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1.
Phytochemistry ; 194: 113017, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34798410

RESUMEN

One undescribed indole alkaloid together with twenty-two known compounds have been isolated from aerial parts of Vinca minor L. (Apocynaceae). The chemical structures of the isolated alkaloids were determined by a combination of MS, HRMS, 1D, and 2D NMR techniques, and by comparison with literature data. The NMR data of several alkaloids have been revised, corrected, and missing data have been supplemented. Alkaloids isolated in sufficient quantity were screened for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7) and butyrylcholinesterase (BuChE; E.C. 3.1.1.8) inhibitory activity. Selected compounds were also evaluated for prolyl oligopeptidase (POP; E.C. 3.4.21.26), and glycogen synthase 3ß-kinase (GSK-3ß; E.C. 2.7.11.26) inhibition potential. Significant hBuChE inhibition activity has been shown by (-)-2-ethyl-3[2-(3-ethylpiperidinyl)-ethyl]-1H-indole with an IC50 value of 0.65 ± 0.16 µM. This compound was further studied by enzyme kinetics, along with in silico techniques, to reveal the mode of inhibition. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion.


Asunto(s)
Enfermedad de Alzheimer , Alcaloides Indólicos/farmacología , Monoterpenos/farmacología , Vinca , Acetilcolinesterasa , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa , Glucógeno Sintasa Quinasa 3 beta , Fitoquímicos/farmacología , Componentes Aéreos de las Plantas/química , Vinca/química
2.
Molecules ; 26(19)2021 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-34641567

RESUMEN

The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.


Asunto(s)
Alcaloides de Amaryllidaceae/síntesis química , Antibacterianos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Alcaloides de Amaryllidaceae/efectos adversos , Alcaloides de Amaryllidaceae/farmacología , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana
3.
Bioorg Med Chem Lett ; 51: 128374, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34555506

RESUMEN

Alzheimers disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.


Asunto(s)
Alcaloides/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Isoquinolinas/farmacología , Simulación del Acoplamiento Molecular , Acetilcolinesterasa/metabolismo , Alcaloides/síntesis química , Alcaloides/química , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-Actividad
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-34361074

RESUMEN

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1-20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.


Asunto(s)
Acetilcolinesterasa/química , Alcaloides de Amaryllidaceae/química , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Simulación del Acoplamiento Molecular , Neuroblastoma/tratamiento farmacológico , Tiramina/análogos & derivados , Proliferación Celular , Inhibidores de la Colinesterasa/química , Simulación por Computador , Humanos , Neuroblastoma/patología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Tiramina/química
5.
J Org Chem ; 86(12): 8078-8088, 2021 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-34032448

RESUMEN

A striking dependence on the method of workup has been found for annulation of benzonitriles ArC≡N to N-methyl 2-toluamide (1), facilitated by n-BuLi (2 equiv): quenching the reaction by a slow addition of water produced the expected 1-isoquinolones 2; by contrast, slow pouring of the reaction mixture into water afforded the cyclic aminals 5 (retaining the NMe group of the original toluamide). The mechanism of the two processes is discussed in terms of the actual H+ concentration in the workup. Both 2 and 5 were then converted into the corresponding 1-chloroisoquinolines 3, coupling of which, mediated by (Ph3P)2NiCl2/Zn, afforded bis-isoquinolines 4.

6.
Molecules ; 26(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652925

RESUMEN

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.


Asunto(s)
Alcaloides/química , Alcaloides de Amaryllidaceae/química , Inhibidores de la Colinesterasa/química , Colinesterasas/ultraestructura , Alcaloides/farmacología , Enfermedad de Alzheimer , Alcaloides de Amaryllidaceae/farmacología , Butirilcolinesterasa/química , Butirilcolinesterasa/ultraestructura , Dominio Catalítico/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Colinesterasas/química , Dicroismo Circular , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
7.
Bioorg Chem ; 107: 104567, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33387730

RESUMEN

Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.


Asunto(s)
Alcaloides/química , Amaryllidaceae/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Alcaloides/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amaryllidaceae/metabolismo , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Conformación Molecular , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad
8.
Biomolecules ; 10(5)2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32455879

RESUMEN

Thirteen known (1-12 and 16) and three previously undescribed Amaryllidaceae alkaloids of belladine structural type, named carltonine A-C (13-15), were isolated from bulbs of Narcissus pseudonarcissus cv. Carlton (Amaryllidaceae) by standard chromatographic methods. Compounds isolated in sufficient amounts, and not tested previously, were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8) and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human BuChE (hBUChE) inhibitory activity was demonstrated by newly described alkaloids carltonine A (13) and carltonine B (14) with IC50 values of 913 ± 20 nM and 31 ± 1 nM, respectively. Both compounds displayed a selective inhibition pattern for hBuChE with an outstanding selectivity profile over AChE inhibition, higher than 100. The in vitro data were further supported by in silico studies of the active alkaloids 13 and 14 in the active site of hBuChE.


Asunto(s)
Alcaloides/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Narcissus/química , Alcaloides/química , Sitios de Unión , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica
9.
Bioorg Chem ; 100: 103928, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32450384

RESUMEN

A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.


Asunto(s)
Alcaloides de Amaryllidaceae/química , Amaryllidaceae/química , Ésteres/química , Fenantridinas/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/uso terapéutico , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Cinética , Simulación del Acoplamiento Molecular , Fenantridinas/metabolismo , Fenantridinas/uso terapéutico , Relación Estructura-Actividad
10.
J Nat Prod ; 83(5): 1359-1367, 2020 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-32309949

RESUMEN

A total of 20 derivatives (1-20) of the crinane-type alkaloid ambelline were synthesized. These semisynthetic derivatives were assessed for their potency to inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). To predict central nervous system (CNS) availability, logBB was calculated, and the data correlated well with those obtained from the parallel artificial membrane permeability assay (PAMPA). All compounds should be able to permeate the blood-brain barrier (BBB) according to the obtained results. A total of 7 aromatic derivatives (5, 6, 7, 9, 10, 12, and 16) with different substitution patterns showed inhibitory potency against human serum BuChE (IC50 < 5 µM), highlighting the three top-ranked compounds as follows: 11-O-(1-naphthoyl)ambelline (16), 11-O-(2-methylbenzoyl)ambelline (6), and 11-O-(2-methoxybenzoyl)ambelline (9) with IC50 values of 0.10 ± 0.01, 0.28 ± 0.02, and 0.43 ± 0.04 µM, respectively. Notably, derivatives 6, 7, 9, and 16 displayed selective human BuChE (hBuChE) inhibition profiles with a selectivity index > 100. The in vitro results were supported by computational studies predicting plausible binding modes of the compounds in the active sites of hBuChE.


Asunto(s)
Alcaloides de Amaryllidaceae/síntesis química , Alcaloides de Amaryllidaceae/farmacología , Amaryllidaceae/química , Butirilcolinesterasa/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Alcaloides de Amaryllidaceae/farmacocinética , Barrera Hematoencefálica , Inhibidores de la Colinesterasa/farmacocinética , Ésteres , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Especificidad por Sustrato
11.
Plants (Basel) ; 9(2)2020 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-31978967

RESUMEN

In this detailed phytochemical study of Narcissus cv. Professor Einstein, we isolated 23 previously known Amaryllidaceae alkaloids (1-23) of several structural types and one previously undescribed alkaloid, 7-oxonorpluviine. The chemical structures were identified by various spectroscopic methods (GC-MS, LC-MS, 1D, and 2D NMR spectroscopy) and were compared with literature data. Alkaloids which had not previously been isolated and studied for cytotoxicity before and which were obtained in sufficient amounts were assayed for their cytotoxic activity on a panel of human cancer cell lines of different histotype. Above that, MRC-5 human fibroblasts were used as a control noncancerous cell line to determine the general toxicity of the tested compounds. The cytotoxicity of the tested alkaloids was evaluated using the WST-1 metabolic activity assay. The growth of all studied cancer cell lines was inhibited by pancracine (montanine-type alkaloid), with IC50 values which were in the range of 2.20 to 5.15 µM.

12.
Phytochemistry ; 165: 112055, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31261031

RESUMEN

Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3ß (GSK-3ß) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Alcaloides de Amaryllidaceae/farmacología , Inhibidores de la Colinesterasa/farmacología , Narcissus/química , Fármacos Neuroprotectores/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/aislamiento & purificación , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Estructura Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Prolil Oligopeptidasas , Serina Endopeptidasas/metabolismo , Relación Estructura-Actividad
13.
Molecules ; 24(7)2019 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-30987121

RESUMEN

Twelve derivatives 1a-1m of the ß-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3ß (GSK-3ß) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3ß inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/metabolismo , Amaryllidaceae/química , Amaryllidaceae/metabolismo , Fenantridinas/química , Fenantridinas/metabolismo , Barrera Hematoencefálica/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Molecular , Permeabilidad , Relación Estructura-Actividad
14.
Chemistry ; 25(34): 8053-8060, 2019 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-30897237

RESUMEN

Pyran-2-ones 3 undergo a novel Pd0 -catalyzed 1,3-rearrangement to afford isomers 6. The reaction proceeds via an η2 -Pd complex, the pyramidalization of which (confirmed by quantum chemistry calculations) offers a favorable antiperiplanar alignment of the Pd-C and allylic C-O bonds (C), thus allowing the formation of an η3 -Pd intermediate. Subsequent rotation and rate-limiting recombination with the carboxylate arm then gives isomeric pyran-2-ones 6. The calculated free energies reproduce the observed kinetics semi-quantitatively.

15.
J Nat Prod ; 82(2): 239-248, 2019 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-30701972

RESUMEN

Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1-2, 5-7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3ß inhibitory activities. Selected compounds were studied for their ability to permeate through the blood-brain barrier. Significant human BuChE ( hBuChE) inhibitory activity was demonstrated by 6 (IC50 = 0.82 ± 0.10 µM). The in vitro data were further supported by computational analysis that showed the accommodation of 6 in the active site of hBuChE.


Asunto(s)
Acetilcolinesterasa/metabolismo , Alcaloides/aislamiento & purificación , Enfermedad de Alzheimer/tratamiento farmacológico , Berberis/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Isoquinolinas/aislamiento & purificación , Alcaloides/química , Alcaloides/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Espectroscopía de Resonancia Magnética , Exudados de Plantas/análisis
16.
Sci Rep ; 8(1): 4829, 2018 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-29555944

RESUMEN

Scoulerine is an isoquinoline alkaloid, which indicated promising suppression of cancer cells growth. However, the mode of action (MOA) remained unclear. Cytotoxic and antiproliferative properties were determined in this study. Scoulerine reduces the mitochondrial dehydrogenases activity of the evaluated leukemic cells with IC50 values ranging from 2.7 to 6.5 µM. The xCELLigence system revealed that scoulerine exerted potent antiproliferative activity in lung, ovarian and breast carcinoma cell lines. Jurkat and MOLT-4 leukemic cells treated with scoulerine were decreased in proliferation and viability. Scoulerine acted to inhibit proliferation through inducing G2 or M-phase cell cycle arrest, which correlates well with the observed breakdown of the microtubule network, increased Chk1 Ser345, Chk2 Thr68 and mitotic H3 Ser10 phosphorylation. Scoulerine was able to activate apoptosis, as determined by p53 upregulation, increase caspase activity, Annexin V and TUNEL labeling. Results highlight the potent antiproliferative and proapoptotic function of scoulerine in cancer cells caused by its ability to interfere with the microtubule elements of the cytoskeleton, checkpoint kinase signaling and p53 proteins. This is the first study of the mechanism of scoulerine at cellular and molecular level. Scoulerine is a potent antimitotic compound and that it merits further investigation as an anticancer drug.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Alcaloides de Berberina/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Antineoplásicos/química , Alcaloides de Berberina/química , Ácidos Carboxílicos/química , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Roturas del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Ésteres/química , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
17.
Artículo en Inglés | MEDLINE | ID: mdl-25363726

RESUMEN

AIMS: The objectives of this pilot study were to assess the potential use of 3D videography for analyzing the motion of the body center of mass (COM) in newborns and to determine differences in spontaneous movements between preterm and full-term infants. METHODS: The group comprised 10 preterm newborns (gestational age at birth between 26 and 37 weeks; birth weight 800 to 2960 g; gestational age at the time of examination 34 to 39 weeks) and 10 full-term infants (gestational week 38 to 41; birth weight 2810 to 4360 g). To determine the range of motion of the COM, 3D videography was used (2 cameras, 25 Hz). When recording their movements, the infants were in the supine position, calm and awake. The recordings were processed using the APAS software. Selected points on the body were marked to obtain data for calculating the basic parameters of COM trajectories. RESULTS: The range of motion of the COM in both craniocaudal and anteroposterior directions was significantly greater in premature infants (P < 0.05 and P < 0.01, respectively) than in full-term babies. The variability of motion of the COM was significantly greater in the craniocaudal (P < 0.01) and anteroposterior (P < 0.05) directions in preterm babies. This was also valid for the velocity of motion of the COM in the craniocaudal direction (P < 0.05). CONCLUSIONS: 3D videography can be used for experimental assessment of motor behavior in preterm infants. Basic kinematic characteristics of the motion of the COM (range, variability, velocity) are greater in preterm infants.


Asunto(s)
Recien Nacido Prematuro/fisiología , Movimiento/fisiología , Fenómenos Biomecánicos , Peso al Nacer/fisiología , Estudios de Casos y Controles , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Masculino , Proyectos Piloto , Postura/fisiología , Rango del Movimiento Articular/fisiología , Grabación en Video
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