RESUMEN
In the present study, numerous acridine derivatives A1-A20 were synthesized via aromatic nucleophilic substitution (SNAr) reaction of 9-chloroacridine with carbonyl hydrazides, amines, or phenolic derivatives depending upon facile, novel, and eco-friendly approaches (Microwave and ultrasonication assisted synthesis). The structures of the new compounds were elucidated using spectroscopic methods. The title products were assessed for their antimicrobial, antioxidant, and antiproliferative activities using numerous assays. Promisingly, the investigated compounds mainstream revealed promising antibacterial and anticancer activities. Thereafter, the investigated compounds' expected mode of action was debated by using an array of in silico studies. Compounds A2 and A3 were the most promising antimicrobial agents, while compounds A2, A5, and A7 revealed the most cytotoxic activities. Accordingly, RMSD, RMSF, Rg, and SASA analyses of compounds A2 and A3 were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel acridine derivatives were investigated. The tested compounds' existing screening results afford an inspiring basis leading to developing new compelling antimicrobial and anticancer agents based on the acridine scaffold.
Asunto(s)
Acridinas , Antibacterianos , Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Acridinas/química , Acridinas/farmacología , Acridinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Proliferación Celular/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Estructura Molecular , Línea Celular Tumoral , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antiinfecciosos/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Relación Dosis-Respuesta a Droga , Bacterias Grampositivas/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis químicaRESUMEN
Cellular and virus-coded long non-coding (lnc) RNAs support multiple roles related to biological and pathological processes. Several lncRNAs sequester their 3' termini to evade cellular degradation machinery, thereby supporting disease progression. An intramolecular triplex involving the lncRNA 3' terminus, the element for nuclear expression (ENE), stabilizes RNA transcripts and promotes persistent function. Therefore, such ENE triplexes, as presented here in Kaposi's sarcoma-associated herpesvirus (KSHV) polyadenylated nuclear (PAN) lncRNA, represent targets for therapeutic development. Towards identifying novel ligands targeting the PAN ENE triplex, we screened a library of immobilized small molecules and identified several triplex-binding chemotypes, the tightest of which exhibits micromolar binding affinity. Combined biophysical, biochemical, and computational strategies localized ligand binding to a platform created near a dinucleotide bulge at the base of the triplex. Crystal structures of apo (3.3 Å) and ligand-soaked (2.5 Å) ENE triplexes, which include a stabilizing basal duplex, indicate significant local structural rearrangements within this dinucleotide bulge. MD simulations and a modified nucleoside analog interference technique corroborate the role of the bulge and the base of the triplex in ligand binding. Together with recently discovered small molecules that reduce nuclear MALAT1 lncRNA levels by engaging its ENE triplex, our data supports the potential of targeting RNA triplexes with small molecules.
Asunto(s)
Herpesvirus Humano 8/metabolismo , Nucleótidos/metabolismo , Poli A/metabolismo , ARN Largo no Codificante/metabolismo , ARN Viral/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Secuencia de Bases , Cristalografía por Rayos X , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/fisiología , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Conformación de Ácido Nucleico , Nucleótidos/genética , Poli A/química , Poli A/genética , Estabilidad del ARN/genética , ARN Largo no Codificante/química , ARN Largo no Codificante/genética , ARN Viral/química , ARN Viral/genética , Sarcoma de Kaposi/virología , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Nucleic acid triplexes may regulate many important biological processes. Persistent accumulation of the oncogenic 7-kb long noncoding RNA MALAT1 is dependent on an unusually long intramolecular triple helix. This triplex structure is positioned within a conserved ENE (element for nuclear expression) motif at the lncRNA 3' terminus and protects the entire transcript from degradation in a polyA-independent manner. A requisite 3' maturation step leads to triplex formation though the precise mechanism of triplex folding remains unclear. Furthermore, the contributions of several peripheral structural elements to triplex formation and protective function have not been determined. We evaluated the stability, conformational fluctuations, and function of this MALAT1 ENE triple helix (M1TH) protective element using in vitro mutational analyses coupled with biochemical and biophysical characterizations. Using fluorescence and UV melts, FRET, and an exonucleolytic decay assay we define a concerted mechanism for triplex formation and uncover a metastable, dynamic triplex population under near-physiological conditions. Structural elements surrounding the triplex regulate the dynamic M1TH conformational variability, but increased triplex dynamics lead to M1TH degradation. Taken together, we suggest that finely tuned dynamics may be a general mechanism regulating triplex-mediated functions.
Asunto(s)
ADN/química , Conformación de Ácido Nucleico , ARN Largo no Codificante/química , Secuencia de Bases , ADN/genética , Humanos , ARN Largo no Codificante/genéticaRESUMEN
In this investigation, we have explored the protective capacity of MoS2 QDs coated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethyleneglycol) -2000] (DSPE-PEG) linked with (3-carboxypropyl) triphenylphosphonium-bromide (TPP), on the secondary structure of proteins in Alzheimer's disease (AD)-affected brain tissues. Using a cohort of fifteen male SWR/J mice, we establish three groups: a control group, a second group induced with AD through daily doses of AlCl3 and D-galactose for 49 consecutive days, and a third group receiving the same AD-inducing doses but treated with DSPE-PEG-TPP-MoS2 QDs. Brain tissues are meticulously separated from the skull, and their molecular structures are analyzed via FTIR spectroscopy. Employing the curve fitting method on the amide I peak, we delve into the nuances of protein secondary structure. The FTIR analysis reveals a marked increase in ß-sheet structures and a concurrent decline in turn and α-helix structures in the AD group in comparison to the control group. Notably, no statistically significant differences emerge between the treated and control mice. Furthermore, multivariate analysis of the FTIR spectral region, encompassing protein amide molecular structures, underscores a remarkable similarity between the treated and normal mice. This study elucidates the potential of DSPE-PEG-TPP-MoS2 QDs in shielding brain tissue proteins against the pathogenic influences of AD.
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Enfermedad de Alzheimer , Molibdeno , Animales , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Amidas , Encéfalo , Bromuros , Molibdeno/farmacología , Molibdeno/químicaRESUMEN
Background: 4-Methylacetophenone is used in the preparation of starting materials, 4-methylphenacyle bromide (2) and 4-methylacetophenone thiosemicarbazole (3). Results: Several novel 2,4-disubstituted-1,3-thiazole analogues were obtained via the treatment of starting materials with 4-methylphenacyl bromide, acetyl chloride, aromatic aldehydes and bromination providing thiazole derivatives 5-8 respectively. Conclusion: Compounds 5-8 were investigated for their cytotoxic activity on MCF-7 and normal breast cells. Active compounds were found and in contrast to staurosporine, compound 8 displayed the most potent cytotoxic action that showed a strong inhibitory effect (aromatase) and (protein tyrosine kinase) enzymes, proving that the novel thiazole derivatives promoted the effective anticancer drug candidates.
[Box: see text].
Asunto(s)
Antineoplásicos , Inhibidores de la Aromatasa , Neoplasias de la Mama , Tiazoles , Humanos , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Aromatasa/metabolismo , Células MCF-7 , Estructura MolecularRESUMEN
Herein, we have shown the interaction of an antibiotic drug ciprofloxacin (CIP) with three surface-active ionic liquids (ILs), having the same cation and different anions, namely, 1-decyl-3-methylimidazoliumtetrafluoroborate [C10mim][BF4], 1-decyl-3-methylimidazolium bromide [C10mim][Br], and 1-decyl-3-methylimidazolium chloride [C10mim][Cl]. This study has been performed by exploiting various spectroscopic techniques such as steady-state fluorescence, time-resolved fluorescence, and UV-visible spectroscopy. The fluorescence emission study of CIP with ILs was performed at various concentrations of all the three ILs. The emission spectra of CIP decreased in the presence of ILs, suggesting complex formation between CIP-IL. The effect of different concentrations of ILs on the emission spectra of CIP was exploited in terms of quenching and binding parameters. Further, fluorescence emission study was validated by the time-resolved fluorescence technique by measuring the average lifetime (τavg) of CIP in the presence of all the three ILs. The τavg value of the drug changed with the addition of ILs, which suggests complex formation between the drug and ILs. This complex formation was also confirmed by UV-visible spectroscopy results of CIP with all the three ILs. Further, for evaluating the thermodynamic parameters of the CIP-IL interactions, isothermal titration calorimetry (ITC) was performed. The ITC experiment yielded the thermodynamic parameters, ΔH (change in the enthalpy of association), ΔG (Gibbs free energy change), ΔS (entropy change), and binding constant (Ka). The binding parameters driven by ITC revealed that CIP-IL interactions are spontaneous in nature and enthalpy-driven, involving hydrophobic forces. Further, the classical density functional theory (DFT) calculations were performed, which provided deep insight for CIP-IL complex formation.
RESUMEN
As an important downstream effector gene in the hippo signaling pathway, large tumor suppressor gene 2 (LATS2) is involved in cell proliferation and differentiation, organ size and tissue regeneration, and plays an important role in regulating the growth and development of animal muscles. The purpose of this study is to explore the temporal expression of bovine LATS2 gene, and determine the key transcription factors for regulating bovine LATS2 gene. The result showed that bovine LATS2 gene was highly expressed in liver and longissimus dorsi, and was up-regulated in infancy muscle. In addition, it was highly expressed on the 2th day during the differentiation stage of myoblast. The upstream 1.7 Kb sequence of the 5 'translation region of bovine LATS2 gene was cloned, and 7 different deletion fragments were amplified by the upstream primers. These fragments were constructed into double luciferase reporter vectors and transfected into myoblasts and myotubes cells, respectively to detect the core promoter regions. In addition, the key transcription factors of the core promoter sequence of the bovine LATS2 gene were analyzed and predicted by online software. Combining with site-directed mutations, siRNA interference and chromatin immunoprecipitation technology, it was identified that MEF2A and MyoG combined in core promoter region (-248/-56) to regulate the transcription activity of bovine LATS2 gene. The results have laid a theoretical foundation for exploring the molecular regulation mechanism of LATS2 gene in the process of muscle growth.
Asunto(s)
Regulación de la Expresión Génica , Factores de Transcripción , Bovinos , Animales , Factores de Transcripción/metabolismo , Proliferación Celular , Regiones Promotoras Genéticas , Diferenciación CelularRESUMEN
Metastasis-associated lung adenocarcinoma transcript 1 ( Malat1/ MALAT1, mouse/human), a highly conserved long noncoding (lnc) RNA, has been linked with several physiological processes, including the alternative splicing, nuclear organization, and epigenetic modulation of gene expression. MALAT1 has also been implicated in metastasis and tumor proliferation in multiple cancer types. The 3' terminal stability element for nuclear expression (ENE) assumes a triple-helical configuration that promotes its nuclear accumulation and persistent function. Utilizing a novel small molecule microarray strategy, we identified multiple Malat1 ENE triplex-binding chemotypes, among which compounds 5 and 16 reduced Malat1 RNA levels and branching morphogenesis in a mammary tumor organoid model. Computational modeling and Förster resonance energy transfer experiments demonstrate distinct binding modes for each chemotype, conferring opposing structural changes to the triplex. Compound 5 modulates Malat1 downstream genes without affecting Neat1, a nuclear lncRNA encoded in the same chromosomal region as Malat1 with a structurally similar ENE triplex. Supporting this observation, the specificity of compound 5 for Malat1 over Neat1 and a virus-coded ENE was demonstrated by nuclear magnetic resonance spectroscopy. Small molecules specifically targeting the MALAT1 ENE triplex lay the foundation for new classes of anticancer therapeutics and molecular probes for the treatment and investigation of MALAT1-driven cancers.