RESUMEN

Cascade reactions are important synthetic tools for the synthesis of heterocyclic molecules, particularly those catalyzed by palladium. Herein, we report a palladium-catalyzed aminocarbonylative cyclization of new 1-alkynyl-2-iodo-d-glucals, which undergo a tandem carbonylative cyclization in the presence of various amine nucleophiles. A broad range of aromatic and aliphatic amines were applied as coupling partners, resulting in the selective and high-yield synthesis of glycosides fused to pyridinones. A plausible mechanism is proposed, proceeding via a tandem palladium aminocarbonylation followed by a palladium-catalyzed endo-dig cyclization.

RESUMEN

In this study, we present the development of two catalytic processes: a Pd-PEPPSI-catalyzed aminocarbonylation and a Pd(OAc)2-Xantphos-catalyzed alkoxycarbonylation of d-glycals, utilizing carbonylative cross-coupling reactions. We explored successfully various types of aromatic amines, as well as alkyl amines and amino acids, to synthesize new d-glycal amides. However, we observed limitations in the reactivity of alkyl and heteroaromatic amines. The processes enabled the synthesis of 20 novel C1-branched glycoamides and 7 new d-gluco esters.

RESUMEN

Glycal amides were prepared for the first time by reacting 2-iodo-D-glycals with L-amino acid esters via a Pd-catalyzed carbonylative cross-coupling reaction, by using Mo(CO)6 as the carbon monoxide source. Glycal amides were synthesized in moderate to good yields under our optimized conditions. In addition, the acetyl groups of the glucal amides could be readily removed to obtain the corresponding trihydroxy derivatives in good yields.

RESUMEN

Herein we report a novel Mo-catalyzed carbonylative Sonogashira cross-coupling between 2-iodoglycals and terminal alkynes. The reaction displays major improvements compared to a related Pd-catalyzed procedure previously published by our group, such as utilizing unprotected sugar derivatives as starting materials and tolerance to substrates bearing chelating groups. In this work we also demonstrate the utility of the glyco-alkynone products as platform for further functionalization by synthesizing glyco-flavones via Au-catalyzed 6-endo-dig cyclization.

RESUMEN

The sickle cell disease (SCD) has a genetic cause, characterized by a replacement of glutamic acid to valine in the ß-chain of hemoglobin. The disease has no effective treatment so far, and patients suffer a range from acute to chronic complications that include chronic hemolytic anemia, vaso-occlusive ischemia, pain, acute thoracic syndrome, cerebrovascular accident, nephropathy, osteonecrosis and reduced lifetime. The oxidation in certain regions of the hemoglobin favors the reactive oxygen species (ROS) formation, which is the cause of many clinical manifestations. Antioxidants have been studied to reduce the hemoglobin ROS levels, and in this sense, we have searched for new antioxidants glucal-based triazoles compounds with anti-sickling activity. Thirty analogues were synthetized and tested in in vitro antioxidant assays. Two of them were selected based in their effects and concentration-response activity and conducted to in cell assays. Both molecules did not cause any hemolysis and could reduce the red blood cell damage caused by hydrogen peroxide, in a model of oxidative stress induction that mimics the SCD. Moreover, one molecule (termed 11m), besides reducing the hemolysis, was able to prevent the cell damage caused by the hydrogen peroxide. Later on, by in silico pharmacokinetics analysis, we could see that 11m has appropriated proprieties for druggability and the probable mechanism of action is the binding to Peroxiredoxin-5, an antioxidant enzyme that reduces the hydrogen peroxide levels, verified after molecular docking assays. Thus, starting from 30 glucal-based triazoles molecules in a structure-activity relationship, we could select one with antioxidant proprieties that could act on RBC to reduce the oxidative stress, being useful for the treatment of SCD.

Asunto(s)

Anemia de Células Falciformes/tratamiento farmacológico , Antioxidantes/farmacología , Gluconato de Calcio/química , Eritrocitos/efectos de los fármacos , Triazoles/farmacología , Antioxidantes/química , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-Actividad , Triazoles/química

RESUMEN

Because of the increased resistance to currently available antifungals, fungal infections represent a significant challenge to human health. Herein, we report the synthesis of 2-aryloxazoline derivatives from the reaction between l-threonine and derivatives of salicylic or naphthoic acid. In total, 26 compounds were obtained and tested against species of Candida, Cryptococcus, and Aspergillus. We found that all of the compounds inhibited the growth of Candida species at low concentrations (<0.25 µg/mL) and exhibited reduced hemolytic and cytotoxic activities. Additionally, compounds 4i and 9i were especially effective against antifungal-resistant isolates and the emerging fungus Candida auris. However, the compounds were less active on Cryptococcus and Aspergillus. Because of the improved in vitro antifungal efficacy and attenuated cytotoxicity, these two 2-aryloxazolines obtained from salicylic and naphthoic acid derivatives, respectively, may be considered lead molecules for the development of novel antifungal drugs.

RESUMEN

The synthesis of 1-benzyl-2-((2-Aminoethyl) amino)-5-oxopyrrolidine-3,4-diyl diacetate (boad), an oxopyrrolidine type ligand; designed to coordinate lanthanides (Eu3+ and Tb3+) to get luminescent material. The target complexes showed good photoluminescence properties, which indicate that this type of compound can be used as sensitizers having luminescence for the green (Tb3+) and red (Eu3+) emission. The obtained results revealed that sensitizer efficiency can be improved by adding ligands like acac (Eu(acac)3, which has also enhanced the luminescence quantum output and period for Eu3+ ions. The ground state geometries were developed by using density functional theory at B3LYP/6-31G** level. The charge transfer analysis and electronic properties were performed. The Europium and Terbium complexes formation with boad ligand was explored based on molecular electrostatic potential, MDC-q charges, and frontier molecular orbitals (FMOs) analysis.

RESUMEN

Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.

Asunto(s)

Antimaláricos/farmacología , Antineoplásicos/farmacología , Leishmania mexicana/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolinas/síntesis química , Quinolinas/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

A mild stereo- and regioselective Cu-catalyzed hydroboration method for the synthesis of (Z)-seleno-alkenyl boronates and (Z)-thio-alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N-heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give a -chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen-containing molecules.

RESUMEN

The carbonylative cross-coupling reactions of 2-iodoglycals with thiols and selenols in the presence of molybdenum hexacarbonyl as a solid source of carbon monoxide is described. This methodology permitted the synthesis of 29 C2-glycosides bearing thioester and selenoester functionalities in moderate to excellent yields and high functional group tolerance. Moreover, this communication describes the first catalytic carbonylative coupling reaction of selenols with a carbon electrophile.

RESUMEN

AIM: More than 40% of the world's population, across 105 countries, live in malaria endemic areas. It is estimated that about 500 million cases of malaria and half a million deaths occur per year. RESULTS: Herein, we demonstrate the biological activity of indole-3-glyoxyl tyrosine against Plasmodium falciparum, which is the causal agent of the most virulent form of malaria in humans. We developed an efficient synthesis of indole-3-glyoxyl tyrosine derivatives, which were then used as key intermediates in the synthesis of functionalized indole-3-glyoxyl biphenyl tyrosines. CONCLUSION: In biological testing, the compounds exhibited a parasite growth inhibition of over 85%. A cell viability assay showed low cytotoxicity against human cells, with no significant changes in cell viability, making these compounds potential antimalarials.

Asunto(s)

Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Tirosina/análogos & derivados , Tirosina/farmacología , Antimaláricos/síntesis química , Células Hep G2 , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Modelos Moleculares , Pruebas de Sensibilidad Parasitaria , Tirosina/síntesis química

RESUMEN

Chemotherapeutic agents used in cancer treatment associated to nanoparticles (LDE) that mimic the composition of low-density lipoprotein and buffer their toxicity can have strong anti-atherosclerosis action, as we showed in cholesterol-fed rabbits. Here, a novel preparation of docetaxel (DTX) carried in LDE was evaluated. Eighteen rabbits were fed 1% cholesterol during 8 weeks. After the first 4 weeks, 9 animals were treated for 4 weeks with intravenous LDE-DTX (1 mg/kg/week) and 9 with LDE only (controls) once a week for 4 weeks. Animals were then euthanized and the aortas were analyzed for morphometry, immunohistochemistry and Western blot. LDE-DTX treated group showed 80% reduction of atheroma area compared to controls. LDE-DTX treatment reduced in 60% the protein expression of macrophage marker CD68 and of MCP-1 in 80%. LDE-DTX pronouncedly lowered expression of pro-inflammatory markers NF-κB, TNF-α, IL-1ß, IL-6 and von Willebrand factor and elicited 40% reduction in cell proliferation marker PCNA. The presence of smooth muscle cells in the intima was 85% smaller than in controls. Pro-apoptotic caspase 3, caspase 9, Bax, and anti-apoptotic Bcl-2 all were reduced by LDE-DTX. Protein expression of MMP-2 and MMP-9, TGF-ß, and collagen 1 and 3 were also markedly lowered by the LDE-DTX treatment. Animals showed no hematological, hepatic or renal toxicity consequent to LDE-DTX treatment. In conclusion, LDE-DTX showed a wide array of strong effects on pro-inflammatory and proliferation-promoting factors that drive the lesion development. These findings and the lack of observable toxicity indicate that LDE-DTX can be a candidate for future clinical trials.

Asunto(s)

Antiinflamatorios/farmacología , Aorta/efectos de los fármacos , Aortitis/prevención & control , Aterosclerosis/prevención & control , Proliferación Celular/efectos de los fármacos , Docetaxel/farmacología , Lípidos/química , Nanopartículas , Placa Aterosclerótica , Animales , Antiinflamatorios/química , Aorta/metabolismo , Aorta/patología , Aortitis/metabolismo , Aortitis/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Muerte Celular/efectos de los fármacos , Colesterol en la Dieta , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Docetaxel/química , Composición de Medicamentos , Colágenos Fibrilares/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Antígeno Nuclear de Célula en Proliferación/metabolismo , Factor de von Willebrand/metabolismo

RESUMEN

The steroselective oxa-Michael addition of the phenol moiety present in tyrosine and 3-iodotyrosine to different propargyl aldehydes delivered products with predominantly Z stereochemistry, as evidenced by X-ray crystallography analysis. When ethyl ropiolate was used as the propargyl ester source, the products were achieved with exclusively E stereochemistry with yields ranging from 17% to 91%. The oxa-Michael addition compounds served as substrates in the synthesis of 5- and 6-membered heterocyclic compounds. The atmosphere applied to the reaction medium directly influenced the formation of the products. When an inert atmosphere of nitrogen was applied, a 2-aryl-3-formyl-5-alanylbenzofuran core was selectively obtained via a Heck intramolecular reaction, while the reactions carried out under a carbon monoxide atmosphere led exclusively to 6-alanyl-2-arylflavone derivatives via reductive intramolecular acylation.

RESUMEN

C-Glycosides are valuable organic compounds in the field of medicinal chemistry due to their ubiquity inside living systems and pronounced biological activity. Herein, we describe an approach to alkyl-ketones bearing glycal units via the Pd-catalyzed carbonylative coupling of 2-iodoglycals and alkyl and aryl halides. Examples bearing a variety of functional groups are presented as well as a mechanistic proposal for this transformation.

RESUMEN

The iron(III)-promoted synthesis of densely-substituted 4H-chalcogenchromene from organochalcogen propargylamines in the presence of diaryl dichalcogenides is reported. Subsequent C2-functionalization with electrophiles and potassium trifluoroborate salts via Suzuki-Miyaura coupling reaction are also presented. A plausible mechanism based on HRMS experiments is proposed and discussed.

RESUMEN

A carbonylative Sonogashira coupling approach to the synthesis of glyco-alkynones is described. Eighteen examples were obtained in moderate do nearly quantitative yields under mild conditions employing Mo(CO)6 as a safe carbon monoxide source. Functionalization of the alkynyl moiety via cycloaddition with organic azides provided six examples of glyco-triazoles.

RESUMEN

The synthesis of amidoglucals and glucal esters in good to high yields using 2-iodo-3,4,6-tri-O-acetyl-d-glucal as a substrate, Mo(CO)(6) as a carbon monoxide source and PdCl2 as a catalyst is reported. This procedure shows advantages when compared to other published methodologies, as it is carried out in one pot relying on short reaction times at mild temperatures, under ligand-free conditions and with only one equivalent of Mo(CO)(6).

RESUMEN

BACKGROUND: Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. OBJECTIVE: The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. METHOD: Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. RESULTS: Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. CONCLUSION: All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells.

Asunto(s)

Antineoplásicos/farmacología , Dipéptidos/síntesis química , Dipéptidos/farmacología , Biblioteca de Péptidos , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Estructura Molecular

RESUMEN

A regioselective ytterbium-catalyzed annulation reaction between ethylglyoxalate, anilines and silyl-alkynes bearing selenyl- and telluryl-moieties for the formation of poly-substituted quinolones is described. A series of examples formed under mild conditions are presented, including a scaled-up reaction and a study on catalyst recyclability.

RESUMEN

BACKGROUND:Structural component of proteins and peptides, amino acids have been used as building blocks in the synthesis of more complex molecules with antitumor activity against several types of cancer. OBJECTIVE:The search for new anticancer compounds is ongoing, especially for cancers that are very aggressive and have poor prognoses, such as leukemia. METHOD:Here, we report a method to synthesize Tyr-Tyr dipeptides via sonochemistry reactions followed by functionalization of these Tyr-Tyr dipeptides with Suzuki-Miyaura and Sonogashira crosscoupling reactions in good yields. Twelve different Tyr-Tyr dipeptides were investigated against three cell lines: HaCaT; Jurkat-E6; and A2058. RESULTS:Some of the Tyr-Tyr dipeptides showed activity against Jurkat-E6 leukaemia cells at low concentration, decreasing their viability, but not against non-tumor HaCaT cells, suggesting a cytotoxicity specific to tumor cells. CONCLUSION:All dipeptides were able to decrease the viability of Jurkat cell line, however the A2058 cell line did not respond well to treatment with the peptides. Some of the modified Tyr-Tyr dipeptides presented selective activity on leukemic tumor cells.