Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.033
Filtrar
1.
Curr Org Synth ; 18(7): 719-725, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34465279

RESUMO

INTRODUCTION: In this study, the synthesis of azo-linked acridine by the reaction of dimedone and synthesized diazoaryl-(2-amino-5-(phenyl)methanone using Ag2S/RHA-MCM-41nanocomposite is reported. MATERIALS AND METHODS: The synthesized catalyst was characterized by FT-IR, XRD, and SEM. According to the obtained results, Ag2S/RHA-MCM-41 nanocomposite exhibited high activity in the synthesis of azo-acridine derivatives based on desirable yields and reaction time. Products were prepared in 1.5-2 h and with 88-93% yield. In all the reactions, the catalyst could be easily removed and reused, and its catalytic activity was maintained after five uses and did not decrease significantly. The structures of all newly synthesized products were characterized by spectroscopic spectra (FT-IR, 1H NMR, 13C NMR) and elemental analyses. RESULTS AND DISCUSSION: The results of the study showed that ionic liquid [DBU]OAc (entry 8) and MCM- 41/Ag2S-RHA nanocomposite (entry 8) possessed better efficiency and shorter time than other reaction conditions. CONCLUSION: In this study, new azo-linked acridine derivatives were synthesized by the reaction of different azo derivatives and dimedone using MCM-41/Ag2S-RHA nanocomposite, and the reaction products were obtained in 1.5-2 h with an efficiency of 88-93%. The short reaction time and high efficiency of the obtained products indicated the high efficiency of this method. In all the reactions, MCM-41/Ag2S-RHA nanocomposite could be easily removed and reused. Its catalytic activity was maintained in the sample reaction after five runs and did not decrease significantly.


Assuntos
Acridinas , Nanocompostos , Dióxido de Silício , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Chemistry ; 27(59): 14681-14689, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34375484

RESUMO

To study the DNA damage caused by a potent platinum-acridine anticancer agent (PA) in cancer cells, an assay based on biorthogonal post-labeling using a click chemistry-enabled, azide-modified derivative (APA) was developed. The method involves biotinylation, affinity capture, and bead-based enrichment of APA-modified genomic DNA. The key steps of the assay were validated and optimized in model duplexes, including full-length plasmids, restriction fragments, and a DNA ladder. Native DNA treated with APA and subsequently subjected to post-labeling with a biotin affinity tag was enzymatically digested and fragments were analyzed by in-line LC-MS and MS/MS. The monofunctional-intercalative adducts formed by APA in 5'-pyrimidine/guanine sequences in double-stranded DNA were quantitatively biotinylated by strain-promoted 1,3-dipolar cycloaddition chemistry. When applied to DNA extracted from A549 lung cancer cells, the assay in combination with qPCR amplification demonstrates that platinum-acridines form adducts in the gene sequences encoding pre-ribosomal RNA, a potential pharmacological target of these agents.


Assuntos
Antineoplásicos , Adutos de DNA , Acridinas , Antineoplásicos/farmacologia , DNA , Genes de RNAr , Platina , Reação em Cadeia da Polimerase , Espectrometria de Massas em Tandem
3.
Adv Healthc Mater ; 10(19): e2100775, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34165250

RESUMO

Antibiotic resistance is considered as one of the serious public health issues. Antibacterial photocatalytic therapy, a clinically proven antibacterial therapy, is gaining increasing attention in recent years owing to its high efficacy. Here, an acridine-based covalent organic framework (COF) photosensitizer, named TPDA, with multiple active sites is synthesized via Schiff base condensation between 2,4,6-triformylphloroglucinol (TFP) and 3,6-diaminoacridine (DAA). Owing to the increased conjugation effect of the COF skeleton and outstanding light harvesting ability of DAA, TPDA exhibits a narrow optical band gap (1.6 eV), enhancing light energy transformation and conferring a wide optical absorption spectrum (intensity arbitrary unit > 0.8) ranging from the UV to near-infrared region. Moreover, TPDA shows high antibacterial activities against both gram-negative and gram-positive bacteria within a short time (10 min) of light irradiation and is found to efficiently protect fish from skin infections. Molecular dynamics simulation data show that the introduction of DAA and TFP facilitates the interaction between TPDA and bacteria and is conducive to reactive oxygen species migration, which further improves the antimicrobial performance. These findings indicate the potential of TPDA as a novel photosensitive material for photodynamic therapy.


Assuntos
Estruturas Metalorgânicas , Fármacos Fotossensibilizantes , Acridinas , Animais , Antibacterianos/farmacologia , Antivirais , Fármacos Fotossensibilizantes/farmacologia
4.
J Hazard Mater ; 419: 126409, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34171666

RESUMO

The goal of the present work was to fabricate a new low-cost, easy-to-prepare, dual-channel fluorescence chemosensor comprised of acridine-diphenylacetyl moieties (NDA) to enable remarkable Sn4+ detection in water and biological medium. The resulting NDA-Sn4+ complex was utilized for the distinguished identification of Cr2O72- ions from other anions and biomolecules. These investigations involve the absorption, fluorescence, and electrochemical methods for the detection of Sn4+ and Cr2O72- ions in pure water. The mechanism for NDA-mediated Sn4+ detection was experimentally determined by FT-IR, NMR titrations, mass (ESI) analyses, and DFT calculations. The obtained results indicate that the NDA chemosensor possessed excellent performance characteristics including good water solubility and compatibility, quick response time (less than 10 s), high sensitivity (Sn4+ = 0.268 µM and Cr2O72- = 0.160 µM), and selectivity against coexisting metals, anions, amino acids, and peptides. The chemosensor NDA induced negligible toxicity in live cells and was successfully utilized as a biomarker for the tracking of Sn4+ in human normal and cancer cells. More importantly, NDA demonstrates distinguished recognition of Sn4+ in human cancer cells rather than in normal live cells. Additionally, NDA was shown to act as a mitochondria-targeted probe in FaDu cells.


Assuntos
Neoplasias , Água , Acridinas , Corantes Fluorescentes , Humanos , Íons , Mitocôndrias , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier
5.
Molecules ; 26(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065674

RESUMO

In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its derivatives, such as mefenamic-, tolfenamic- and flufenamic acid, with acridine were obtained and the X-ray structures were discussed. Formation of the crystals is determined by the presence of the intermolecular O-H…N hydrogen bond that occur between fenamic acids and acridine. Intermolecular interactions stabilizing the crystals such as π…π stacking, C-H…X (X = O, Cl) intermolecular hydrogen bonds as well as C-H…π and other dispersive interactions were analyzed by theoretical methods: the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) approaches.


Assuntos
Acridinas/química , Compostos Heterocíclicos/química , ortoaminobenzoatos/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Teoria Quântica
6.
Invest Ophthalmol Vis Sci ; 62(6): 24, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34036313

RESUMO

Purpose: To test the hypothesis that acutely correcting a sustained presence of outer retina free radicals measured in vivo in 24-month-old mice corrects their reduced visual performance. Methods: Male C57BL/6J mice two and 24 months old were noninvasively evaluated for unremitted production of paramagnetic free radicals based on whether 1/T1 in retinal laminae are reduced after acute antioxidant administration (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]). Superoxide production was measured in freshly excised retina (lucigenin assay). Combining acute antioxidant administration with optical coherence tomography (i.e., QUEST OCT) tested for excessive free radical-induced shrinkage of the subretinal space volume. Combining antioxidant administration with optokinetic tracking tested for a contribution of uncontrolled free radical production to cone-based visual performance declines. Results: At two months, antioxidants had no effect on 1/T1 in vivo in any retinal layer. At 24 months, antioxidants reduced 1/T1 only in superior outer retina. No age-related change in retinal superoxide production was measured ex vivo, suggesting that free radical species other than superoxide contributed to the positive QUEST MRI signal at 24 months. Also, subretinal space volume did not show evidence for age-related shrinkage and was unresponsive to antioxidants. Finally, visual performance declined with age and was not restored by antioxidants that were effective per QUEST MRI. Conclusions: An ongoing uncontrolled production of outer retina free radicals as measured in vivo in 24 mo C57BL/6J mice appears to be insufficient to explain reductions in visual performance.


Assuntos
Antioxidantes/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Radicais Livres/metabolismo , Azul de Metileno/uso terapêutico , Ácido Tióctico/uso terapêutico , Transtornos da Visão/tratamento farmacológico , Acridinas/metabolismo , Fatores Etários , Animais , Injeções Intraperitoneais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nistagmo Optocinético/fisiologia , Retina/diagnóstico por imagem , Retina/enzimologia , Superóxidos/metabolismo , Tomografia de Coerência Óptica , Transtornos da Visão/diagnóstico por imagem , Transtornos da Visão/metabolismo , Transtornos da Visão/fisiopatologia
7.
Eur J Med Chem ; 219: 113408, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33989911

RESUMO

Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.


Assuntos
Antimaláricos/química , Malária/tratamento farmacológico , Acridinas/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Artemisininas/química , Artemisininas/uso terapêutico , Desenho de Fármacos , Meia-Vida , Humanos , Quinolinas/química , Tetraoxanos/química
8.
Eur J Med Chem ; 221: 113480, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33964649

RESUMO

With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.


Assuntos
Acridinas/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Acridinas/síntese química , Acridinas/química , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
9.
Cell Mol Biol Lett ; 26(1): 11, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33730996

RESUMO

Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α's endonuclease activity.


Assuntos
Acridinas/farmacologia , Endorribonucleases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Splicing de RNA/genética , Triazóis/farmacologia , Proteína 1 de Ligação a X-Box/genética , Acridinas/química , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Himecromona/análogos & derivados , Himecromona/química , Himecromona/farmacologia , Splicing de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triazóis/química
10.
Vestn Otorinolaringol ; 86(1): 78-81, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33720657

RESUMO

Evaluation of the effectiveness of various schemes of local immunotherapy in immunocompromised patients with allergic rhinitis was carried out. MATERIALS AND METHODS: A comparative analysis of the treatment of 72 patients with allergic rhinitis, divided into groups: I (main, n=21), which included immunocompromised patients who received sublingual allergen-specific immunotherapy with antipollin and inhaled immunotherapy with cycloferon (every other day, a course of 10 procedures, the total dose of Cycloferon per course is 1250 mg); II (comparison, n=22) - immunocompromised patients who received monotherapy with antipollinum and III (control, n=29) - patients with allergic rhinitis without signs of immunocompromise, who also received antipollinum. The effectiveness of therapy was assessed by the quality of life (RQLQ questionnaire), the severity of nasal symptoms (the patient's self-observation diary) and the need for drugs after a course of intranasal immunotherapy. RESULTS: The inclusion of cycloferon in the treatment of immunocompromised patients with allergic rhinitis increased its effectiveness - the severity of nasal symptoms decreased: in terms of sneezing, a decrease of 53.5 times versus 1.82 - in the control, «nasal congestion¼ - 6.3 times versus 2.6 - in the control, «itching in the nose¼ - 4.9 and 4.2 times, respectively (p<0.05). The changes had a positive effect on the total indicator of the quality of life of patients - an increase of 6.2 times (by 83.7%) (p>0.05) and significantly reduced the need for cromones (18 times, versus 10.3 - in the group comparison), inhaled corticosteroids (10.4 times versus 8 times in the comparison group, and in decongestans - 8.1 times versus 6.1 - in the comparison group (p>0.05)). CONCLUSIONS: The combined use of local immunotherapy with cycloferon and sublingual allergen-specific immunotherapy with antipollinum in immunocompromised patients with allergic rhinitis is the first-line method of choice that statistically significantly changes the quality of life of patients.


Assuntos
Rinite Alérgica , Rinite , Acridinas , Humanos , Imunoterapia , Qualidade de Vida , Rinite Alérgica/diagnóstico , Rinite Alérgica/terapia
11.
Mycopathologia ; 186(2): 221-236, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33550536

RESUMO

Candida albicans has been reported globally as the most widespread pathogenic species contributing candidiasis from superficial to systemic infections in immunocompromised individuals. Their metabolic adaptation depends on glyoxylate cycle to survive in nutrient-limited host. The long term usage of fungistatic drugs and the lack of cidal drugs frequently result in strains that could resist commonly used antifungals and display multidrug resistance (MDR). In search of potential therapeutic intervention and novel fungicidals, we have explored a plant alkaloids, namely arborinine and graveoline for its antifungal potential. Alkaloids belongs to Rutaceae family have been reported with numerous antimicrobial activities. In this study, we aimed to isolate and identify the antifungal active alkaloids of R. angustifolia and assess antifungal effect targeting C. albicans isocitrate lyase (ICL) gene which regulates isocitrate lyase, key enzyme in glyoxylate cycle contributing to the virulence potential of C. albicans. Alkaloids were extracted by bioassay guided isolation technique which further identified by TLC profile and compared with the standard through HPLC and NMR analysis. The antifungal activities of the extracted alkaloids were quantified by means of MIC (Minimum Inhibitory Concentration). The gene expression of the targeted gene upon treatment was analysed using RT-qPCR and western blot. Additionally, this study looked at the drug-likeness and potential toxicity effect of the active alkaloid compounds in silico analysis. Spectroscopic analysis showed that the isolated active alkaloids were characterized as acridone, furoquinoline, 4-quinolone known as arborinine and graveoline. Results showed that each compound significantly inhibited the growth of C. albicans at the dose of 250 to 500 µg/mL which confirm its antifungal activity. Each alkaloid was found to successfully downregulate the expression of both ICL1 gene CaIcl1 protein. Finally, ADMET analysis suggests a good prediction of chemical properties, namely absorption, distribution, metabolism, excretion and toxicity (ADMET) that will contribute in drug discovery and development later on.


Assuntos
Alcaloides , Ruta , Acridinas , Antifúngicos , Candida albicans , Humanos , Isocitrato Liase , Metoxaleno/análogos & derivados , Testes de Sensibilidade Microbiana
12.
Artigo em Inglês | MEDLINE | ID: mdl-33586599

RESUMO

Acridine and its derivatives are well known for their DNA binding properties. In this report, we present our findings on evaluating different binding parameters of the interaction of 9-phenylacridine (ACPH) with DNA. Absorption spectroscopic studies including standard and reverse titration, the effects of ionic strength and temperature on titration, and Job plot analysis were done to calculate the binding constant and determine the different thermodynamic parameters and stoichiometry of the binding. Spectrofluorimetry and circular dichroism (CD) spectral titration were also utilized to confirm these findings. The results indicated that ACPH binds to DNA reversibly through non-electrostatic interactions by hydrogen bonding and van der Waals interactions. The binding constant and the number of binding sites were of the order 103 M-1 and ≈2, respectively with a binding stoichiometry of 1:4. The binding of ACPH with DNA was spontaneous, exothermic and enthalpy-driven. The extent of uptake of ACPH in B16 melanoma cells was estimated. As this compound absorbs in the UVA region, the effect of treatment with ACPH prior to UVA exposure was assessed to evaluate its phototoxicity in these cells. Our results indicated that the binding to DNA enhanced damage to sensitize cells to killing through apoptosis. Our findings indicated its potential to act as a photosensitizer.


Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , DNA/química , Fármacos Fotossensibilizantes/farmacologia , Raios Ultravioleta , Acridinas/química , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Concentração Osmolar , Fármacos Fotossensibilizantes/química , Espectrometria de Fluorescência , Termodinâmica
13.
Luminescence ; 36(4): 1097-1106, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33617125

RESUMO

Multicolor chemiluminescent acridinium derivatives were synthesized by attaching various common fluorophores to the N10 -acridinium position through a piperazine linker. Triggering of each acridinium derivative using alkaline hydrogen peroxide resulted in a chemiluminescence spectrum dominated by a strong emission (>95%) from the attached fluorophore. The highly quenched emission from the triggered acridinium, acting as a donor, points to a highly efficient intramolecular energy transfer in acridinium-based chemiluminophore-fluorophore tandems. A variable, and in many cases minimal, spectral overlap between the donor emission and the acceptor absorption may indicate that in such tandems the energy transfer follows the Dexter electron exchange mechanism. Moreover, fluorophores affixed through the acridinium 9-position produce a typical acridinium emission profile, demonstrating the need for close distances and favorable intramolecular orientation of the donor and acceptor moieties for the energy transfer to occur. A family of red-shifted chemiluminescent labels, all sharing a uniform triggering method, will find immediate application in multicolor ligand-receptor assays. Along with the multiplexing capabilities, the red-shifted chemiluminescent detection offers a higher tolerance to green-colored biological interferences and will therefore benefit many screening and diagnostic clinical tests.


Assuntos
Acridinas , Luminescência , Peróxido de Hidrogênio , Medições Luminescentes
14.
Biomolecules ; 11(2)2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578987

RESUMO

Marine sponges (porifera) have proved to be a prolific source of unique bioactive secondary metabolites, among which the alkaloids occupy a special place in terms of unprecedented structures and outstanding biological activities. Identification of active cytotoxic alkaloids extracted from marine animals, particularly sponges, is an important strive, due to lack of knowledge on traditional experiential and ethnopharmacology investigations. In this report, a comprehensive survey of demospongian bioactive alkaloids in the range 1987-2020 had been performed with a special emphasis on the potent cytotoxic activity. Different resources and databases had been investigated, including Scifinder (database for the chemical literature) CAS (Chemical Abstract Service) search, web of science, Marin Lit (marine natural products research) database. More than 230 representatives of different classes of alkaloids had been reviewed and classified, different genera belonging to the phylum porifera had been shown to be a prolific source of alkaloidal molecules, including Agelas sp., Suberea sp., Mycale sp., Haliclona sp., Epipolasis sp., Monanchora sp., Crambe sp., Reniera sp., and Xestospongia sp., among others. The sufficient production of alkaloids derived from sponges is a prosperous approach that requires more attention in future studies to consider the constraints regarding the supply of drugs, attained from marine organisms.


Assuntos
Alcaloides/química , Produtos Biológicos/química , Poríferos/fisiologia , Acridinas/química , Alcaloides/metabolismo , Animais , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Química/métodos , Células HCT116 , Células HeLa , Humanos , Concentração Inibidora 50 , Células K562 , Células MCF-7 , Estrutura Molecular
15.
Biochem Biophys Res Commun ; 546: 40-45, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33561747

RESUMO

The emergence of worldwide spreading drug-resistant bacteria has been a serious threat to public health during the past decades. The development of new and effective antibacterial agents to address this critical issue is an urgent action. In the present study, we investigated the antibacterial activity of two 9,10-dihydroacridine derivatives and their mechanism. Both compounds were found possessing strong antibacterial activity against some selected Gram-positive bacteria including MRSA, VISA and VRE. The biological study suggests that the compounds promoted FtsZ polymerization and also disrupted Z-ring formation at the dividing site and consequently, the bacterial cell division is interrupted and causing cell death.


Assuntos
Acridinas/química , Acridinas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Desenho de Fármacos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Divisão Celular/efeitos dos fármacos , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos
16.
Mikrochim Acta ; 188(1): 24, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33404755

RESUMO

A rolling circle amplification chemiluminescence immunoassay (RCA-CLIA) was developed for precise quantitation of Aß in plasma. Capture antibodies conjugated with magnetic beads and detection antibodies with collateral single-stranded DNA (ssDNA) were bound to Aß42/Aß40 antigens to form a typical double-antibody sandwich structure. The RCA reaction was triggered by the addition of ssDNA, which generated products with a large number of sites for the binding of acridinium ester (AE)-labeled detection probes, thereby realizing the purpose of the amplification. The RCA-CLIA method had higher sensitivity than conventional CLIA without loss of specificity. Under optimum conditions, the linear range of Aß42 and Aß40 detection was 3.9-140 pg/mL and 3.9-180 pg/mL, respectively, with corresponding low detection limits of 1.99 pg/mL and 3.14 pg/mL, respectively. Plasma Aß42 and Aß40 were detected in the blood of 21 AD patients and 22 healthy people, wherein this ratio could significantly distinguish AD patients from healthy individuals with a sensitivity of 90.48% and specificity of 63.64% for a cutoff value of 154. The Aß42/Aß40 ratio of plasma acts as an accurate indicator for AD diagnosis; therefore, detection of plasma Aß using the RCA-CLIA exhibits great potential in noninvasive diagnosis and progressive assessment of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Imunoensaio/métodos , Acridinas/química , Peptídeos beta-Amiloides/imunologia , Anticorpos Imobilizados/imunologia , Biomarcadores/sangue , Sondas de DNA/química , DNA de Cadeia Simples/química , Humanos , Limite de Detecção , Substâncias Luminescentes/química , Medições Luminescentes/métodos , Técnicas de Amplificação de Ácido Nucleico , Reprodutibilidade dos Testes
17.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513818

RESUMO

In Alzheimer's disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-ß (Aß). The purpose of this study was to investigate the effect of pharmacological inhibition of Aß efflux transporters on BBB function and Aß accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/administração & dosagem , Doença de Alzheimer/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Modelos Animais de Doenças , Imunoglobulina G/metabolismo , Imuno-Histoquímica , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Junções Íntimas/metabolismo
18.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466280

RESUMO

DNA G-quadruplexes (G4s) form in relevant genomic regions and intervene in several biological processes, including the modulation of oncogenes expression, and are potential anticancer drug targets. The human KRAS proto-oncogene promoter region contains guanine-rich sequences able to fold into G4 structures. Here, by using circular dichroism and differential scanning calorimetry as complementary physicochemical methodologies, we compared the thermodynamic stability of the G4s formed by a shorter and a longer version of the KRAS promoter sequence, namely 5'-AGGGCGGTGTGGGAATAGGGAA-3' (KRAS 22RT) and 5'-AGGGCGGTGTGGGAAGAGGGAAGAGGGGGAGG-3' (KRAS 32R). Our results show that the unfolding mechanism of KRAS 32R is more complex than that of KRAS 22RT. The different thermodynamic stability is discussed based on the recently determined NMR structures. The binding properties of TMPyP4 and BRACO-19, two well-known G4-targeting anticancer compounds, to the KRAS G4s were also investigated. The present physicochemical study aims to help in choosing the best G4 target for potential anticancer drugs.


Assuntos
Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Acridinas/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação/genética , Varredura Diferencial de Calorimetria/métodos , Dicroísmo Circular , DNA/genética , Quadruplex G , Guanina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Oncogenes/genética , Porfirinas/farmacologia , Termodinâmica
19.
Molecules ; 26(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498868

RESUMO

Malaria is among the deadliest infectious diseases in the world caused by Plasmodium parasites. Due to the high complexity of the parasite's life cycle, we partly depend on antimalarial drugs to fight this disease. However, the emergence of resistance, mainly by Plasmodium falciparum, has dethroned most of the antimalarials developed to date. Given recent reports of resistance to artemisinin combination therapies, first-line treatment currently recommended by the World Health Organization, in Western Cambodia and across the Greater Mekong sub-region, it seems very likely that artemisinin and its derivatives will follow the same path of other antimalarial drugs. Consequently, novel, safe and efficient antimalarial drugs are urgently needed. One fast and low-cost strategy to accelerate antimalarial development is by recycling classical pharmacophores. Quinacrine, an acridine-based compound and the first clinically tested synthetic antimalarial drug with potent blood schizonticide but serious side effects, has attracted attention due to its broad spectrum of biological activity. In this sense, the present review will focus on efforts made in the last 20 years for the development of more efficient, safer and affordable antimalarial compounds, through recycling the classical quinacrine drug.


Assuntos
Acridinas/química , Antimaláricos/química , Acridinas/farmacologia , Animais , Antimaláricos/farmacologia , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos
20.
ChemMedChem ; 16(2): 412-419, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-32975041

RESUMO

Liposomal formulations have been developed for a highly cytotoxic platinum-acridine agent, [PtCl(pn)(C18 H21 N4 )](NO3 )2 (PA, pn=propane-1,3-diamine), and fully characterized. Nanoliposomes consisting of hydrogenated soybean phosphatidylcholine (HSPC), 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), and polyethylene glycol-2000-distearoylphosphatidylethanolamine (DSPE-mPEG2k ) were able to stably encapsulate PA at payload-to-lipid ratios of 2-20 %. The fusogenic properties of the liposomes promote efficient cellular uptake of PA across the plasma membrane, which results in vesicular transport of payload to the nucleus in cultured lung cancer cells. Unencapsulated PA and one of the newly designed liposomal formulations show promising tumor growth inhibition in tumor xenografts derived from A549 lung adenocarcinoma cells of 76 % and 72 %, respectively. Cisplatin showed no significant efficacy at a 10-fold higher dose. These findings underscore the utility of platinum-acridine agents for treating aggressive, chemoresistant forms of cancer and validate nanoliposomes as a biocompatible, expandable platform for their intravenous delivery and other potential routes of administration.


Assuntos
Acridinas/farmacologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Modelos Biológicos , Compostos Organoplatínicos/farmacologia , Platina/farmacologia , Células A549 , Acridinas/química , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lipossomos/química , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Platina/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...