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1.
Front Cell Infect Microbiol ; 12: 856711, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774410

RESUMO

Porcine epidemic diarrhea virus (PEDV) could cause lethal diarrhea and dehydration in suckling piglets, which can adversely affect the development of the global swine industry. The lack of effective therapeutical and prophylactic treatment especially for PEDV variant strains underlines the importance of effective antiviral strategies, such as identification of novel antiviral agents. In the present study, the antiviral activity of cinchonine against PEDV was investigated in Vero CCL81 and LLC-PK1 cells at a non-cytotoxic concentration determined by Cell Counting Kit-8 assay in vitro. We found that cinchonine exhibited a significant suppression effect against PEDV infection and its inhibitory action was primarily focused on the early stage of PEDV replication. Moreover, we also observed that cinchonine could significantly induce autophagy by detecting the conversion of LC3-I to LC3-II by using western blot analysis. Cinchonine treatment could inhibit PEDV replication in a dose-dependent manner in Vero CCL81 cells, while this phenomenon disappeared when autophagy was attenuated by pre-treatment with autophagy inhibitor 3MA. Consequently, this study indicated that cinchonine can inhibit PEDV replication via inducing cellular autophagy and thus from the basis for successful antiviral strategies which potentially suggest the possibility of exploiting cinchonine as a novel antiviral agent.


Assuntos
Infecções por Coronavirus , Vírus da Diarreia Epidêmica Suína , Doenças dos Suínos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Autofagia , Chlorocebus aethiops , Alcaloides de Cinchona , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/veterinária , Vírus da Diarreia Epidêmica Suína/fisiologia , Suínos , Doenças dos Suínos/tratamento farmacológico , Células Vero , Replicação Viral
2.
Chirality ; 34(8): 1065-1077, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35596543

RESUMO

Chiral zwitterion ion exchangers represent efficient chiral stationary phases for stereoselective resolution of various analytes including chiral acids, bases, and zwitterions. In this contribution, we have focused on utilization of chiral zwitterionic sorbents, denoted as ZWIX (+A) and ZWIX (-A). These are analogical chiral systems to commercially available columns, Chiralpak ZWIX (+) and Chiralpak ZWIX (-), which are usually operated with buffered mobile phases. In this contribution, we have studied the enantiorecognition power of the ZWIX (+A) and ZWIX (-A) columns on a series of dipeptides operated under buffer-free reversed-phase conditions. Retention characteristics of zwitterionic dipeptides are discussed using an electrostatically driven adsorption model, which provides a good fit with both monotonous and U-shaped curves.


Assuntos
Alcaloides de Cinchona , Cinchona , Cromatografia Líquida de Alta Pressão , Dipeptídeos , Estereoisomerismo
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 279: 121417, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35636141

RESUMO

An analysis of FT-Raman spectra of quinidine (C20H24N2O2) aqueous solutions with varying pH (which was regarded as an external perturbation) was performed using the 2D correlation method. The main course of changes in the quinidine solution appears to be: protonation changes of the quinuclidine nitrogen N1, followed by protonation changes of nitrogen N13 in the quinoline, leading to the appearance of cross-peaks in the synchronous and asynchronous correlation maps. The intensity changes of peaks at 1369 cm-1 for the unprotonated quinidine molecule, and characteristic peaks at 1387 cm-1 and 1389 cm-1 for protonated quinuclidine and double protonated quinidine, respectively, along with the decrease in pH, confirmed that the change in the pH of the quinidine solution has an influence on the protonation process of the Cinchona alkaloid. The negative synchronous and asynchronous cross-peaks at (1385, 823) cm-1 and (1387, 822) cm-1, respectively, indicate the importance of remodeling the quinoline fragment, during the process of a double protonation of the quinidine molecule. Bands correlating with 2809 cm-1 confirmed the importance of the methoxy group in the process of quinidine protonation. The creation of hydrogen bonds after double protonation of the Cinchona alkaloids, assisted by the CH3-O group, give an interesting insight into the changes in the studied compound occurring along with a decrease in pH.


Assuntos
Alcaloides de Cinchona , Quinolinas , Alcaloides de Cinchona/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Quinidina/química
4.
Bioorg Med Chem ; 67: 116855, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35640378

RESUMO

Since the first application of natural quinine as an anti-malarial drug, cinchona alkaloids and their derivatives have been exhaustively studied for their biological activity. In our work, we tested 13 cinchona alkaloid organocatalysts, synthesised from quinine. These derivatives were screened against MES-SA and Dx5 uterine sarcoma cell lines for in vitro anticancer activity and to investigate their potential to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR). Decorating quinine with hydrogen-bond donor units, such as thiourea and (thio)squaramide, resulted in decreased half-maximal growth inhibition values on both cell lines (1.3-21 µM) compared to quinine and other cinchona alcohols (47-111 µM). Further cytotoxicity studies conducted in the presence of the P-gp inhibitor tariquidar indicated that several analogues, especially cinchona amines and squaramides, but not thiosquaramide, were expelled from MDR cells by P-gp. Similarly to the established P-gp inhibitor quinine, 6 cinchona analogues were shown to inhibit calcein-AM efflux. Interestingly, quinine and didehydroquinine exhibited a marginally increased toxicity against the multidrug resistant Dx5 cells. Collateral sensitivity of the MDR cell line was more pronounced when the cinchona thiosquaramide was complexed with Cu(II) acetate. Based on the results, cinchona derivatives are good anticancer candidates for further drug development.


Assuntos
Alcaloides de Cinchona , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias Uterinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Alcaloides de Cinchona/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Quinina/farmacologia , Sarcoma/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/metabolismo
5.
J Am Chem Soc ; 144(17): 7805-7814, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35471031

RESUMO

Visible-light-driven photocatalytic reductive azaarylation has been widely used to construct the important imine-containing azaarene derivatives. In addition to the direct use of various commercially available cyanoazaarenes as feedstocks, the synthetic advantages include precise regioselectivity, high efficiency, mild reaction conditions, and good functional group tolerance. However, although many efficient reductive azaarylation methods have been established, the example of an enantioselective manner is still unmet, which most likely can be ascribed to the highly reactive radical coupling as the key step of forming stereocenters. Exploring the feasibility of enantiocontrol thus constitutes an attractive but highly challenging task. Here, we demonstrate that chiral hydrogen-bonding/photosensitizer catalysis is a viable platform as it enables the realization of the first enantioselective manifold. A variety of acyclic and cyclic enones as the reaction partners are compatible with the dual catalyst system, leading to a wide array of valuable enantioenriched azaarene variants with high yields and ees. Regulating the types of chiral catalysts represents one of the important manners to success, in which several readily accessible Cinchona alkaloid-derived bifunctional catalysts are introduced in asymmetric photochemical reactions.


Assuntos
Alcenos , Alcaloides de Cinchona , Catálise , Iminas , Estereoisomerismo
6.
Angew Chem Int Ed Engl ; 61(24): e202202548, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35343034

RESUMO

Simultaneous control over the configuration of multiple stereocenters is accomplished by numerous catalytic methods, providing a reliable basis for the synthesis of stereochemically complex targets in isomerically defined form. In contrast, addressing the configurations of multiple stereogenic axes with diastereodivergent catalyst control is thus far only possible by stepwise approaches. Herein we now describe that all four stereoisomers of atropisomeric two-axis systems are directly tractable by assembling a central aromatic unit of teraryls through an arene-forming aldol condensation. By using cinchona alkaloid-based ion-pairing catalysts, the four feasible reaction pathways are differentiated from identical substrates under defined basic conditions without preactivation, thus enabling complete stereodivergence with enantioselectivities of up to 99 : 1 e.r.


Assuntos
Aldeídos , Alcaloides de Cinchona , Catálise , Estereoisomerismo
7.
J Chromatogr A ; 1670: 462974, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35320750

RESUMO

The enantioselective separation of newly synthesized fluorine-substituted ß-phenylalanines has been performed utilizing Cinchona alkaloid-based ion-exchanger chiral stationary phases. Experiments were designed to study the effect of eluent composition, counterion content, and temperature on the chromatographic properties in a systematic manner. Mobile phase systems containing methanol or mixtures of methanol and acetonitrile together with acid and base additives ensured highly efficient enantioseparations. Zwitterionic phases [Chiralpak ZWIX (+) and ZWIX(-)] were found to provide superior performance compared to that by the anion-exchangers (Chiralpak QN-AX and QD-AX). A detailed thermodynamic characterization was also performed by employing van't Hoff analysis. Using typical liquid chromatographic experimental conditions, no marked effect of the flow rate could be observed on the calculated thermodynamic parameters. In contrast, a clear tendency has been revealed about the effect of the eluent composition on the thermodynamics for the zwitterionic phases.


Assuntos
Alcaloides de Cinchona , Cinchona , Cromatografia Líquida de Alta Pressão/métodos , Cinchona/química , Alcaloides de Cinchona/química , Metanol , Fenilalanina , Estereoisomerismo , Termodinâmica
8.
J Org Chem ; 87(7): 4617-4630, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35266689

RESUMO

Herein, we report the asymmetric Ru/cinchonine dual catalysis that provides straightforward access to enantioselective synthesis of C-3 substituted phthalides via tandem C-H activation/Michael addition cascade. The use of readily accessible and less expensive [RuCl2(p-cym)]2 and cinchonine catalyst for the one-pot assembly of chiral phthalides greatly overcomes the present trend of using highly sophisticated catalysts. The developed method provides access to both enantiomers of a product using pseudoenantiomeric cinchona alkaloids as catalysts streamlining the synthesis of phthalide in both the optically active forms.


Assuntos
Acrilatos , Alcaloides de Cinchona , Benzoatos , Benzofuranos , Catálise , Estrutura Molecular , Estereoisomerismo
9.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948226

RESUMO

ß-thalassemias are among the most common inherited hemoglobinopathies worldwide and are the result of autosomal mutations in the gene encoding ß-globin, causing an absence or low-level production of adult hemoglobin (HbA). Induction of fetal hemoglobin (HbF) is considered to be of key importance for the development of therapeutic protocols for ß-thalassemia and novel HbF inducers need to be proposed for pre-clinical development. The main purpose on this study was to analyze Cinchona alkaloids (cinchonidine, quinidine and cinchonine) as natural HbF-inducing agents in human erythroid cells. The analytical methods employed were Reverse Transcription quantitative real-time PCR (RT-qPCR) (for quantification of γ-globin mRNA) and High Performance Liquid Chromatography (HPLC) (for analysis of the hemoglobin pattern). After an initial analysis using the K562 cell line as an experimental model system, showing induction of hemoglobin and γ-globin mRNA, we verified whether the two more active compounds, cinchonidine and quinidine, were able to induce HbF in erythroid progenitor cells isolated from ß-thalassemia patients. The data obtained demonstrate that cinchonidine and quinidine are potent inducers of γ-globin mRNA and HbF in erythroid progenitor cells isolated from nine ß-thalassemia patients. In addition, both compounds were found to synergize with the HbF inducer sirolimus for maximal production of HbF. The data obtained strongly indicate that these compounds deserve consideration in the development of pre-clinical approaches for therapeutic protocols of ß-thalassemia.


Assuntos
Alcaloides de Cinchona/farmacologia , Células Precursoras Eritroides/metabolismo , Hemoglobina Fetal/biossíntese , Talassemia beta/metabolismo , Células Precursoras Eritroides/patologia , Humanos , Células K562 , Talassemia beta/tratamento farmacológico
10.
J Med Chem ; 64(19): 14513-14525, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34558909

RESUMO

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines autophagy modulation and apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Alcaloides de Cinchona/farmacologia , Neoplasias Hepáticas/patologia , Ureia/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Microambiente Tumoral/efeitos dos fármacos
11.
Nature ; 597(7874): 70-76, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34471272

RESUMO

Control of molecular chirality is a fundamental challenge in organic synthesis. Whereas methods to construct carbon stereocentres enantioselectively are well established, routes to synthesize enriched heteroatomic stereocentres have garnered less attention1-5. Of those atoms commonly present in organic molecules, nitrogen is the most difficult to control stereochemically. Although a limited number of resolution processes have been demonstrated6-8, no general methodology exists to enantioselectively prepare a nitrogen stereocentre. Here we show that control of the chirality of ammonium cations is easily achieved through a supramolecular recognition process. By combining enantioselective ammonium recognition mediated by 1,1'-bi-2-naphthol scaffolds with conditions that allow the nitrogen stereocentre to racemize, chiral ammonium cations can be produced in excellent yields and selectivities. Mechanistic investigations demonstrate that, through a combination of solution and solid-phase recognition, a thermodynamically driven adductive crystallization process is responsible for the observed selectivity. Distinct from processes based on dynamic and kinetic resolution, which are under kinetic control, this allows for increased selectivity over time by a self-corrective process. The importance of nitrogen stereocentres can be revealed through a stereoselective supramolecular recognition, which is not possible with naturally occurring pseudoenantiomeric Cinchona alkaloids. With practical access to the enantiomeric forms of ammonium cations, this previously ignored stereocentre is now available to be explored.


Assuntos
Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/síntese química , Cátions/síntese química , Cátions/química , Alcaloides de Cinchona/química , Nitrogênio/química , Estereoisomerismo , Termodinâmica
12.
Anal Chim Acta ; 1180: 338928, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34538320

RESUMO

Single enantiomers of mandelic acid (1), 3-phenyllactic acid (2), and 3-(4-hydroxyphenyl)lactic acid (3) are the subject of many fields of investigation, spanning from the pharmaceutical synthesis to that of biocompatible and biodegradable polymers, while passing from the interest towards their antimicrobial activity to their role as biomarkers of particular pathological conditions or occupational exposures to specific xenobiotics. All above mentioned issues justify the need for accurate analytical methods enabling the correct determination of the individual enantiomers. So far, all the developed liquid chromatography (LC) methods were not or hardly compatible with mass spectrometry (MS) detection. In this paper, a commercially available Cinchona-alkaloid derivative zwitterionic chiral stationary phase [that is, the CHIRALPAK® ZWIX(-)] was successfully used to optimize the enantioresolution of compounds 1-3 under polar-ionic (PI) conditions with a mobile phase consisting of an acetonitrile/methanol 95/5 (v/v) mixture with 80 mM formic acid. With the optimized conditions, enantioseparation and enantioresolution values up to 1.46 and 4.41, respectively, were obtained. In order to assess the applicability of the optimized enantioselective chromatography conditions in real-life scenarios and on MS-based systems, a proof-of-concept application was efficiently carried out by analysing dry urine spot samples spiked with 1 by means of a LC-MS system. The (S)<(R) enantiomer elution order (EEO) was established for compounds 1 and 2 by analysing a pure enantiomeric standard of known configuration. This was not possible for 3 because not commercially available. For this compound, the same EEO was identified applying a procedure based on ab initio time-dependent density-functional theory simulations coupled to electronic circular dichroism analyses. Moreover, a molecular dynamics simulation unveiled the role of the phenolic OH in compound 3 in the retention mechanism.


Assuntos
Alcaloides de Cinchona , Preparações Farmacêuticas , Cromatografia Líquida de Alta Pressão , Hidroxiácidos , Íons , Estereoisomerismo
13.
J Org Chem ; 86(17): 11782-11793, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34347451

RESUMO

Mechanistic studies clarifying how chiral primary amines control the stereochemistry of vinylogous processes are rare. We report a density functional theory (DFT) computational study for the comprehension of the reaction mechanism of the vinylogous atroposelective desymmetrization of N-(2-t-butylaryl)maleimide catalyzed by 9-amino(9-deoxy)epi-quinine. Our results illustrate how the origin of the atroposelectivity was realized by the catalyst through steric and dispersion interactions. The role of N-Boc-l-Ph-glycine was crucial for the formation of a closed transition-state geometry and the activation of both reaction partners.


Assuntos
Aminas , Alcaloides de Cinchona , Catálise , Maleimidas , Estereoisomerismo
14.
Org Lett ; 23(15): 5714-5718, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34254813

RESUMO

Maleimides are often used as electrophiles in conventional reactions; however, their application as nucleophiles is limited to only a few reactions, and reactions utilizing α-aminomaleimides as asymmetric Michael donors have not been reported to date. Thus, in this work, asymmetric Michael addition of α-aminomaleimides as Michael donors to ß-nitrostyrenes was conducted for the first time using an organocatalyst derived from a Cinchona alkaloid. Density functional theory investigations were crucial to improve the enantioselectivity of the adduct.


Assuntos
Alcaloides de Cinchona/química , Maleimidas/química , Estirenos/química , Reação de Cicloadição , Estrutura Molecular
15.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199504

RESUMO

The substance class of the well-known Cinchona alkaloids is widened by 6'-Amino-cinchonine and 6'-Amino-cinchonidine, novel compounds which incorporate a primary amino function in the quinolinic ring system. These key intermediates open the field for a range of fruitful chemistry. Here is described a short and direct pathway for the synthesis of triazole containing derivatives of the above-mentioned substances using the [3 + 2] Huisgen cycloaddition. For this purpose, the amines were first converted into the corresponding azides. Based on this, non-substituted and silyl-protected triazoles were synthesized as examples. Furthermore, didehydrated derivatives of quincorine and quincoridine were used as addition partners, resulting in compounds that carry the quinuclidine ring of the cinchona alkaloids at both ends. Some of these compounds were examined radiographically to investigate the position of the quinuclidine ring to the triazole. The solid-state structures of compounds 10, 11 and 28 were determined by X-ray diffraction analyses.


Assuntos
Alcaloides de Cinchona/química , Triazóis/síntese química , Cristalografia por Raios X , Reação de Cicloadição , Modelos Moleculares , Estrutura Molecular , Triazóis/química
16.
J Sep Sci ; 44(14): 2735-2743, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33999502

RESUMO

Enantiomers of cationic compounds of pharmaceutical relevance, namely tetrahydro-ß-carboline and 1,2,3,4-tetrahydroisoquinoline analogs, were separated by high-performance liquid chromatography. Separations were performed on Cinchona-alkaloid-based zwitterionic ion exchanger type chiral stationary phases applied as cation exchangers using mixtures of methanol and acetonitrile or tetrahydrofuran as bulk solvent components containing triethylammonium acetate or ammonium acetate as organic salt additives. On the zwitterionic ZWIX(+) and ZWIX(-) columns investigated, retention and enantioseparation of the studied basic analytes were influenced by the nature and concentration of the organic components of the mobile phase. The effect of organic salt additives on the retention behavior of the studied analytes can be described by the stoichiometric displacement model related to the counterion concentration. Investigations on the structure-retention relationships were performed applying different mobile phase systems for the two types of cationic analytes. For the thermodynamic characterization, parameters such as changes in standard enthalpy (Δ(ΔH°)), entropy (Δ(ΔS°)), and free energy (Δ(ΔG°)) were calculated on the basis of van't Hoff plots derived from the ln α versus 1/T curves. In most cases, enthalpy-driven enantioseparations were observed, with a consistent dependence of the calculated thermodynamic parameters on the mobile phase composition. Elution sequences of the studied compounds were determined in all cases.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Alcaloides de Cinchona , Cinchona/química , Cátions/isolamento & purificação , Alcaloides de Cinchona/análise , Alcaloides de Cinchona/química , Preparações Farmacêuticas/isolamento & purificação
17.
J Asian Nat Prod Res ; 23(2): 163-175, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32091234

RESUMO

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal; 6'-OCH3 moiety is not necessary, removal of it is also acceptable. [Formula: see text].


Assuntos
Inseticidas , Animais , Alcaloides de Cinchona , Inseticidas/farmacologia , Larva , Estrutura Molecular
18.
J Cell Physiol ; 236(3): 1854-1865, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32700766

RESUMO

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor ß-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1ß (PGC1ß), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1ß resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.


Assuntos
Diferenciação Celular , Alcaloides de Cinchona/farmacologia , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Alcaloides de Cinchona/química , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/patologia , Lipopolissacarídeos , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas Nucleares/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ovariectomia , Ligante RANK/farmacologia , Células RAW 264.7 , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição/metabolismo
19.
Biotechnol Appl Biochem ; 68(4): 832-840, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32757395

RESUMO

The ability of quinoline alkaloids (cinchonine, cinchonidine, quinine, and quinidine) to sensitize different human cancer cell lines to doxorubicin (DOX)-induced cell death was evaluated. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the alkaloids ability to enhance DOX-induced apoptosis was explored using Western blotting analysis. Also, flow cytometry was applied to analyze cell fractions in the different cell cycle phases. All alkaloids showed a significant enhancement of DOX-induced cell death in HeLa and HepG2 cell lines. The chemosensitizing activity of the quinoline alkaloids was attributed to the induction of apoptosis as indicated by splitting of caspase-3 and its substrate poly (ADP-ribose) polymerase (PARP). In addition, there was an increase in the cell fractions in sub-G0/G1 phase in case of DOX combination with the alkaloids. This study proves the ability of the quinoline alkaloids to enhance DOX-induced apoptotic cell death in human cervical and hepatocellular carcinoma cells.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular , Alcaloides de Cinchona/farmacologia , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Hepáticas , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Neoplasias do Colo do Útero , Células CACO-2 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células MCF-7 , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
20.
J Pharm Biomed Anal ; 193: 113724, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33197835

RESUMO

In this study, we present results obtained on the diastereo- and enantioseparation of some basic natural and synthetic Cinchona alkaloid analogs by applying liquid chromatographic (LC) and subcritical fluid chromatographic (SFC) modalities on amylose and cellulose tris-(phenylcarbamate)-based stationary phases using n-hexane/alcohol/DEA or CO2/alcohol/DEA mobile phase systems. Seven chiral stationary phases in their immobilized form were employed to explore their stereoselectivity for a series of closely related group of analytes. The most important characteristics of LC and SFC systems were evaluated through the variation of the applied chromatographic conditions (e.g., the nature and content of the alcohol modifier, the concentration of additives, temperature). The columns Chiralpak IC and IG turned out to be the best in both LC and SFC modalities. Temperature-dependence study indicated enthalpy-controlled separation in most cases; however, separation controlled by entropy was also registered.


Assuntos
Alcaloides de Cinchona , Cinchona , Cromatografia Líquida de Alta Pressão , Polissacarídeos , Estereoisomerismo
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