RESUMO
The bioprospection of indigenous microorganism strains with biotechnological potential represents a prominent trend. Metschnikowia yeasts exhibit diverse capabilities, such as ethanol reduction in winemaking, biocontrol potential, and lipid production. In this work, local Metschnikowia strains were isolated from different fruits by their ability to produce pulcherrimic acid, a molecule that has been linked to biocontrol activity and that binds iron giving colored colonies. Five strains were selected, each from one of five distinct sources. All of them were identified as M. pulcherrima. All five were able inhibit other yeasts and one M. pulcherrima, called M7, inhibited the growth of Aspergillus nidulans. The selected strains accumulated lipid bodies in stationary phase. Certain non-conventional yeasts like Hanseniaspora vineae are very sensitive to biomass drying, but cell extracts from M. pulcherrima added to the growth media as a source of antioxidant lipids increased their tolerance to drying. All strains isolated showed good stress tolerance (particularly to heat) and have nutrient requirements similar to a commercial M. pulcherrima strain. In addition, the M7 strain had a good growth in sugarcane and beet molasses and behaved like Saccharomyces cerevisiae in a growth medium derived from agricultural waste, a persimmon hydrolysate. Therefore, the isolation of local strains of Metschnikowia able to grow in a variety of substrates is a good source of biocontrol agents.
Assuntos
Metschnikowia , Vinho , Saccharomyces cerevisiae/metabolismo , Metschnikowia/metabolismo , Vinho/análise , Frutas , LipídeosRESUMO
Cyclopropanation reactions between C60 and different malonates decorated with monosaccharides and steroids using the Bingel-Hirsch methodology have allowed the obtention of a new family of hybrid compounds in good yields. A complete set of instrumental techniques has allowed us to fully characterize the hybrid derivatives and to determine the chemical structure of monocycloadducts. Besides, the proposed structures were investigated by cyclic voltammetry, which evidenced the exclusive reductive pattern of fullerene Bingel-type monoadducts. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level of the synthesized conjugates predict the most stable conformation and determine the factors that control the hybrid molecules' geometry. Some parameters such as polarity, lipophilicity, polar surface area, hydrophilicity index, and solvent-accessible surface area were also estimated, predicting its potential permeability and capability as cell membrane penetrators. Additionally, a molecular docking simulation has been carried out using the main protease of SARS-CoV-2 (Mpro) as the receptor, thus paving the way to study the potential application of these hybrids in biomedicine.
RESUMO
3,4-Dihydro-2(1H)-pyridones (3,4-DHPo) and their derivatives are privileged structures, which has increased their relevance due to their biological activity in front of a broad range of targets, but especially for their importance as synthetic precursors of a variety of compounds with marked biological activity. Taking into account the large number of contributions published over the years regarding this kind of heterocycle, here, we presented a current view of 3,4-dihydro-2(1H)-pyridones (3,4-DHPo). The review includes general aspects such as those related to nomenclature, synthesis, and biological activity, but also highlights the importance of DHPos as building blocks of other relevant structures. Additional to the conventional multicomponent synthesis of the mentioned heterocycle, nonconventional procedures are revised, demonstrating the increasing efficiency and allowing reactions to be carried out in the absence of the solvent, becoming an important contribution to green chemistry. Biological activities of 3,4-DHPo, such as vasorelaxant, anti-HIV, antitumor, antibacterial, and antifungal, have demonstrated this heterocycle's potential in medicinal chemistry.
Assuntos
Antifúngicos , Piridonas , Antibacterianos , Antifúngicos/química , Química Farmacêutica , Piridonas/químicaRESUMO
The reaction of C60 with pregnen-20-carboxaldehyde, a biologically active synthetic steroid, by using a 1,3-dipolar cycloaddition reaction (Prato's protocol) results in the formation of pyrrolidine rings bearing a new stereogenic center on the C2 of the five-membered ring. The formation of the fullerene-steroid hybrids proceeds with preference for the Re face of the 1,3-dipole, with formation of a diastereomeric mixture in 73:15 ratio. The investigation of the chiroptical properties of these conjugates allowed determining the absolute configuration of the new fulleropyrrolidines. In addition, a thorough spectroscopical study permitted to determine the structure of the two mono-cycloadducts. The electrochemical properties of the new hybrids were also evaluated by cyclic voltammetry, both systems exhibit three quasi-reversible reduction waves which are cathodically shifted in regard to the parent C60. Theoretical calculations help supporting the experimental data. A conformational study combining semiempirical methods and density functional theory has predicted the most stable diastereomer. On the basis of this agreement, a possible reaction mechanism is presented. Additionally, a molecular docking simulation has been carried out using the HIV-1 protease as receptor, thus paving the way to study the possible application of these stereoisomers in biomedicine.
RESUMO
A study on the electrophile-induced rearrangement of two 15-hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15-diol acetonide being the main product obtained. The δ-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken.
RESUMO
The diastereoselective synthesis of cis and trans steroid-fulleropyrrolidines hybrids by reaction of N-metalated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C60 is described. The experimental findings reveal that the azomethine ylide stabilized by an allylic group cycloadds to [60]fullerene in an efficient manner and with a good diastereomeric excess. Furthermore, the new generated stereocenters are fully controlled by the catalytic systems used without being influenced by the chirality of the steroid. Interestingly, by this synthetic methodology the each one of the four possible stereoisomers have efficiently been obtained and characterized by CD spectra.
RESUMO
The retro-cycloaddition thermal reaction of isoxazolino[4,5:1,2][60]fullerenes to pristine fullerene seems to be guided by the electronic nature of the substituted nitrile oxide 1,3-dipole in the isoxazoline ring. Trapping experiments proved that the reaction mechanism occurs by thermal removal of the nitrile oxide 1,3-dipole in a process that is favored in the presence of a big excess of a highly efficient dipolarophile such as maleic anhydride. Theoretical gas phase calculations carried out at the B3LYP/6-31G(d) and M06-2X/6-31G(d) levels of theory underpin the experimental findings and predict that compound 1c, bearing the p-(CH3)2N-Ph substituent on the isoxazoline ring and with a remarkable experimental conversion efficiency in just 12 h, showed the lowest activation energy. Solvent calculations have predicted the same behavior in gas phase. Different approaches such as electrostatic natural population analysis and Houk's distortion/interaction model have been applied to understand how the electronic nature of these substituents affects the retro-cycloaddition reaction process. Analysis of the values of the condensed Fukui functions and dual descriptor shed light on the mechanism of the retro-cycloaddition reaction.
RESUMO
RATIONALE: We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-, pyrrolidino- and methanofullerene moieties. METHODS: The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. RESULTS: The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. CONCLUSIONS: The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions.
RESUMO
A wide range of new dipoles and catalysts have been used in 1,3-dipolar cycloadditions of N-metalated azomethine ylides onto C60 yielding a full stereodivergent synthesis of pyrrolidino[60]fullerenes with complete diastereoselectivities and very high enantioselectivities. The use of less-explored chiral α-iminoamides as starting 1,3-dipoles leads to an interesting double asymmetric induction resulting in a matching/mismatching effect depending upon the absolute configuration of the stereocenter in the starting α-iminoamide. An enantioselective process was also found in the retrocycloaddition reaction as revealed by mass spectrometry analysis on quasi-enantiomeric pyrrolidino[60]fullerenes. Theoretical DFT calculations are in very good agreement with the experimental data. On the basis of this agreement, a plausible reaction mechanism is proposed.
RESUMO
New [60]fullerene-steroid conjugates (4-6) have been synthesized by 1,3-dipolar cycloaddition and Bingel-Hirsch cyclopropanation reactions from suitably functionalized epiandrosterone and [60]fullerene. Since a new stereocenter is created in the formation of the Prato monoaduct, two different diastereomers were isolated by HPLC (4, 5) whose absolute configurations were assigned according to the highly reliable "sector rule" on fullerenes. A further reaction of the malonate-containing diastereomer 5 with a second C60 molecule has afforded dumbbell fullerene 6 in which the two fullerene units are covalently connected through an epiandrosterone moiety. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltametry, reveal three reversible reduction waves for hybrids 4 and 5, whereas these signals are split in dumbbell 6. Theoretical calculations at semiempirical (AM1) and single point B3LYP/6-31G(d) levels have predicted the most stable conformations for the hybrid compounds (4-6), showing the importance of the chlorine atom on the D ring of the steroid. Furthermore, TDDFT calculations have allowed assignments of the experimentally determined circular dichroism (CD) of the [60]fullerene-steroid hybrids based on the sign and position of the Cotton effects, despite the exceptionally large systems under study.
Assuntos
Fulerenos/química , Esteroides/química , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Modelos Teóricos , Conformação Molecular , EstereoisomerismoRESUMO
OBJECTIVES: The objective of this work was to establish the analgesia protocols for different types of urological surgery and to analyze the impact on pain during the first 24 h after surgery. METHODS: The study included 186 patients undergoing urological surgery between 2011 and 2013. Seven analgesia protocols were established and applied according to the surgical procedure. At 24 h post-surgery, i.e., the initiation of analgesic treatment, patients` pain was evaluated by visual analog scale/numeric scale (VAS/NS), and their degree of satisfaction and nausea were assessed. RESULTS: The study sample comprised 137 males (73.7%) and 49 females (26.3%), with a mean age of 58.5 ± 14.7 yrs. Analgesia protocol 1 was applied in 5.9% of patients, protocol 2 in 17.8%, protocol 3 in 8.6%, protocol 4 in 38.9%, protocol 5 in 13.5%, protocol 6 in 14.6%, and protocol 7 in 0.5%. At 24 h post-surgery, the VAS/NS score was = 3 in 82.3% of patients; hence, only 17.7% required rescue analgesia; 71% of patients were highly satisfied with the treatment provided and 22.6% were satisfied. 6.4% were not satisfied. CONCLUSION: Establishing analgesia protocols according to the type of surgery is a valid and useful measure to control postoperative pain during the first 24 h and to provide appropriate treatment standardization and follow-up.
Assuntos
Analgesia , Protocolos Clínicos , Medição da Dor , Dor Pós-Operatória/prevenção & controle , Satisfação do Paciente , Procedimentos Cirúrgicos Urológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios , Fatores de TempoRESUMO
Background and Purpose: Plasmodium falciparum and P. vivax are responsible for most malaria cases in humans in the African Region and the Americas; these parasites have developed resistance to classic antimalarial drugs. On the other hand, previous investigations of the alkyl-linked bis tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) derivatives compounds show satisfactory results against protozoan parasites such as Trypanosoma cruzi, Trypanosoma vaginalis, Trypanosoma brucei rhodesiense and Leishmania donovani. Therefore, it is possible to see some effect of bis-THTT derivatives on other protozoan parasites, such as Plasmodium. Experimental Approach: This study aimed to perform an in vivo biological evaluation of bis-THTT (JH1 to JH6) derivatives compounds as possible anti-malaria drugs in BALB/c mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL strains. In this work, we evaluated the compounds as potential antimalarial drugs in BALB/c mice infected with Plasmodium strains. Key Results: For each compound, we assess the percentages of parasitemia by smears from tail blood and the humoral response by indirect ELISA test using each compound as an antigen. We also evaluated the B lymphocyte response and the cytotoxicity of the bis-THTT derivatives compounds with MTT cell proliferation assays. Conclusions: Our results show that the bis-THTT derivatives JH2 and JH4 presented effective parasitemia control in mice infected with P. berghei; JH5 and JH6 compounds have similar infection control results as chloroquine in mice infected P. yoelii strain. The evaluation of bis-THTT derivatives compounds in a model of BALB/c mice infected with P. berghei and P. yoelii allowed us to conclude that some of them have an antimalarial effect; however, none of the tested compounds exceeded the efficiency of chloroquine.
RESUMO
The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.
Assuntos
Fulerenos/química , Esteroides/química , Ciclização , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , EstereoisomerismoRESUMO
Cysteine-based perfluoroaromatic (hexafluorobenzene (HFB) and decafluorobiphenyl (DFBP)) were synthesized and established as a chemoselective and available core to construct molecular systems ranging from small molecules to biomolecules with interesting properties. The DFBP was found more effective than HFB for the monoalkylation of decorated thiol molecules. As proof of concept of the potential application of perfluorinated derivatives as non-cleavable linkers, some antibody-perfluorinated conjugates were prepared via thiol through two different strategies, i)â using thiol from reduced cystamine coupling to carboxylic acids from mAb by amide bond, and ii)â using thiols from reduction of mAb disulfide bond. Conjugates cell binding analysis demonstrated that the bioconjugation does not affect the macromolecular entity. Besides, some molecular properties of synthesized compounds are evaluated through spectroscopic characterization (FTIR and 19 Fâ NMR chemical shifts) and theoretical calculations. The comparison of calculated and experimental 19 Fâ NMR shifts and IR wavenumbers give excellent correlations, asserting as powerful tools in structurally identifying HFB and DFBP derivatives. Moreover, molecular docking was also developed to predict cysteine-based perfluorated derivatives' affinity against topoisomerase Il and cyclooxygenase 2 (COX-2). The results suggested that mainly cysteine-based DFBP derivatives could be potential topoisomerase II α and COX-2 binders, becoming potential anticancer agents and candidates for anti-inflammatory treatment.
Assuntos
Antineoplásicos , Cisteína , Cisteína/química , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2/metabolismo , Antineoplásicos/química , Compostos de Sulfidrila/químicaRESUMO
Stereodivergent syntheses of cis/trans pyrrolidino[3,4:1,2]fullerenes and endo/exo pyrrolidines are reported with high enantioselectivity levels. Fullerenes are revealed as a useful benchmark to develop suitable catalysts to control the stereochemical outcome and to shed light on the mechanism involved in the related 1,3-dipolar cycloaddition.
Assuntos
Compostos Azo/química , Fulerenos/química , Pirrolidinas/síntese química , Catálise , Cobre , Reação de Cicloadição , EstereoisomerismoRESUMO
The 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione scaffold has found many applications in recent years. This review is aimed at highlighting the most important aspects of these compounds: synthesis, spectroscopic characterization and biological activities. How the chemical nature of N-substituents influences the overall activity and cytotoxicity profile will also be discussed.
Assuntos
Tiadiazinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Espectroscopia de Ressonância Magnética , Tiadiazinas/síntese química , Tiadiazinas/químicaRESUMO
Cancer is one of the diseases with the highest mortality rate. Treatments to mitigate cancer are usually so intense and invasive that they weaken the patient to cure as dangerous as the own disease. From some time ago until today, to reduce resistance generated by the constant administration of the drug and improve its pharmacokinetics, scientists have been developing drug delivery system (DDS) technology. DDS platforms aim to maximize the drugs' effectiveness by directing them to reach the affected area by the disease and, therefore, reduce the potential side effects. Erythrocytes, antibodies, and nanoparticles have been used as carriers. Eleven antibody-drug conjugates (ADCs) involving covalent linkage has been commercialized as a promising cancer treatment in the last years. This review describes the general features and applications of DDS focused on the covalent conjugation system that binds the antibody carrier to the cytotoxic drug.
RESUMO
A green approach for the synthesis of a set of ten 4-aryl substituted-5-alcoxy carbonyl-6-methyl-3,4-dihydro-2(1H)-pyridones using Meldrum's acid has been devised, the absence of solvent and the activation with infrared irradiation in addition to a multicomponent protocol are the main reaction conditions. The transformations proceeded with moderated yields (50-75%) with a reasonable reaction rate (3 h). It is worth noting that two novel molecules of the new class of the bis-3,4-dihydropyridones were also obtained. In addition, a comparison without the use of infrared irradiation was performed.
Assuntos
Raios Infravermelhos , Piridonas/química , Química Verde , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piridonas/síntese química , Solventes/químicaRESUMO
Here we describe the efficient synthesis of alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylates and 4-arylsubstituted-4,7-dihydro-furo[3,4-b]pyridine-2,5(1H,3H)-diones via microwave-accelerated reaction of alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylates with the appropriate reagents. This eco-friendly approach to these valuable dihydropyridine derivatives does not involve the harsh or highly contaminating conditions common in classical heating and offers a reduction or even elimination of solvent use and recovery, simplification of the work-up procedures, facility of scale up, and low energy consumption, in addition to moderate to higher yields.
Assuntos
Ácidos Carboxílicos/síntese química , Di-Hidropiridinas/síntese química , Química Verde/métodos , Compostos Heterocíclicos/síntese química , Micro-Ondas , Piridinas/síntese química , Ácidos Carboxílicos/química , Di-Hidropiridinas/química , Descoberta de Drogas , Compostos Heterocíclicos/química , Estrutura Molecular , Piridinas/químicaRESUMO
Invited for this month's cover are the collaborating groups of Dr. Margarita Suárez at Universidad de La Habana, Cuba, and Dr. Nazario Martín at Universidad Complutense de Madrid, Spain, together with groups at other institutions worldwide. The Front Cover shows a representation of the H2 @C60 hybrid molecule with a dehydroepiandrosterone moiety interacting with the active site of the SARS Cov-2. Read the full text of the article at 10.1002/cplu.202000770.