fusion in an HA-polykaryon assay and did not inhibit the low-pH-induced refolding of the HA in a tryptic digestion assay. However, a marked inhibitory effect on the transduction exerted by retroviral pseudoparticles carrying an HA or vesicular stomatitis virus glycoprotein (VSV-G) fusion protein was noted, suggesting that SA-19 targets a cellular factor with a role in influenza virus and VSV entry. Using confocal microscopy with antinucleoprotein staining, SA-19 was proven to completely prevent the influenza virus nuclear entry. This virus arrest was characterized by the formation of cytoplasmic aggregates. SA-19 appeared to disturb the endocytic uptake and trap the influenza virus in vesicles distinct from early, late, or recycling endosomes. The aglycoristocetin derivative SA-19 represents a new class of potent and broad-acting influenza virus inhibitors with potential clinical relevance.
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Antivirales/farmacología , Citoplasma/virología , Glicopéptidos/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Animales , Antivirales/química , Línea Celular , Citoplasma/efectos de los fármacos , Perros , Glicopéptidos/química , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/fisiología , Virus de la Influenza A/fisiología , Virus de la Influenza B/fisiología , Gripe Humana/tratamiento farmacológico , Gripe Humana/virología , Estructura Molecular , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not only on the substitution pattern and electron-density of the double bond but also on the nature and substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2 : 3,4-di-O-isopropylidene-6-thio-α-d-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, providing a (3 â 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol-ene coupling reaction.
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Alquenos/química , Radicales Libres/química , Monosacáridos/química , Compuestos de Sulfhidrilo/química , Fenoles/química , EstereoisomerismoRESUMEN
Hydrogen sulfide (H2S) plays an important role in cardiac protection by regulating various redox signalings associated with myocardial ischemia/reperfusion (I/R) induced injury. The goal of the present investigations is the synthesis of a newly designed H2S-releasing ibuprofen derivative, BM-88, and its pharmacological characterization regarding the cardioprotective effects in isolated rat hearts. Cytotoxicity of BM-88 was also estimated in H9c2 cells. H2S-release was measured by an H2S sensor from the coronary perfusate. Increasing concentrations of BM-88 (1.0 to 20.0 µM) were tested in vitro studies. Preadministration of 10 µM BM-88 significantly reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from its drug-free control value of 92% to 12%. However, no clear dose dependent reduction in the incidence of reperfusion-induced VF was observed while different concentrations of BM-88 were used. It was also found that 10 µM BM-88 provided a substantial protection and significantly reduced the infarct size in the ischemic/reperfused myocardium. However, this cardiac protection was not reflected in any significant changes in coronary flow and heart rates. The results support the fact that H2S release plays an important role mitigating reperfusion-induced cardiac damage.
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Sulfuro de Hidrógeno , Daño por Reperfusión , Ratas , Animales , Sulfuro de Hidrógeno/farmacología , Ibuprofeno/farmacología , Ibuprofeno/uso terapéutico , Corazón , ReperfusiónRESUMEN
Drug-resistant Plasmodium falciparum (Pf) infections are a major burden on the population and the healthcare system. The establishment of Pf resistance to most existing antimalarial therapies has complicated the problem, and the emergence of resistance to artemisinin derivatives is even more concerning. It is increasingly difficult to cure malaria patients due to the limited availability of effective antimalarial drugs, resulting in an urgent need for more efficacious and affordable treatments to eradicate this disease. Herein, new nucleoside analogues including morpholino-nucleoside hybrids and thio-substituted nucleoside derivatives were prepared and evaluated for in vitro and in vivo antiparasitic activity that led a few hits especially nucleoside-thiopyranoside conjugates, which are highly effective against Pf3D7 and PfRKL-9 strains in submicromolar concentration. One adenosine derivative and four pyrimidine nucleoside analogues significantly reduced the parasite burden in mouse models infected with Plasmodium berghei ANKA. Importantly, no significant hemolysis and cytotoxicity towards human cell line (RAW) was observed for the hits, suggesting their safety profile. Preliminary research suggested that these thiosugar-nucleoside conjugates could be used to accelerate the antimalarial drug development pipeline and thus deserve further investigation.
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Antimaláricos , Malaria Falciparum , Malaria , Animales , Ratones , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Nucleósidos/farmacología , Nucleósidos/uso terapéutico , Azúcares/farmacología , Plasmodium falciparum , Malaria/tratamiento farmacológico , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Plasmodium bergheiRESUMEN
Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid that can be found in Cannabis sativa and possesses numerous pharmacological effects. Due to these promising effects, CBD can be used in a wide variety of diseases, for instance cardiovascular diseases. However, CBD, like tetrahydrocannabinol (THC), has low bioavailability, poor water solubility, and a variable pharmacokinetic profile, which hinders its therapeutic use. Chemical derivatization of CBD offers us potential ways to overcome these issues. We prepared three new CBD derivatives substituted on the aromatic ring by Mannich-type reactions, which have not been described so far for the modification of cannabinoids, and studied the protective effect they have on cardiomyocytes exposed to oxidative stress and hypoxia/reoxygenation (H/R) compared to the parent compound. An MTT assay was performed to determine the viability of rat cardiomyocytes treated with test compounds. Trypan blue exclusion and lactate dehydrogenase (LDH) release assays were carried out to study the effect of the new compounds in cells exposed to H2O2 or hypoxia/reoxygenation (H/R). Direct antioxidant activity was evaluated by a total antioxidant capacity (TAC) assay. To study antioxidant protein levels, HO-1, SOD, catalase, and Western blot analysis were carried out. pIC50 (the negative log of the IC50) values were as follows: CBD1: 4.113, CBD2: 3.995, CBD3: 4.190, and CBD: 4.671. The newly synthesized CBD derivatives prevented cell death induced by H/R, especially CBD2. CBD has the largest direct antioxidant activity. The levels of antioxidant proteins were increased differently after pretreatment with synthetic CBD derivatives and CBD. Taken together, our newly synthesized CBD derivatives are able to decrease cytotoxicity during oxidative stress and H/R. The compounds have similar or better effects than CBD on H9c2 cells.