RESUMO
BACKGROUND: Faced with the need to develop new herbicides with modes of action different to those observed for existing agrochemicals, one of the most promising strategies employed by synthetic chemists involves the structural modification of molecules found in natural products. Molecules containing amides, imides, and epoxides as functional groups are prevalent in nature and find extensive application in synthesizing more intricate compounds due to their biological properties. In this context, this paper delineates the synthesis of N-phenylnorbornenesuccinimide derivatives, conducts biological assays, and carries out in silico investigation of the protein target associated with the most potent compound in plant organisms. The phytotoxic effects of the synthesized compounds (2-29) were evaluated on Allium cepa, Bidens pilosa, Cucumis sativus, Sorghum bicolor, and Solanum lycopersicum. RESULTS: Reaction of endo-bicyclo[2.2.1]hept-5-ene-3a,7a-dicarboxylic anhydride (1) with aromatic amines led to the N-phenylnorbornenesuccinic acids (2-11) with yields ranging from 75% to 90%. Cyclization of compounds (2-11) in the presence of acetic anhydride and sodium acetate afforded N-phenylnorbornenesuccinimides (12-20) with yields varying from 65% to 89%. Those imides were then subjected to epoxidation reaction to afford N-phenylepoxynorbornanesuccimides (21-29) with yields from 60% to 90%. All compounds inhibited the growth of seedlings of the plants evaluated. Substance 23 was the most active against the plants tested, inhibiting 100% the growth of all species in all concentrations. Cyclophilin was found to be the enzymatic target of compound 23. CONCLUSION: These findings suggest that derivatives of N-phenylnorbornenesuccinimide are promising compounds in the quest for more selective and stable agrochemicals. This perspective reinforces the significance of these derivatives as potential innovative herbicides and emphasizes the importance of further exploring their biological activity on weeds. © 2024 Society of Chemical Industry.
Assuntos
Herbicidas , Herbicidas/farmacologia , Herbicidas/química , Succinimidas/farmacologia , Succinimidas/química , Solanum lycopersicum/efeitos dos fármacos , Solanum lycopersicum/crescimento & desenvolvimento , Cebolas/efeitos dos fármacos , Sorghum/efeitos dos fármacos , Sorghum/crescimento & desenvolvimento , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/crescimento & desenvolvimentoRESUMO
Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu-DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation.
Assuntos
Dendrímeros/farmacologia , Lutécio/farmacologia , Melanoma Experimental/metabolismo , Metais/metabolismo , Nanoestruturas , Nylons/farmacologia , Radioisótopos/farmacologia , Neoplasias Cutâneas/metabolismo , Succinimidas/farmacologia , Animais , Dendrímeros/química , Íons/metabolismo , Lutécio/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Nylons/química , Radioisótopos/química , Succinimidas/químicaRESUMO
Eighteen (3R) and (3R,4R)-N-phenyl-, N-phenylalkyl and N-arylsuccinimides were prepared with high enantioselectivity by biotransformation of maleimides with A. fumigatus. This environmentally friendly, clean and economical procedure was performed by the whole-cell fungal bioconversion methodology. Their corresponding eighteen racemic succinimides were prepared instead by synthetic methods. Both, the racemic and the chiral succinimides were tested simultaneously by the microbroth dilution method of CLSI against a panel of human opportunistic pathogenic fungi of clinical importance. Chiral succinimides showed higher antifungal activity than the corresponding racemic ones and the differences in activity were established by statistical methods. The bottlenecks for developing chiral drugs are how to obtain them through a low-cost procedure and with high enantiomeric excess. Results presented here accomplish both these objectives, opening an avenue for the development of asymmetric succinimides as new antifungal drugs for pharmaceutical use.
Assuntos
Antifúngicos , Aspergillus fumigatus/metabolismo , Succinimidas , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Biotransformação , Humanos , Metilação , Micoses/tratamento farmacológico , Micoses/microbiologia , Estereoisomerismo , Succinimidas/química , Succinimidas/isolamento & purificação , Succinimidas/metabolismo , Succinimidas/farmacologiaRESUMO
Stress is closely related with levels of corticosteroid and corticotrophin releasing factor, which at the same time can modify 5-HT(1A) receptors and brain serotonin levels. Consequently, the absence of corticosteroids in rats induced by an adrenalectomy could be useful to understand the functionality of the brain serotonergic system after a stressing event. The influence of 15 min of forced swimming was explored on sham and adrenalectomized rats by measuring the 5-HT(1A) receptor density in raphe and hippocampus. Other previously stressed groups (sham and adrenalectomized) were tested in two anxiety models with the 5-HT(1A) agonist 8-OH-DPAT, the postsynaptic antagonist MM-77, and with a combination of these two compounds. It was found that the removal of adrenals in rats that were not previously stressed induced an increase in the postsynaptic 5-HT(1A) receptor density. On the other hand, an adrenalectomy in rats that were previously stressed induced a reduction in the same receptor density. Adrenal gland removal induced an anxiolytic-like effect. However, after the injection of 8-OH-DPAT, adrenalectomized rats showed anxiogenic-like actions, an effect which was reversed by MM-77. Data show that changes in 5-HT(1A) receptors density caused by a stressful session can have behavioral consequences, thus emphasizing the need to reconsider the clinical use of 5-HT(1A) ligands after traumatic events.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Adrenalectomia , Ansiolíticos , Hipocampo/metabolismo , Receptor 5-HT1A de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Ansiedade/psicologia , Autorradiografia , Hipocampo/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/farmacologia , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT1 de Serotonina , Estresse Psicológico/psicologia , Succinimidas/farmacologia , Natação/psicologiaRESUMO
The synthesis and antifungal properties of a series of new N-aryl alpha,beta-substituted succinimides against a panel of dermatophytes of clinical relevance are reported. Among those compounds possessing a N-phenyl substituent, 7-thia-2-azabicyclo[2,2,1]hept-2-en-3-amine[5,6-c]succinimide was the better inhibitor of Trichophyton rubrum, the major ethiological agent of all infections produced by dermatophytes. In contrast, succinimides containing a N-(p-sulfonylphenyl) substituent, only inhibited Epidermophyton floccosum, all active compounds possessing an oxabicyclo group in positions alpha,beta of the imide. Substituents on the oxabicyclo group were important for the activity. Regarding the mechanism of action, N-(p-N'-4-methoxyphenylsulfamoylphenyl)-8-oxabicyclo[2,2,1]hept-4-en-3- methyl[5,6-c]succinimide produced a mottled inhibition halo in the Neurospora crassa assay, showing that it would act by inhibiting the synthesis or assembly of the fungal cell wall.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Succinimidas/síntese química , Succinimidas/farmacologia , Arthrodermataceae/ultraestrutura , Testes de Sensibilidade Microbiana , Neurospora crassa/efeitos dos fármacos , Neurospora crassa/ultraestruturaRESUMO
Glycosylphosphatidylinositol (GPI)-anchored proteins are clustered mainly in sphingolipid-cholesterol microdomains of the plasma membrane. The distribution of GPI-anchored fusion yellow fluorescent protein (GPI-YFP) in the plasma membrane of Chinese hamster ovary (CHO)-K1 cells with different glycolipid compositions was investigated. Cells depleted of glycosphingolipids by inhibiting glucosylceramide synthase activity or cell lines expressing different gangliosides caused by stable transfection of appropriate ganglioside glycosyltransferases or exposed to exogenous GM1 were transfected with GPI-YFP cDNA. The distribution of GPI-YFP fusion protein expressed at the plasma membrane was studied using the membrane-impermeable cross-linking agent bis(sulfosuccinimidyl)suberate. Results indicate that GPI-YFP forms clusters at the surface of cells expressing GM3, or cells depleted of glycolipids, or transfected cells expressing mainly GD3 and GT3, or GM1 and GD1a, or mostly GM2, or highly expressing GM1. However, no significant changes in membrane microdomains of GPI-YFP were detected in the different glycolipid environments provided by the membranes of the cell lines under study. On the other hand, wild type CHO-K1 cells exposed to 100 microm GM1 before cross-linking with bis(sulfosuccinimidyl)suberate showed a dramatic reduction in the amount of GPI-YFP clusters. These findings clearly indicate that manipulating the glycolipid content of the cellular membrane, just by changing the ganglioside biosynthetic activity of the cell, did not significantly affect the association of GPI-YFP on the cell surface of CHO-K1 cells. The effect of exogenous GM1 gangliosides on GPI-YFP plasma membrane distribution might be a consequence of the ganglioside level reached in plasma membrane and/or the effect of particular ganglioside species (micelles) that lead to membrane architecture and/or dynamic modifications.
Assuntos
Membrana Celular , Gangliosídeo G(M1)/farmacologia , Glicosilfosfatidilinositóis/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Células CHO , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Reagentes de Ligações Cruzadas/farmacologia , Meios de Cultura Livres de Soro , Gangliosídeo G(M1)/metabolismo , Glucosiltransferases/metabolismo , Glicolipídeos/metabolismo , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Succinimidas/farmacologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismoRESUMO
The antibacterial activity of several phyllanthimide analogs were investigated by the Minimum Inhibitory Concentration Method (MIC) against E. coli and S. aureus. It was found that maleimides were approximately 30 times more active than succinimides indicating that the cyclic imido double bond is an important factor related to the activity. Electron-donor and electron-withdrawing substituents in the aromatic ring of N-phenylmaleimides decrease the activity of these compounds indicating the possibility of steric effects. The distance between the aromatic and the imido rings when separated by methylene groups does not affect the antibacterial activity.
Assuntos
Alcaloides/farmacologia , Bactérias/efeitos dos fármacos , Maleimidas/farmacologia , Piperidonas , Succinimidas/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
In this study we describe a simple and rapid method that uses sulfo-N-hydroxy-succinimidobiotin (sulfo-NHS-biotin) to label Trypanosoma cruzi surface proteins stably without significant loss of biological function. Efficient labelling can be obtained with as little as a 5 minute incubation of parasites in an appropriate concentration of sulfo-NHS-biotin at 4 degrees C. After labelling under these conditions, biotinylated parasites exhibited levels of motility, viability, and in vivo infectivity comparable to those seen with unlabelled control parasites. Moreover, the biological activity of T-DAF, a complement regulatory protein found on the parasite surface, was unaffected when biotinylated under these conditions. Biotinylated surface proteins can be easily detected in a variety of non-radioactive assays employing conjugated streptavidin as a developer. Compared to alternative techniques of surface labelling described in the literature, this method offers better preservation of biological function as well as greater ease of use and safety.