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On the basis of the observed biological activity of coumarin and acrylamide derivatives, a new set of coumarin-acrylamide-CA-4 hybrids was designed and synthesized. These compounds were investigated for their cytotoxic activity against cancerous human liver cell line HepG2 cells using 5-fluorouracil (5-FU) as a reference drug. Compound 6e had promising antiproliferative activity with an IC50 value of 1.88 µM against HepG2 cells compared to 5-FU (IC50 = 7.18 µM). The results of ß-tubulin polymerization inhibition indicated that coumarin-acrylamide derivative 6e was the most active, with a percentage inhibition value of 84.34% compared to podophyllotoxin (88.19% ß-tubulin inhibition). Moreover, the active coumarin-acrylamide molecule 6e exerted cell cycle cession at the G2/M phase stage of HepG2 cells. In addition, this compound produced a 15.24-fold increase in apoptotic cell induction compared to no-treatment control. These observations were supported by histopathological studies of liver sections. The conducted docking studies illustrated that 6e is perfectly positioned within the tubulin colchicine binding site, indicating a significant interaction that may underlie its potent tubulin inhibitory activity. The main objective of the study was to develop new potent anticancer compounds that might be further optimized to prevent the progression of cancer disease.
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A variety of 3-(4-chlorophenyl) acrylic acids 4a,b and 3-(4-chlorophenyl)acrylate esters 5a-i were synthesized and structurally proven by spectroscopic studies such as IR, 1H NMR, and 13C NMR as well as mass spectrometry. All substances were investigated for their antiproliferative efficacy against the MDA-MB-231 cell line. Among these, acrylic acid compound 4b demonstrated the most potent cytotoxic effect with an IC50 value of 3.24 ± 0.13 µM, as compared to CA-4 (IC50 = 1.27 ± 09 µM). Additionally, acrylic acid molecule 4b displayed an inhibitory effect against ß-tubulin polymerization with a percentage inhibition of 80.07%. Furthermore, compound 4b was found to produce considerable cell cycle arrest at the G2/M stage and cellular death, as demonstrated by FACS analysis. In addition, the in vivo antitumor screening of the sodium salt of acrylic acid 4b was carried out, and the results have shown that the tested molecule showed a significant decrease in viable EAC count and EAC volume, accompanied by a considerable increase in the life span prolongation, if compared to the positive control group. Furthermore, molecular modeling studies were performed to understand how the highly efficient chemicals 4b and 5e interact with the colchicine-binding region on tubulin. This work aims to shed light on the reasons behind their exceptional cytotoxicity and their better capacity to inhibit tubulin in comparison to CA-4.
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Disubstituted five-membered heterocycles (1,2,4-triazole and 1,3,4 oxadiazole) were synthesized and investigated as inhibitors for signal transducer and activator of transcription 3 (STAT3) enzyme of breast cancer. 3-(Benzylthio)-5-(4-chlorobenzyl)-4H-1,2,4-triazol-4-amine (12d) was found to be the most active among the synthesized compounds with a half-maximal inhibitory concentration (IC50 ) value of 1.5 µM on MCF7 cells and was found to show a great inhibitory effect on the STAT3 enzyme. Compounds 9a,b,d,e,f, 11, and 12a,b,f,e show IC50 values in the range of 3-12 µM for the MCF7 cell line. Molecular modeling was used to investigate the biological results of the synthesized compounds.
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Neoplasias da Mama , Humanos , Feminino , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias da Mama/tratamento farmacológico , Fator de Transcrição STAT3 , Oxidiazóis/farmacologia , Simulação de Acoplamento MolecularRESUMO
Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 µM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kß, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1ß, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.
Three series of curcumin-based analogs, incorporating other heterocycles, were synthesised with the intention of exploring their potential as anti-inflammatory agents.Subsequently, these analogs underwent biological assessment in macrophages induced by LPS to determine their anti-inflammatory efficacy.Among the fourteen coumarin derivatives synthesised, the most potent anti-inflammatory activity was observed in the coumarin compound 14b, which featured a 3,4-dimethoxybenzylidene hydrazinyl moiety, with an EC50 value of 5.32 µM.The anti-inflammatory effects of compound 14b were achieved through the modulation of signalling pathways such as AKT/mTOR and Nrf2/HO-1, as well as the downregulation of NF-kß, resulting in decreased production of pro-inflammatory cytokines including IL-6, IL-1ß, and TNF-α.Molecular modelling studies revealed that both compound 14b and dexamethasone bind to the same binding site on TNF-α, suggesting that 14b has the potential to serve as a therapeutic agent for TNF-α and other pro-inflammatory cytokines that surpasses that of dexamethasone.
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Anti-Inflamatórios , Cumarínicos , Curcumina , NF-kappa B , Humanos , Anti-Inflamatórios/farmacologia , Cumarínicos/farmacologia , Curcumina/farmacologia , Citocinas/metabolismo , Dexametasona/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos , Macrófagos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This research aims to use eco-friendly Corallina officinalis as an adsorbent for removing harmful malachite green dye streams from industrial effluent, promoting sustainable living and effective microbial growth inhibition. Corallina officinalis biomass was tested for textile dye biosorption, as well as its antibacterial, antioxidant, and cytotoxic properties. The effects of certain parameters, involving pH solution, initial dye concentration, algae dose, and contact time, were investigated on the sorption of dye. Fourier transform infrared spectroscopy and scanning electron microscopy were also used and, the results showed that the functional groups on the surface of algae played an important part in the biosorption process. It was noted that the kinetic data were significantly prominent by the Pseudo-second-order model with regression correlation coefficient [Formula: see text] values with an average of 0.95232. The biosorption was compatible with both the Freundlich (R2 = 0.9843), and Langmuir (R2 = 0.9653) isotherms, and the maximum removal efficiency for dye reached up to 99.9% in 2 h, 27 °C, stirring speed 120 rpm, pH 6, initial dye concentration 20 mg L-1, and biomass dose 0.03 g L-1. Corallina officinalis had higher antimicrobial activity, with values of minimum inhibitory concentrations ranging from 0.156 to 5 mg mL-1. Corallina officinalis exerted significant radical scavenging activity against tested free radicals. The extract was examined for cytotoxic activity using nine cancer cell lines, which exhibited high cytotoxicity for colon adenocarcinoma with an IC50 value of 25.895 µg mL-1.
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Adenocarcinoma , Neoplasias do Colo , Rodófitas , HumanosRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predisposed to the emergence of worldwide catastrophe that impels the evolution of safe and effective therapeutic system. Polyphenols as resveratrol (RSV) exhibit a well evidenced antiviral activity. Unfortunately, like most phenolic nutraceuticals, RSV suffers from restrained solubility and massive degradation in GIT and liver which in turn prohibit its clinical use. Herein, PEGylated bilosomes (PBs) contain PEGylated edge activator along with the traditional components as (Span 60, cholesterol and bile salts) were proposed to boost both permeability and bioavailability of RSV. The investigation of the prominent effect of the diverse variables on the characteristics of the vesicles and picking of the optimum formula were conducted via construction of 23 factorial experiment. The appraisal of the formulae was conducted on the basis of entrapment efficiency percent (EE%), particle size (PS) and zeta potential (ZP). In addition, the spherical shaped optimal formula (F5) exhibited EE% of 86.1 ± 2.9%, PS of 228.9 ± 8.5 nm, and ZP of -39.8 ± 1.3 mV. The sorted optimum formula (F5) exhibited superior dissolution behaviors, and boosted Caco-2 cells cellular uptake by a round 4.7 folds relative to RSV dispersion. In addition, F5 demonstrated a complete in vitro suppression of SARS-CoV-2 at a concentration 0.48 µg/ml with 6.6 times enhancement in antiviral activity relative to RSV dispersion. The accomplished molecular modeling heavily provided proof for the possible interactions of resveratrol with the key residues of the SARS-CoV2 Mpro enzyme. Finally, F5 could be proposed as a promising oral panel of RSV for curation from SARS-CoV-2 infection.
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COVID-19 , SARS-CoV-2 , Humanos , Células CACO-2 , Resveratrol/farmacologia , Antivirais/farmacologia , RNA Viral , Polietilenoglicóis , Permeabilidade , Tamanho da PartículaRESUMO
A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of ß-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit ß-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.
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Antineoplásicos , Nanopartículas , Amidas/farmacologia , Antineoplásicos/farmacologia , Bibenzilas , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Solubilidade , Estilbenos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologiaRESUMO
Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat experimental model. The PEGylated edge activator combined with the conventional components of chylomicrons (CMs) amplify the transport of the drug across the intestine and its circulation period, hence its therapeutic impact. The implementation of variables in the in vitro characterization of the vesicles was investigated. Using Design Expert® software, a 24 factorial design was conducted, and the resulting PCM formulations were fabricated utilizing a thin-film hydration technique. The efficacy of the formulations was assessed according to their zeta potential (ZP), entrapment efficiency percentage (EE%), amount of drug released after 8 h (Q8h), and particle size (PS) data. Formulation F9, which was deemed to be the optimal formula, used compritol as the lipidic core together in defined amounts with phosphatidylcholine (PC) and Brij52. Computer-aided studies revealed that MH alone in a suspension had both diminished intestinal permeability and absorption, but was enhanced when loaded in PCMs. This was affirmed by the superiority of formulation F9 results in ex vivo permeation and pharmacokinetic studies. Furthermore, formulation F9 had a superior safety profile and antiviral activity over a pure MH suspension. Molecular-docking studies revealed the capability of MH to inhibit MERS-CoV 3CLpro, the enzyme shown to exhibit a crucial role in viral replication. Additionally, F9 suppressed both MERS-CoV-induced histopathological alteration in lung tissue and resulting oxidative and inflammatory biomarkers. Collectively, the results reported herein affirmed the potential of PCMs as nanocarriers for the effective oral administration of MH as an antiviral.
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VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the "DFG out" motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound's oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).
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STAT3 signaling is known to be associated with tumorigenesis and further cancer cell-intrinsic activation of STAT3 leads to altered regulation of several oncogenic processes. Given the importance of STAT3 in cancer development and progression particularly breast cancer, it is crucial to discover new chemical entities of STAT3 inhibitor to develop anti-breast cancer drug candidates. Herein, 4-benzyl-2-benzylthio-5-methyl-1H-imidazole (2a) and 4-benzyl-5-methyl-2-[(2,6-difluorobenzyl)thio]-1H-imidazole (2d) from a group of thirty imidazole-bearing compounds showed greater STAT3 inhibition than their lead compounds VS1 and the oxadiazole derivative MD77. Within all tested compounds, ten derivatives effectively inhibited the growth of the two tested breast cancer cells with IC50 values ranging from 6.66 to 26.02 µM. In addition, the most potent derivatives 2a and 2d inhibited the oncogenic function of STAT3 as seen in the inhibition of colony formation and IL-6 production of breast cancer cell lines. Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the STAT3-SH2 domain. Collectively, our present study suggests 2-substituted-4-benzyl-5-methylimidazoles are a new class of anti-cancer drug candidates to inhibit oncogenic STAT3 function.
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Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/química , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Interleucina-6/metabolismo , Simulação de Acoplamento Molecular , Fator de Transcrição STAT3/antagonistas & inibidores , Relação Estrutura-Atividade , Domínios de Homologia de srcRESUMO
A limited range of redox-active, rotaxane-based, molecular switches exist, despite numerous potential applications for them as components of nanoscale devices. We have designed and synthesised a neutral, redox-active [2]rotaxane, which incorporates an electron-deficient pyromellitic diimide (PmI)-containing ring encircling two electron-rich recognition sites in the form of dioxynaphthalene (DNP) and tetrathiafulvalene (TTF) units positioned along the rod section of its dumbbell component. Molecular modeling using MacroModel guided the design of the mechanically interlocked molecular switch. The binding affinities in CH(2)Cl(2) at 298 K between the free ring and two electron-rich guests--one (K(a) = 5.8 × 10(2) M(-1)) containing a DNP unit and the other (K(a) = 6.3 × 10(3) M(-1)) containing a TTF unit--are strong: the one order of magnitude difference in their affinities favouring the TTF unit suggested to us the feasibility of integrating these three building blocks into a bistable [2]rotaxane switch. The [2]rotaxane was obtained in 34% yield by relying on neutral donor-acceptor templation and a double copper-catalysed azide-alkyne cycloaddition (CuAAC). Cyclic voltammetry (CV) and spectroelectrochemistry (SEC) were employed to stimulate and observe switching by this neutral bistable rotaxane in solution at 298 K, while (1)H NMR spectroscopy was enlisted to investigate switching upon chemical oxidation. The neutral [2]rotaxane is a chemically robust and functional switch with potential for applications in device settings.
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Rotaxanos/química , Ciclização , Estrutura Molecular , OxirreduçãoRESUMO
BACKGROUND: Age-related macular degeneration (ARMD) is the leading cause of blindness in people over 65 years of age. A rapid loss of vision occurs especially in cases with choroidal neovascularisation. Early detection of ARMD and timely treatment are mandatory. We have prospectively studied the results of two diagnostic self tests for the early detection of metamorphopsia and scotoma, the PHP test and the Amsler grid test, in different stages of ARMD. PATIENTS AND METHODS: Patients with ARMD and best corrected visual acuity of 6/30 or better (Snellen charts) were examined with a standardised protocol, including supervised Amsler grid examination and PHP, a new device for metamorphopsia or scotoma measurement, based on the hyperacuity phenomenon in the central 14 degrees of the visual field. The stages of ARMD were independently graded in a masked fashion by stereoscopic ophthalmoscopy, stereoscopic fundus colour photographs, fluorescein angiography, and OCT. The patients were subdivided into 3 non-neovascular groups [early, late (RPE atrophy > 175 microm) and geographic atrophy], a neovascular group (classic and occult CNV) and an age-matched control group (healthy volunteers). RESULTS: 140 patients, with ages ranging from 50 to 90 years (median 68 years), were included in the study. Best corrected visual acuity ranged from 6/30 to 6/6 with a median of 6/12. 95 patients were diagnosed as non-neovascular ARMD. Thirty eyes had early ARMD (9 were tested positive by the PHP test and 9 by the Amsler grid test), and 50 late ARMD (positive: PHP test 23, Amsler grid test 26). The group with geographic atrophy consisted of 15 eyes (positive: PHP test 13, Amsler grid test 10). Forty-five patients presented with neovascular ARMD (positive: PHP test 38, Amsler grid test 36), 34 volunteers served as control group (positive: PHP test 1, Amsler grid test 5). CONCLUSIONS: The PHP and Amsler grid tests revealed comparable results detecting metamorphopsia and scotoma in early ARMD (30 vs. 30 %) and late ARMD (46 vs. 52 %). However, the PHP test more often revealed disease-related functional changes in the groups of geographic atrophy (87 vs. 67 %) and neovascular ARMD (84 vs. 80 %). This implies that the PHP and Amsler grid self tests are useful tools for detection of ARMD and that the PHP test has a greater sensitivity in the groups of geographic atrophy and neovascular AMD.
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Diagnóstico por Computador/métodos , Degeneração Macular/diagnóstico , Testes de Campo Visual/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Autoexame/instrumentação , Autoexame/métodos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Acuidade VisualRESUMO
A new methodology for focusing ultrasonic beams noninvasively in the presence of the rib cage is investigated. This investigation is motivated by the need to employ high intensity focused ultrasound (HIFU) using phased array applicators for the treatment of liver tumors partially shadowed by the rib obstacles. This approach enables us to efficiently perform the ultrasound computational analysis and pattern synthesis in the interior region of the rib cage. The proposed technique consists of two main steps. First, a virtual array is introduced along the intercostal spacings between the solid ribs to generate the prespecified intensity levels at a set of control points within the target region. The second step involves the design of the actual feed array that induces the virtual sources between the intercostal spacings. This design optimization is carried out via the pseudo-inverse technique (minimum norm least squares solution) and by enforcing a constrained preconditioned pseudo-inverse method. The proposed procedure calculates the required primary sources (feed array) while maintaining minimal power deposition over the solid obstacles.
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A computationally efficient hybrid ray-physical optics (HRPO) model is presented for the analysis and synthesis of multiple-focus ultrasound heating patterns through the human rib cage. In particular, a ray method is used to propagate the ultrasound fields from the source to the frontal plane of the rib cage. The physical-optics integration method is then employed to obtain the intensity pattern inside the rib cage. The solution of the matrix system is carried out by using the pseudo inverse technique to synthesize the desired heating pattern. The proposed technique guides the fields through the intercostal spacings between the solid ribs and, thus, minimal intensity levels are observed over the solid ribs. This simulation model allows for the design and optimization of large-aperture phased-array applicator systems for noninvasive ablative thermal surgery in the heart and liver through the rib cage.