Lung cancer is the leading cause of cancer deaths. Nonsmall cell lung cancer (NSCLC) accounts for the vast majority of the histological subtypes and at advanced stage exhibits extremely low survival ...rate. Certain compounds, such as glycols, inhibit migration and decreased viability of the highly metastatic NSCLC cells A549_3R has been recently shown. The glycols‐induced effects are associated with a parallel reduction of ATP production, detected in A549_3R spheroids embedded in 3D desmoplastic‐like extracellular matrix, following overnight treatment. Herein, selected glycols are tested for their ability to acutely compromise bioenergetics, metabolism, and viability of A549_3R cells. Therefore, 1,5‐pentanediol (1,5‐PD), 1,6‐hexanediol (1,6‐HD), and 1,7‐heptanediol (1,7‐Hept) turn out to be the most effective. They interfere with key enzymes in glycolysis and elicit most or all of the following responses: acute collapse of the critical mitochondrial membrane potential, substantial reduction of ATP, pyruvate and L‐lactate levels, and massive increase in reactive oxygen species production. Moreover, computational docking analysis reveals that the glycols bind to the substrate‐binding residues of lactate dehydrogenase A, which catalyzes the interconversion of pyruvate and lactate and is upregulated in aggressive tumors. Hence, the effective glycols may be promising anticancer compounds, or lead substances, for localized and intratumoral applications.
The proposed mechanism of the action of 1,5‐PD, 1,6‐HD, and 1,7‐Hept that negatively impacts the metabolism and bioenergetics of aggressive lung cancer cells is discussed.
The small compound Pitstop‐2 is a recent potent inhibitor of clathrin‐mediated endocytosis (CME), widely used in biomedical research areas. In recent years, however, it is observed that it exhibits ...CME‐independent inhibitory effects on nuclear pore complexes (NPCs), the nucleocytoplasmic gatekeepers. NPCs are elaborate proteinaceous transport nano‐machineries of crucial physiological importance rendering them novel targets for various medical applications. They mediate all nucleocytoplasmic transport forming a physiologically essential selective nucleocytoplasmic barrier. The direct Pitstop‐2 disruptive effects on NPCs manifested themselves at both the structural and functional integrity levels. Moreover, they are massive, acute, and detectable at concentrations equal to CME‐inhibitory concentrations. Pitstop‐2 inhibits CME by binding to the terminal β‐propeller domain of the heavy chain of clathrin. Several NPC scaffold proteins, critical for the structural and functional integrity of the NPC, possess β‐propeller folds. Herein, utilizing computational docking analysis, it is demonstrated that Pitstop‐2 exhibits particularly high binding affinities to β‐propeller folds of NPC scaffold proteins, similar to its binding affinity to the terminal β‐propeller domain of clathrin. The authors, therefore, conclude that Pitstop‐2 is a potent disruptor of NPCs, an activity which, separately or in synergy with CME inhibition, may be exploited for a myriad of pharmacological applications.
Pitstop‐2 disrupts nuclear pore complexes (NPCs) by interference with β‐propeller folds in Y‐complexes of the NPC scaffold, compromising the integrity of the nuclear envelope.
Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell‐physiological processes. It is hypothesized that NPCs are critical for malignant ...transformation and survival of lung cancer cells, and test the hypothesis in lowly and highly metastatic non‐small human lung cancer cells (NSCLCs). It is shown that malignant transformation is paralleled by an increased NPCs density, and a balanced pathological weakening of the physiological stringency of the NPC barrier. Pharmacological interference using barrier‐breaking compounds collapses the stringency. Concomitantly, it induces drastic overall structural changes of NSCLCs, terminating their migration. Moreover, the degree of malignancy is found to be paralleled by substantially decreased lamin A/C levels. The latter provides crucial structural and mechanical stability to the nucleus, and interacts with NPCs, cytoskeleton, and nucleoskeleton for cell maintenance, survival, and motility. The recent study reveals the physiological importance of the NPC barrier stringency for mechanical and structural resilience of normal cell nuclei. Hence, reduced lamin A/C levels in conjunction with controlled pathological weakening of the NPC barrier stringency may facilitate deformability of NSCLCs during the metastasis steps. Modulation of the NPC barrier presents a potential strategy for suppressing the malignant phenotype or enhancing the effectiveness of currently existing chemotherapeutics.
Malignant transformation of aggressive lung cancer cells is associated with pathophysiological alteration of the nuclear envelope and the physiological stringency of the selective barrier function of nuclear pore complexes (NPCs). Pharmacological disruption of the NPC barrier instantly gives rise to both drastic structural changes of cancer cells and loss of their motility and migratory behavior.
Clathrin‐mediated endocytosis (CME) is an essential cell physiological process of broad biomedical relevance. Since the recent introduction of Pitstop‐2 as a potent CME inhibitor, we and others have ...reported on substantial clathrin‐independent inhibitory effects. Herein, we developed and experimentally validated a novel fluorescent derivative of Pitstop‐2, termed RVD‐127, to clarify Pitstop‐2 diverse effects. Using RVD‐127, we were able to trace additional protein targets of Pitstop‐2. Besides inhibiting CME, Pitstop‐2 and RVD‐127 proved to directly and reversibly bind to at least two members of the small GTPase superfamily Ran and Rac1 with particularly high efficacy. Binding locks the GTPases in a guanosine diphosphate (GDP)‐like conformation disabling their interaction with their downstream effectors. Consequently, overall cell motility, mechanics and nucleocytoplasmic transport integrity are rapidly disrupted at inhibitor concentrations well below those required to significantly reduce CME. We conclude that Pitstop‐2 is a highly potent, reversible inhibitor of small GTPases. The inhibition of these molecular switches of diverse crucial signaling pathways, including nucleocytoplasmic transport and overall cell dynamics and motility, clarifies the diversity of Pitstop‐2 activities. Moreover, considering the fundamental importance and broad implications of small GTPases in physiology, pathophysiology and drug development, Pitstop‐2 and RVD‐127 open up novel avenues.
•Organoselenium compounds have shown mimetic GPx and also act as substrates of TrxR.•The amino group inclusion in monoselenides did not allow the formation of selenol.•Monoselenides showed redox ...effect due to the nucleophilicity of the amino group.•The diselenides showed antioxidant effect due to the formation of selenol dgroups.•The novel diselenides were able to mimetic the GPx and increase the TrxR activity.
This study was designed to examine the antioxidant activity in vitro of novel mono- and diselenide compounds. We compared whether the formation of p-methyl-selenol from compounds 1-phenyl-3-(p-tolylselanyl)propan-2-amine (C1) and 1,2-dip-tolyldiselenide (C4) and o-methoxy-selenol from compounds 1-(2-methoxyphenylselanyl)-3-phenylpropan-2-amine (C2) and 1,2-bis(2-methoxyphenyl)diselenide (C3) may be involved in their antioxidant effects. The compounds were tested against Fe(II) and sodium nitroprusside (SNP)-induced lipid peroxidation in rat brain and liver homogenates. Likewise, the antioxidant capacity of the compounds was assessed by their ability to decolorize the DPPH radical as well as the Fe(II) chelating assay through the reduction of molybdenum(VI) (Mo6+) to molybdenum(V) (Mo5+). This colorimetric assay was also used to quantify thiol peroxidase (GPx) and oxidase activity and thioredoxin reductase (TrxR) activity. The results showed that the novel selenide compounds inhibit the thiobarbituric acid reactive species (TBARS) induced by different pro-oxidants, but the monoselenides effects were significant only at concentrations higher than the concentrations of the diselenides. Similarly, the total antioxidant activity was higher in the diselenides. Moreover, GPx and TrxR activity was only observed for the diselenides, which indicates that these compounds are more stable selenol molecules than monoselenides.
Solanum guaraniticum is a shrub belonging to the Solanaceae family popularly known in Brazil as jurubeba or false-jurubeba. The aim of this study was to evaluate the antioxidant activity of crude ...extract and chloroform, ethyl acetate and n-butanol fractions from its leaves, verifying the ability to remove reactive species and identify and quantify phenolic compounds. The ethyl acetate fraction showed the highest amount of total polyphenols (546.57 ± 2.35 mg gallic acid equivalent/g) and the lowest IC(50) (9.11 ± 0.75 µg/mL) by the DPPH method. Furthermore, the chloroform fraction presented the highest content of flavonoids (75.73 ± 0.34 mg rutin equivalents/g), tannins (56.03 ± 0.68 mg catechin equivalents/g) and alkaloids (10.79 ± 0.06 mg/g). This fraction was effective in the scavenging of reactive species by 2',7'-dichlorofluorescein diacetate assay, in addition to completely reducing protein carbonyl content and reducing lipid peroxidation at basal levels even at low concentrations. Chlorogenic, caffeic and rosmarinic acids were identified and quantified by HPLC/DAD. These results show that S. guaraniticum is rich in phenolic compounds and has potential as an antioxidant.
Vitex megapotamica (Sprengel) Moldenke belongs to the Verbenaceae family and is popularly known as "tarumã". The antioxidant capacity of fractions and crude extract from the leaves of V. megapotamica ...were determined in this study through the capacity to remove reactive species and phenolic compounds were quantified in the various fractions. The IC50 (DPPH) ranged from 14.17 ± 0.76 to 37.63 ± 0.98 µg/mL. The ethyl acetate fraction might contain the strongest lipid peroxidation inhibitory compounds with an IC50 of 16.36 ± 5.09 µg/mL, being also the one with the highest content of polyphenols (522.4 ± 1.12 mg/g), flavonoids (220.48 ± 0.30 mg/g) and condensed tannins (3.86 ± 0.53 mg/g). Compounds quantified by HPLC/DAD in the crude extract and fractions were chlorogenic and rosmarinic acids. Higher dosages of the extracts were more effective in reducing levels of plasma protein carbonyls and were also shown to be able to remove reactive species by a 2',7'-dichlorofluorescein diacetate assay, reducing oxidative stress in all tested fractions. Results obtained indicated that V. megapotamica exhibits good potential to prevent diseases caused by the overproduction of free radicals and it might also be used as a potential source of natural antioxidant agents.
The antibacterial activity of sulfadiazine Au-PPh3, sulfadiazine Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3, sulfamethoxazole Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3 were tested against Pseudomonas ...aeruginosa. The antibacterial activity of sulfonamide was tested against P. aeruginosa through the MIC assay, quantitative analysis of biofilm inhibition and observation of biofilm formation with fluorescence microscopy. Besides, the compounds presented remarkable inhibition of P. aeruginosa biofilm formation. Furthermore, molecular docking was performed to identify the key structural features of these compounds with the binding site of the LasR receptor.
•Gold-complexed sulfonamides have antibacterial activity against P. aeruginosa.•Gold-complexed sulfonamides have shown antibiofilm activity.•Sulfonamides reduce the bacteria virulence and spread.•Gold-complexed sulfonamides interacted with LasR active site.
The synthesis of chiral azido organochalcogenium compounds prepared from inexpensive and commerciallyavailable α‐amino alcohols through diazo transfer reaction are disclosed. The products were ...obtained in good yields in a modulate synthetic route, affording an efficient methodology for preparing new chiral β‐aryl‐chalcogenium azide compounds. These compounds were evaluated for in vitro antitumoral lung carcinoma A549 as well as electrochemical and antioxidant assays. They presented prominent activities of apoptosis and cell cycle arrest induction as well as antioxidant properties. Additionally, the toxicities in vivo for the most effective compounds were evaluated and no overt sign of toxicity was observed.
A new β‐aryl‐chalcogenium azide compounds were prepared from α‐amino alcohols. These compounds were evaluated for in vitro antitumoral lung carcinoma A549 as well as eletrochemical and antioxidant assays, presenting prominent activities of apoptosis as well as cell cycle arrest induction and antioxidant properties.
The drug-resistant strains of Staphylococcus aureus have been considered as one of the serious health threats, which are related to high patient hospitalization rates. Besides, Staphylococcus aureus ...biofilm formation exhibits a drug-tolerant nature and shows nonspecific resistance against a broad-spectrum of antibiotics. The emergence of drug-resistant bacteria stimulated the development of novel medicines as a strategy to control infections. In this study, we evaluated the antibacterial and anti-biofilm activity of gold-complexed sulfonamides against Staphylococcus aureus strains such as methicillin-resistant S. aureus and clinical isolates. Our data showed that the exposure of gold-complexed sulfonamides promoted a remarkable reduction in the bacterial adhesion. Also, confocal microscopy displayed the effects of the compounds on in the bacterial cell biofilm, revealed that the compounds decreased the biofilm formation. Our results also demonstrated that gold-complexed sulfonamides exhibited potent antibacterial activity against Staphylococcus aureus strains. Besides, all compounds presented a synergic antibacterial activity when were associated with classical antibiotics. Gold-complexed sulfonamide compounds did not promote toxic effects on Caenorhabditis elegans. Thus, our results showed that the coordination of sulfonamide with gold is a promising alternative in the development of safe and active compounds against methicillin-resistant and clinical isolates S. aureus.
•Gold-complexed sulfonamides have shown antibacterial and also antibiofilm activity.•The presence of gold allows a more effective antibacterial action of the sulfonamide.•Gold-complexed sulfonamides have synergistic activity with classic antibiotics.•The novel compounds were more effective than SMZ.