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Tuberculosis is a highly lethal bacterial disease worldwide caused by Mycobacterium tuberculosis (Mtb). Caespitate is a phytochemical isolated from Helichrysum caespititium, a plant used in African traditional medicine that shows anti-tubercular activity, but its mode of action remains unknown. It is suggested that there are four potential targets in Mtb, specifically in the H37Rv strain: InhA, MabA, and UGM, enzymes involved in the formation of Mtb's cell wall, and PanK, which plays a role in cell growth. Two caespitate conformational structures from DFT conformational analysis in the gas phase (GC) and in solution with DMSO (CS) were selected. Molecular docking calculations, MM/GBSA analysis, and ADME parameter evaluations were performed. The docking results suggest that CS is the preferred caespitate conformation when interacting with PanK and UGM. In both cases, the two intramolecular hydrogen bonds characteristic of caespitate's molecular structure were maintained to achieve the most stable complexes. The MM/GBSA study confirmed that PanK/caespitate and UGM/caespitate were the most stable complexes. Caespitate showed favorable pharmacokinetic characteristics, suggesting rapid absorption, permeability, and high bioavailability. Additionally, it is proposed that caespitate may exhibit antibacterial and antimonial activity. This research lays the foundation for the design of anti-tuberculosis drugs from natural sources, especially by identifying potential drug targets in Mtb.
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Modulation of the CXCL12-CXCR4 signaling axis is of the utmost importance due to its central involvement in several pathological disorders, including inflammatory diseases and cancer. Among the different currently available drugs that inhibit CXCR4 activation, motixafortide-a best-in-class antagonist of this GPCR receptor-has exhibited promising results in preclinical studies of pancreatic, breast, and lung cancers. However, detailed information on the interaction mechanism of motixafortide is still lacking. Here, we characterize the motixafortide/CXCR4 and CXCL12/CXCR4 protein complexes by using computational techniques including unbiased all-atom molecular dynamics simulations. Our microsecond-long simulations of the protein systems indicate that the agonist triggers changes associated with active-like GPCR conformations, while the antagonist favors inactive conformations of CXCR4. Detailed ligand-protein analysis indicates the importance of motixafortide's six cationic residues, all of which established charge-charge interactions with acidic CXCR4 residues. Furthermore, two synthetic bulky chemical moieties of motixafortide work in tandem to restrict the conformations of important residues associated with CXCR4 activation. Our results not only elucidate the molecular mechanism by which motixafortide interacts with the CXCR4 receptor and stabilizes its inactive states, but also provide essential information to rationally design CXCR4 inhibitors that preserve the outstanding pharmacological features of motixafortide.
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Antineoplásicos , Receptores CXCR4 , Receptores CXCR4/metabolismo , Unión Proteica , Péptidos/metabolismo , Quimiocina CXCL12/metabolismoRESUMEN
PURPOSE: The authors aim to review available reports on the potential effects of masks on voice and speech parameters. METHODS: A literature search was conducted using MEDLINE and Google Scholar databases through July 2021. Several targeted populations, mask scenarios and methodologies were approached. The assessed voice parameters were divided into self-reported, acoustic and aerodynamic. RESULTS: It was observed that the wearing of a face mask has been shown to induce several changes in voice parameters: (1) self-reported-significantly increased vocal effort and fatigue, increased vocal tract discomfort and increased values of voice handicap index (VHI) were observed; (2) acoustics-increased voice intensity, altered formants frequency (F2 and F3) with no changes in fundamental frequency, increased harmonics-to-noise ratio (HNR) and increased mean spectral values in high-frequency levels (1000-8000 Hz), especially with KN95 mask; (3) aerodynamics-maximum phonatory time was assessed in only two reports, and showed no alterations. CONCLUSION: Despite the different populations, mask-type scenarios and methodologies described by each study, the results of this review outline the significant changes in voice characteristics with the use of face masks. Wearing a mask shows to increase the perception of vocal effort and an alteration of the vocal tract length and speech articulatory movements, leading to spectral sound changes, impaired communication and perception. Studies analyzing the effect of masks on voice aerodynamics are lacking. Further research is required to study the long-term effects of face masks on the potential development of voice pathology.
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Trastornos de la Voz , Voz , Acústica , Humanos , Fonación , Habla , Acústica del Lenguaje , Trastornos de la Voz/etiología , Trastornos de la Voz/prevención & control , Calidad de la VozRESUMEN
The cannabinoid receptors (CB1/CB2) and the T-type calcium channels are involved in disorders associated with both physiological pain and depressive behaviors. Valuable pharmacological species carbazole derivatives such as the NMP-4, NMP-7, and NMP-181 (Neuro Molecular Production) regulate both biological entities. In this work, DFT calculations were performed to characterize theoretically their structural and chemical reactivity properties using the BP86/cc-pVTZ level of theory. The molecular orbital contributions and the chemical reactivity analysis reveal that a major participation of the carbazole group is in the donor-acceptor interactions of the NMP compounds. The DFT analysis on the NMP compounds provides insights into the relevant functional groups involved during the ligand-receptor interactions. Molecular docking analysis is used to reveal possible sites of interaction of the NMP compounds with the Cav3.2 calcium channel. The interaction energy values and reported experimental evidence indicate that the site denominated as "Pore-blocking", which is formed mainly by hydrophobic residues and the T586 residue, is a probable binding site for the NMP compounds.
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Simulación del Acoplamiento MolecularRESUMEN
Transition metal-based compounds have shown promising uses as therapeutic agents. Among their unique characteristics, these compounds are suitable for interaction with specific biological targets, making them important potential drugs to treat various diseases. Copper compounds, of which Casiopeinas® are an excellent example, have shown promising results as alternatives to current cancer therapies, in part because of their intercalative properties with DNA. Vanadium compounds have been extensively studied for their pharmacological properties and application, mostly in diabetes, although recently, there is a growing interest in testing their activity as anti-cancer agents. In the present work, two compounds, [Cu(Metf)(bipy)Cl]Cl·2H2O and [Cu(Impy)(Gly)(H2O)]VO3, were obtained and characterized by visible and FTIR spectroscopies, single-crystal X-ray diffraction, and theoretical methods. The structural and electronic properties of the compounds were calculated through the density functional theory (DFT) using the Austin-Frisch-Petersson functional with dispersion APFD, and the 6-311 + G(2d,p) basis set. Non-covalent interactions were analyzed using Hirshfeld surface analysis (HSA) and atom in molecules analysis (AIM). Additionally, docking analysis to test DNA/RNA interactions with the Casiopeina-like complexes were carried out. The compounds provide metals that can interact with critical biological targets. In addition, they show interesting non-covalent interactions that are responsible for their supramolecular arrangements.
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Antineoplásicos/química , Cobre/química , Compuestos Organometálicos/química , Compuestos de Vanadio/química , Antineoplásicos/síntesis química , Cristalografía por Rayos X , ADN/química , ADN/metabolismo , Teoría Funcional de la Densidad , Simulación del Acoplamiento Molecular , Compuestos Organometálicos/síntesis química , ARN de Transferencia/química , ARN de Transferencia/metabolismo , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , Compuestos de Vanadio/síntesis químicaRESUMEN
The morphological, optical, and structural changes in crystalline chiral imines derived from 2-naphthaldehyde as a result of changing the -F, -Cl, and -Br halogen (-X) atoms are reported. Scanning electron microscopy (SEM), optical absorption, photoluminescence (PL), and powder X-ray diffraction (XRD) studies were performed. Theoretical results of optical and structural properties were calculated using the PBE1PBE hybrid functional and compared with the experimental results. Differences in surface morphology, absorbance, XRD, and PL of crystals were due to the change of halogen atoms in the chiral moiety of the imine. Absorption spectra exhibited the typical bands of the naphthalene chromophore located in the ~200-350 nm range. Observed absorption bands in the UV region are associated with πâπ* and nâπ* electronic transitions. The band gap energy was calculated using the Tauc model. It showed a shift in the ~3.5-4.5 eV range and the crystals exhibited different electronic transitions associated with the results of absorbance in the UV region. XRD showed the monoclinicâorthorhombic crystalline phase transition. PL spectra displayed broad bands in the visible region and all the samples have an emission band (identified as a green emission band) in the ~400-750 nm range. This was associated with defects produced in the morphology, molecular packing, inductive effect and polarizability, crystalline phase transition, and increase in size of the corresponding halogen atoms; i.e., changes presumably induced by -C-X X-, -C-X N-, -C-N π, and -C-X π interactions in these crystalline materials were associated with morphological, optical, and structural changes.
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Teoría Funcional de la Densidad , Halogenación , Iminas/química , Mediciones Luminiscentes , Cristalografía por Rayos X , Conformación Molecular , Fenómenos Ópticos , Electricidad EstáticaRESUMEN
We report single crystal X-ray diffraction (hereafter, SCXRD) analyses of derivatives featuring the electron-donor N-ethylcarbazole or the (4-diphenylamino)phenyl moieties associated with a -CN group attached to a double bond. The compounds are (2Z)-3-(4-(diphenylamino)-phenyl)-2-(pyridin-3-yl)prop-2-enenitrile (I), (2Z)-3-(4-(diphenylamino)phenyl)-2-(pyridin-4-yl)-prop-2-enenitrile (II) and (2Z)-3-(9-ethyl-9H-carbazol-3-yl)-2-(pyridin-2-yl)enenitrile (III). SCXRD analyses reveal that I and III crystallize in the monoclinic space groups P2/c with Z' = 2 and C2/c with Z' = 1, respectively. Compound II crystallized in the orthorhombic space group Pbcn with Z' = 1. The molecular packing analysis was conducted to examine the pyridine core effect, depending on the ortho, meta- and para-positions of the nitrogen atom, with respect to the optical properties and number of independent molecules (Z'). It is found that the double bond bearing a diphenylamino moiety introduced properties to exhibit a strong π-π-interaction in the solid state. The compounds were examined to evaluate the effects of solvent polarity, the role of the molecular structure, and the molecular interactions on their self-assembly behaviors. Compound I crystallized with a cell with two conformers, anti and syn, due to interaction with solvent. DFT calculations indicated the anti and syn structures of I are energetically stable (less than 1 eV). Also electrochemical and photophysical properties of the compounds were investigated, as well as the determination of optimization calculations in gas and different solvent (chloroform, cyclohexane, methanol, ethanol, tetrahydrofuran, dichloromethane and dimethyl sulfoxide) in the Gaussian09 program. The effect of solvent by PCM method was also investigated. The frontier HOMO and LUMO energies and gap energies are reported.
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Acrilonitrilo/química , Carbazoles/química , Estructura Molecular , Acrilonitrilo/síntesis química , Carbazoles/síntesis química , Cristalografía por Rayos X , Electrones , Modelos Moleculares , Piridinas/químicaRESUMEN
The synthesis and characterization of the precursor isomers trans-4-(2-(pyridin-2-yl)vinylbenzaldehyde (I), trans-4-(2-(pyridin-4-yl)vinylbenzaldehyde (II), trans-4-(2-(pyridin-2-yl)vinylbenzoic acid (III) and (E)-4-(2-(pydridin-4-yl)vinylbenzoic acid (IV) are reported. These compounds were prepared in order to obtain trans-4-((E)-2-(pyridin-2-yl)vinyl)benzamide-TEMPO (V). Compounds I and II were obtained by using a Knoevenagel reaction in the absence of a condensing agent and solvent. Oxidation of the aldehyde group using the Jones reagent afforded the corresponding acid forms III and IV. A condensation reaction with 4-amino-TEMPO using oxalyl chloride/DMF/CH2Cl2 provided the 4-((E)-2-(pyridin-2-yl)vinyl)benzamide-TEMPO. Single crystals of compounds I, II and III were obtained and characterized by X-ray diffraction. Compound I belongs to space group P2(1)/c, a = 12.6674(19) Å, b = 7.2173(11) Å, c = 11.5877(14) Å, b = 97.203(13)° and the asymmetric unit was Z = 4, whereas compound II was in the space group P2(1), with a = 3.85728(9) Å, b = 10.62375(19) Å, c = 12.8625(2) Å, b = 91.722 (2)° and the asymmetric unit was Z = 2. Compound III crystallized as single colorless needle crystals, belonging to the monoclinic system with space group P2(1), with Z = 2, with a = 3.89359(7) Å, b = 17.7014(3) Å, c = 8.04530(12) Å, b = 94.4030 (16)°. All compounds were completely characterized by IR, (1)H-NMR, EI-MS and UV-Vis.
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Benzaldehídos/química , Benzaldehídos/síntesis química , Ácido Benzoico/química , Ácido Benzoico/síntesis química , Cristalografía por Rayos X , Óxidos N-Cíclicos/química , Isomerismo , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Piridinas/químicaRESUMEN
Citrulline (C6H13N3O3) is an amino acid found in the body as a zwitterion. This means its carboxylic and amine groups can act as Lewis donors to chelate metal cations. In addition, citrulline possesses a terminal ureido group on its aliphatic chain, which also appears to coordinate. Here, two new mixed complexes of citrulline were made with 1,10-phenanthroline and 2,2'-bipyridine. These compounds, once dissolved in water, gave aquo-complexes that were subject to DFT studies and in vitro toxicity studies on cancer cell lines (HeLa, MDA-MB-231, HCT 15, and MCF7) showed promising results. Docking studies with DNA were also conducted, indicating potential anticancer properties.
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A combined theoretical and experimental study on the structure, infrared, UV-Vis and 1H NMR data of trans-2-(m-cyanostyryl)pyridine, trans-2-[3-methyl-(m-cyanostyryl)]pyridine and trans-4-(m-cyanostyryl)pyridine is presented. The synthesis was carried out with an efficient Knoevenagel condensation using green chemistry conditions. Theoretical geometry optimizations and their IR spectra were carried out using the Density Functional Theory (DFT) in both gas and solution phases. For theoretical UV-Vis and 1H NMR spectra, the Time-Dependent DFT (TD-DFT) and the Gauge-Including Atomic Orbital (GIAO) methods were used, respectively. The theoretical characterization matched the experimental measurements, showing a good correlation. The effect of cyano- and methyl- substituents, as well as of the N-atom position in the pyridine ring on the UV-Vis, IR and NMR spectra, was evaluated. The UV-Vis results showed no significant effect due to electron-withdrawing cyano- and electron-donating methyl-substituents. The N-atom position, however, caused a slight change in the maximum absorption wavelengths. The IR normal modes were assigned for the cyano- and methyl-groups. 1H NMR spectra showed the typical doublet signals due to protons in the trans position of a double bond. The theoretical characterization was visibly useful to assign accurately the signals in IR and 1H NMR spectra, as well as to identify the most probable conformation that could be present in the formation of the styrylpyridine-like compounds.
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SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.
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OBJECTIVES/HYPOTHESIS: Vocal fold sulcus and scars are benign vocal fold lesions that present as a challenge to the laryngologist. A number of different surgical techniques have been proposed, aiming at restoring the lamina propria (LP), closing the glottal gap, or both. This study aimed to provide a systematic review of surgical treatment for sulcus and scar and to propose a new classification for these techniques. STUDY DESIGN: A literature search using MEDLINE and Google Scholar through August 2020. METHODS: Data on study design were retrieved and outcomes were classified as acoustic, aerodynamic, self-reported, perceptual, and stroboscopic. Methodological quality was assessed using the MINORs criteria. Each technique was classified as direct, indirect, or combined. RESULTS: Our search included 31 studies with a total of 617 patients. Direct techniques included dissection, graft interposition, or LP regeneration/scar degradation while indirect techniques aimed for glottal gap closure. Only one article performed a comparison between different types of techniques and only eight studied the five types of outcomes. No superiority of any technique was noted in our analysis. Self-reported outcomes were the most frequently improved. CONCLUSIONS: There seems to not exist a one-fits-all treatment for this clinical picture and no clear decision-making pattern. A recent trend toward sequential approaches, starting with less invasive procedures, can be observed. Laryngoscope, 132:822-830, 2022.
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Cicatriz , Pliegues Vocales , Acústica , Cicatriz/etiología , Cicatriz/patología , Cicatriz/cirugía , Humanos , Músculos Laríngeos/patología , Estroboscopía , Pliegues Vocales/patología , Pliegues Vocales/cirugíaRESUMEN
The anandamide is a relevant ligand due to its capacity of interacting with several proteins, including the T-type calcium channels, which play an important role in neuropathic pain and depression disorders. Hence, a detailed characterization of the chemical properties and conformational stability of anandamide may provide valuable information to understand its behavior in a biological context. Herein, conceptual DFT and QTAIM analyses were performed to theoretically characterize the chemical reactivity properties and the structural stability of conformations of anandamide, using the BP86/cc-pVTZ level of theory. Global reactivity description, based on conceptual DFT, indicates that the hardness increases and the electrophilicity index decreases for both, the hairpin and U-shape conformers relative to the extended conformers. Also, an increase in the chemical potential value and a decrease in the electronegativity and the electrophilicity index is observed in the ethanolamide open ring conformers in comparison with the corresponding closed ring structures. In addition, regarding the characterization of local reactivity descriptors, the maximum values of the Fukui and Parr functions indicate that the most probable location for a nucleophilic attack is either the hydroxyl oxygen located in the ethanolamide closed ring conformers or the carbonyl oxygen present in the open ring conformers. The most probable location for an electrophilic attack is in the alkyl double bond region in all anandamide conformers. According to the QTAIM results, the intramolecular hydrogen bond formation stabilizing the structure of anandamide has interaction energy values for the closed ring conformations of 12.33-12.46 kcal mol-1, indicating a strong interaction. Lastly, molecular docking calculations determined that a region in the pore, denominate as pore-blocking, is a probable site for the interaction of anandamide with the human Cav3.2 isoform of the T-type calcium channel family. The pore-blocking site contains hydrophobic residues where the non-polar part in the final alkyl region of anandamide established mainly alkyl-alkyl interactions, while the polar part (the ethanolamide group) interacts with the polar residue S900. The information based on conceptual DFT presented may aid in the design of drugs with similar chemical characteristics as those identified in anandamide so as to bind anandamide-interacting proteins, including the T-type calcium channels.
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The synthesis and theoretical-experimental characterization of a novel diprotanated decavanadate is presented here due to our search for novel anticancer metallodrugs. Tris(2-pyridylmethyl)amine (TPMA), which is also known to have anticancer activity in osteosarcoma cell lines, was introduced as a possible cationic species that could act as a counterpart for the decavanadate anion. However, the isolated compound contains the previously reported vanadium (V) dioxido-tpma moieties, and the decavanadate anion appears to be diprotonated. The structural characterization of the compound was performed by infrared spectroscopy and single-crystal X-ray diffraction. In addition, DFT calculations were used to analyze the reactive sites involved in the donor-acceptor interactions from the molecular electrostatic potential maps. The level of theory mPW1PW91/6-31G(d)-LANL2DZ and ECP = LANL2DZ for the V atom was used. These insights about the compounds' main interactions were supported by analyzing the noncovalent interactions utilizing the AIM and Hirshfeld surfaces approach. Molecular docking studies with small RNA fragments were used to assess the hypothesis that decavanadate's anticancer activity could be attributed to its interaction with lncRNA molecules. Thus, a combination of three potentially beneficial components could be evaluated in various cancer cell lines.
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INTRODUCTION: Patient-reported outcome measures (PROMs) are important for systematically assessing a person's perspectives and experiences with disease to inform clinical decision-making. However, PROMs can occasionally fail to capture subtle differences amongst subgroups. In response to this problem, the aim of the current study was to examine the convergent validity of four patient-reported voice activity and participation scales to better reflect and describe the impact of a voice problem in a patient's work, home, social and overall life. It was hypothesized that augmenting the validated PROM with a directed situational short instrument may enhance patient and clinician communication. This would allow for further description of individual areas of activity limitations or participation restrictions that are relevant to the patient, potentially informing therapeutic goals. METHODS: The Voice Problem Impact Scales (VPIS) were developed following the criteria outlined by Francis et al (2016). A retrospective chart review was completed for voice therapy treatment seeking patients at the USC Voice Center. Results from the Voice Handicap Index-10 (VHI-10) and VPIS scores were recorded at the time of the evaluation. Consensus Auditory Perceptual Evaluation of Voice (CAPE-V) assessment was performed by an SLP with fellowship training in voice. RESULTS: Three hundred four charts were reviewed, and 198 met inclusion criteria. When considering all patients, VHI-10 scores were significantly correlated with each domain of the VPIS, including overall (R = 0.635, P < 0.001), work (R = 0.436, P < 0.001), social (R = 0.714, P < 0.001), and home (R = 0.637, P < 0.001). For females aged 18-39 and aged ≥60, the VHI-10 was correlated with all domains except work. CAPE-V score was significantly correlated with the social domain (R = 0.236, P = 0.001). Using the corrected significance level, it was not correlated with the overall (R = 0.165, P = 0.022), home (R = 0.197, P = 0.006), or work domains (R = 0.042, P = 0.567). The VHI-10 was not correlated with any of the VPIS domains for males aged 18-39, was correlated with all domains for males aged 40-59, and was correlated with all domains except work for males aged ≥60. Age was the only significant predictor of the work domain (ß = -4.631 P < 0.001), with a model fit of R2 = 0.101. CONCLUSIONS: Scores from each domain of the VPIS are significantly correlated with VHI-10 scores thus confirming the instrument's convergent validity. There are certain groups for which currently used questionnaires may underrepresent the impact of dysphonia on the patient's life. The VPIS represents a broad tool that might allow the patient to interpret each scale within their individual context and cultural background. The VPIS emphasizes the significance of the dysphonia on quality of life in four common environments. Using this instrument can augment questionnaires and initiate conversations between the provider and patient to determine the area(s) where voice impairment is most important enhancing shared decision-making on therapeutic goals for plan of care.
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Regulation of cellular excitability and oscillatory behavior of resting membrane potential in nerve cells are largely mediated by the low-voltage activated T-type calcium channels. This calcium channel family is constituted by three isoforms, namely, CaV3.1, CaV3.2, and CaV3.3, that are largely distributed in the nervous system and other parts of the body. Dysfunction of T-type calcium channels is associated with a wide range of pathophysiologies including epilepsy, neuropathic pain, cardiac problems, and major depressive disorders. Due to their pharmacological relevance, finding molecular agents able to modulate the channel's function may provide therapeutic means to ameliorate their related disorders. Here we used electrophysiological experiments to show that genistein, a canonical tyrosine kinase inhibitor, reduces the activity of the human CaV3.3 channel in a concentration-dependent manner. The inhibitory effect of genistein is independent of tyrosine kinase modulation and does not affect the voltage-dependent gating of the channel. Subsequently, we used computational methods to identify plausible molecular poses for the interaction of genistein and the CaV3.3 channel. Starting from different molecular poses, we carried out all-atom molecular dynamics (MD) simulations to identify the interacting determinants for the CaV3.3/genistein complex formation. Our extensive (microsecond-length) simulations suggest specific binding interactions that seem to stabilize the protein/inhibitor complex. Furthermore, our results from the unbiased MD simulations are in good agreement with the recently solved cryoelectron microscopy structure of the CaV3.1/Z944 complex in terms of both the location of the ligand binding site and the role of several equivalent amino acid residues. Proposed interacting complex loci were subsequently tested and corroborated by electrophysiological experiments using another naturally occurring isoflavone derivative, daidzein. Thus, by using a combination of in vitro and in silico techniques, we have identified interacting determinants relevant to the CaV3.3/genistein complex formation and propose that genistein directly blocks the function of the human CaV3.3 channel as a result of such interaction. Specifically, we proposed that a combination of polar interactions involving the three hydroxyl groups of genistein and an aromatic interaction with the fused rings are the main binding interactions in the complex formation. Our results pave the way for the rational development of improved and novel low-voltage activated T-type calcium channel inhibitors.
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Canales de Calcio Tipo T , Trastorno Depresivo Mayor , Isoflavonas , Microscopía por Crioelectrón , Genisteína/farmacología , HumanosRESUMEN
The synthesis of six Mannich bases derived from hydroxycoumarins was carried out in moderate yields, two of these derivatives were described for the first time. Conformational analysis was performed through DFT theoretical calculations explaining the formation of stable six membered rings based on intramolecular hydrogen bonds within the structure. These findings were correlated with the antiproliferative activity. The biological activity of the Mannich bases through their antiproliferative activity in the HeLa cancer cell line is described for the first time, showing that the compounds were able to inhibit proliferation in cervical cancer by more than 60%. Likewise, the theoretical modeling of the photophysical properties was realized with promising results, showing that the HOMO-LUMO energies of the new compounds present the lowest electronic gap values for those with donor groups in their structure, which makes them potential fluorophores.
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INTRODUCTION: Celiac disease (CD) is a gluten-sensitive enteropathy characterized by a chronic injury of the small bowel, caused by gluten intolerance in genetically predisposed individuals. The different forms of presentation of CD resemble more a multisystem disorder than a primary gastrointestinal disease and it is frequently underdiagnosed. OBJECTIVE: To determine the prevalence of CD diagnosis in the population of affiliates to the HMO of the Hospital Italiano de Buenos Aires. METHODS: This is a cross sectional study, using secondary databases of diagnosis and laboratory from the electronic medical record (EMR) in a HMO population between 1998 and 2006. The criteria used to define a case was based on a diagnosis of CD in the EMR and/or a IgA antitransglutaminase antibodies value >15 AU/mL. RESULTS: According to these criteria, 283 patients with CD were identified in 128,748 individuals of the HMO. The prevalence of CD was 0.22%. The mean age of this group was of 42.3 years, and 80.2% of them were female. CONCLUSIONS: In a primary care HMO setting, using secondary databases from EMR we found 1 case of celiac disease every 470 affiliates, giving a prevalence of 0.22%. The rate between serological prevalence of CD and clinical diagnosis carried out in our center was near 3.3 to 1. Although this level of diagnosis could be considered relatively high, an important proportion of patients are left without diagnosis, considering the local estimated prevalence reported using serological tests. An increased level of awareness and clinical suspicion is needed at the primary care level.
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Enfermedad Celíaca/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Argentina/epidemiología , Autoanticuerpos/sangre , Enfermedad Celíaca/diagnóstico , Niño , Preescolar , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Hospitales Comunitarios , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Transglutaminasas/inmunología , Adulto JovenRESUMEN
Over the last decade, copper and vanadium complexes have shown promising properties for the treatment of several types of cancer. In particular, Casiopeinas®, a group of copper-based complexes, has received specific attention, and their mechanism of action has been extensively studied since their structure is simple and their synthesis may be affordable. Similarly, vanadium-containing compounds in the form of complexes and simple polyoxovanadates have also been studied as antitumor agents. Here, potential prodrugs that would release the two metals, V and Cu, in usable form to act in conjunction against cancer cells are reported. The new series of Casiopeinas-like compounds are bridged by a cyclotetravanadate ion with the generic formula [Cu(N,N')(AA)]2â¢(V4O12), where (N,N') represent 1,10-phenanthroline and 2,2'-bipyridine, and (AA) are aminoacidate ions (Lysine and Ornithine). The compounds were characterized by elemental analysis, single-crystal X-ray diffraction and Visible, FTIR, and Raman spectroscopies, as well as 51V NMR, EPR, and Thermogravimetric Analysis. Additionally, theoretical calculations based on the Density Functional Theory (DFT) were carried out to model the compounds. Optimized structures, theoretical IR, and Raman spectra were also obtained, as well as docking analysis to test DNA interactions with the casiopeina-like complexes. The compounds may act as prodrugs by providing acting molecules that have showed potential pharmacological properties for the treatment of several types of cancer.
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Antineoplásicos , Complejos de Coordinación , Cobre , Neoplasias/tratamiento farmacológico , Profármacos , Vanadatos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Cobre/química , Cobre/farmacología , Humanos , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Vanadatos/síntesis química , Vanadatos/química , Vanadatos/farmacologíaRESUMEN
Photodynamic therapy (PDT) is an alternative treatment widely used against cancer. PDT requires molecular systems, known as photosensitizers (PS), which not only exhibit strong absorption at a particular wavelength range, but also need to be selectively accumulated inside cancer cells. PS are activated by specific wavelengths that cause tumor cell death by mechanisms related with oxidative stress. In this paper, three oxidovanadium(V) complexes linked to a Schiff base, which exhibit anticancer activity by displaying desirable accumulation inside malignant cells, are studied using Density Functional Theory (DFT) and Time Dependent-DFT (TD-DFT) methodologies to characterize their structural and photophysical properties as possible PS. The maximum absorption of these complexes in aqueous solution was predicted to be approximately 460â¯nm presenting a ligand-to-metal charge transfer. Additionally, we describe the photodynamic type reaction that these complexes can undergo when considered as PS candidates. Our results suggest that the system, containing triethylammonium as substituent, is the most suitable complex to act both as PS and as a possible therapeutic candidate in PDT.