Design, synthesis, biological and in silico evaluation of coumarin-hydrazone derivatives as tubulin targeted antiproliferative agents.

Coumarin-based different series of hydrazone derivatives were synthesized and evaluated for anticancer activity against four different human cancer cell lines. The activity of the compounds were compared with doxorubicin as a standard drug and all the compounds exhibited good to moderate cytotoxicity with IC50 values ranging from 6.07 to 60.45 µM against all the examined cancer cell lines. Based on the screening results, it was concluded that the compounds 12a and 18a were the most promising medicinal entities. In vitro tubulin polymerisation inhibition assay was performed for the compounds 12a and 18a and these two compounds displayed good potency when compared with colchicine as the standard drug. The interaction of these compounds with tubulin protein was also studied with the help of molecular docking technique using Discovery studio software. Furthermore, the molecular and ADMET properties of the compounds were computed with Osiris property software and PreADMET server. The compounds exhibited exciting in vitro and in silico results. Hence we propose that the compounds 12a and 18a could be developed as tubulin targeted potential antiproliferative agents.

Synthesis and biological evaluation of novel 4,7-dihydroxycoumarin derivatives as anticancer agents.

A series of novel 4,7-dihydroxycoumarin based acryloylcyanohydrazone derivatives were synthesized and evaluated for antiproliferative activity against four different cancer cell lines (A549, HeLa, SKNSH, and MCF7). Most of the compounds displayed potent cytotoxicity with IC50 values ranging from 3.42 to 31.28 µM against all the tested cancer cell lines. The most active compound, 8h was evaluated for pharmacological mechanistic studies on cell cycle progression and tubulin polymerization inhibition assay. The results revealed that the compound 8h induced the cell cycle arrest at G2/M phase and inhibited tubulin polymerization with IC50 = 6.19 µM. Experimental data of the tubulin polymerization inhibition assay was validated by molecular docking technique and the results exhibited strong hydrogen bonding interactions with amino acids (ASN-101, TYR-224, ASN-228, LYS-254) of tubulin.

Repeated oral dose toxicity study of nickel oxide nanoparticles in Wistar rats: a histological and biochemical perspective.

Despite the increasing use of nickel oxide (NiO) nanoparticles (NPs), limited information is available on their toxicological effects. Health consequences of 28 days repeated oral exposure to NiO NPs have not been explored thoroughly. Hence, toxicity investigations were performed after 28-day daily exposure in albino Wistar rats with NiO NPs following Organization for Economic Co-operation and Development test guideline 407. Histopathology, biochemical indices including oxidative stress and biodistribution patterns were evaluated to decipher the toxicological impact of NiO NPs. NiO NP characterization by transmission electron microscopy showed an average size of 12.9 (±3.4) nm. Histological studies depicted a prominent impact on the vital organs of the rats. A dose-dependent rise in both aminotransferase enzyme values was recorded in the homogenates of liver and kidney tissues. A significant decrease in superoxide dismutase activity and increase in catalase activity was noted. Further, a dose-dependent decrease in reduced glutathione content was recorded in rats, which suggested generation of reactive oxygen species and oxidative stress. Increase in the malondialdehyde levels was observed with an increase in the dose substantiating the antioxidant enzyme activity profiles. Biodistribution studies indicated maximum accumulation of Ni content in liver followed by kidney. Excretion of Ni was predominantly through feces and a little through renal clearance. Our study indicated that NiO NPs adversely alter the biochemical profile of the rats and cause histological damage. Further investigations are warranted to address the mechanism by which physiological path these NiO NPs exhibit their toxic nature in in vivo.

Comparative study of toxicological assessment of yttrium oxide nano- and microparticles in Wistar rats after 28 days of repeated oral administration.

Despite their enormous advantages, nanoparticles (NPs) have elicited disquiet over their safety. Among the numerous NPs, yttrium oxide (Y2O3) NPs are utilised in many applications. However, knowledge about their toxicity is limited, and it is imperative to investigate their potential adverse effects. Therefore, this study explored the effect of 28 days of repeated oral exposure of Wistar rats to 30, 120 and 480 mg/kg body weight (bw) per day of Y2O3 NPs and microparticles (MPs). Before initiation of the study, characterisation of the particles by transmission electron microscopy, dynamic light scattering, Brunauer-Emmett-Teller and laser Doppler velocimetry was undertaken. Genotoxicity was evaluated using the comet and micronucleus (MN) assays. Biochemical markers aspartate transaminase, alanine transaminase, alkaline phosphatase, malondialdehyde, superoxide dismutase, reduced glutathione, catalase and lactate dehydrogenase in serum, liver and kidney were determined. Bioaccumulation of the particles was analysed by inductively coupled plasma optical emission spectrometry. The results of the comet and MN assays showed significant differences between the control and groups treated with 120 and 480 mg/kg bw/day Y2O3 NPs. Significant biochemical alterations were also observed at 120 and 480 mg/kg bw/day. Haematological and histopathological changes were documented. Yttrium (Y) biodistribution was detected in liver, kidney, blood, intestine, lungs, spleen, heart and brain in a dose- and the organ-dependent manner in both the particles. Further, the highest levels of Y were found in the liver and the lowest in the brain of the treated rats. More of the Y from NPs was excreted in the urine than in the faeces. Furthermore, NP-treated rats exhibited much higher absorption and tissue accumulation. These interpretations furnish rudimentary data of the apparent genotoxicity of NPs and MPs of Y2O3 as well as the biodistribution of Y. A no-observed adverse effect level of 30 mg/kg bw/day was found after oral exposure of rats to Y2O3 NPs.

In vitro genotoxicity assessment of nickel(II) oxide nanoparticles on lymphocytes of human peripheral blood.

The current study was intended to elucidate the cytotoxicity, genotoxicity ability of nickel oxide (NiO) nanoparticles (NPs) and assessment of preliminary mechanism of the toxicity. Characterization studies showed that NiO-NPs have a particle size of 17.94 (±3.48) nm. The particle size of the NPs obtained by dynamic light scattering method in Milli-Q and RPMI 1640 media was 189.9 (±17.1) and 285.9 (±19.6) nm, respectively. The IC50 concentration for NiO-NPs after 24 hours of treatment was estimated as 23.58 µg/mL. Comet and cytokinesis-block micronucleus assays revealed a significant dose- and time-dependent genotoxic potential of NiO-NPs. Morphological assessment of the lymphocytes upon exposure to NiO-NPs showed that the mechanism of toxicity was apoptosis. Reactive oxygen species analysis and lipid peroxidation patterns were aligned with the cytotoxicity and genotoxicity endpoints. Thus, the preliminary mechanism of NiO-NPs for cytotoxicity on lymphocytes was assumed to be oxidative stress-mediated apoptosis and DNA damage. Furthermore, these NiO-NPs are considered a potentially hazardous substance at environmentally significant levels. Further investigations are suggested to understand the immunotoxic effects of NiO-NPs.

1,2,3-Triazole Tagged 3H-Pyrano[2,3-d]pyrimidine-6-carboxylate Derivatives: Synthesis, in Vitro Cytotoxicity, Molecular Docking and DNA Interaction Studies.

A series of novel ethyl 2,7-dimethyl-4-oxo-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carboxylate derivatives 7a - 7m were efficiently synthesized employing click chemistry approach and evaluated for in vitro cytotoxic activity against four tumor cell lines: A549 (human lung adenocarcinoma cell line), HepG2 (human hematoma), MCF-7 (human breast adenocarcinoma), and SKOV3 (human ovarian carcinoma cell line). Among the compounds tested, the compounds 7a, 7b, 7f, 7l, and 7m have shown potential and selective activity against human lung adenocarcinoma cell line (A549) with IC50 ranging from 0.69 to 6.74 µm. Molecular docking studies revealed that the compounds 7a, 7b, 7f, 7l, and 7m are potent inhibitors of human DNA topoisomerase-II and also showed compliance with stranded parameters of drug likeness. The calculated binding constants, kb , from UV/VIS absorptional binding studies of 7a and 7l with CT-DNA were 10.77 × 104 , 6.48 × 104 , respectively. Viscosity measurements revealed that the binding could be surface binding mainly due to groove binding. DNA cleavage study showed that 7a and 7l have the potential to cleave pBR322 plasmid DNA without any external agents.

Allium cepa root tip assay in assessment of toxicity of magnesium oxide nanoparticles and microparticles.

Allium cepa bioassay had been used from decades for the assessment of toxicants and their harmful effects on environment as well as human health. Magnesium oxide (MgO) particles are being utilized in different fields. However, reports on the adverse effects of MgO nanoparticles on the environment and mankind are scarce. Hence, the toxicity of MgO particles is of concern because of their increased utilization. In the current study, A. cepa was used as an indicator to assess the toxicological efficiency of MgO nano- and microparticles (NPs and MPs) at a range of exposure concentrations (12.5, 25, 50, and 100µg/mL). The toxicity was evaluated by using various bioassays on A. cepa root tip cells such as comet assay, oxidative stress and their uptake/internalization profile. Results indicated a dose dependent increase in chromosomal aberrations and decrease in mitotic index (MI) when compared to control cells and the effect was more significant for NPs than MPs (at p<0.05). Comet analysis revealed that the Deoxyribonucleic acid (DNA) damage in terms of percent tail DNA ranged from 6.8-30.1 over 12.5-100µg/mL concentrations of MgO NPs and was found to be significant at the exposed concentrations. A significant increase in generation of hydrogen peroxide and superoxide radicals was observed in accordance with the lipid peroxidation profile in both MgO NPs and MPs treated plants when compared with control. In conclusion, this investigation revealed that MgO NPs exposure exhibited greater toxicity on A. cepa than MPs.

Comparative study of cyto- and genotoxic potential with mechanistic insights of tungsten oxide nano- and microparticles in lung carcinoma cells.

The exigency of semiconductor and super capacitor tungsten oxide nanoparticles (WO3 NPs) is increasing in various sectors. However, limited information on their toxicity and biological interactions are available. Hence, we explored the underlying mechanisms of toxicity induced by WO3 NPs and their microparticles (MPs) using different concentrations (0-300 µg ml-1 ) in human lung carcinoma (A549) cells. The mean size of WO3 NPs and MPs by transmission electron microscopy was 53.84 nm and 3.88 µm, respectively. WO3 NPs induced reduction in cell viability, membrane damage and the degree of induction was size- and dose-dependent. There was a significant increase in the percentage tail DNA and micronuclei formation at 200 and 300 µg ml-1 after 24 hours of exposure. The DNA damage induced by WO3 NPs could be attributed to increased oxidative stress and inflammation through reactive oxygen species generation, which correlated with the depletion of reduced glutathione content, catalase and an increase in malondialdehyde levels. Cellular uptake studies unveiled that both the particles were attached/surrounded to the cell membrane according to their size. In addition, NP inhibited the progression of the cell cycle in the G2 /M phase. Other studies such as caspase-9 and -3 and Annexin-V-fluorescein isothiocyanate revealed that NPs induced intrinsic apoptotic cell death at 200 and 300 µg ml-1 concentrations. However, in comparison to NPs, WO3 MPs did not incite any toxic effects at the tested concentrations. Under these experimental conditions, the no-observed-significant-effect level of WO3 NPs was determined to be ≤200 µg ml-1 in A549 cells.

Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents.

A novel series of substituted pyrazolo-quinoline derivatives 7pa-7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on 1H NMR, 13C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC50 values of 3.76, 3.87 and 3.83 µM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC50 values of 2.43 and 6.01 µM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti-proliferative evaluation of pyrazolo-quinoline derivatives.

Genotoxicity, biochemical, and biodistribution studies of magnesium oxide nano and microparticles in albino wistar rats after 28-day repeated oral exposure.

Increased utilization and exposure levels of Magnesium oxide (MgO) nanoparticles (NPs) to humans and environment may raise unexpected consequences. The goal of this study was to evaluate the toxicological implications of MgO NPs and MPs after 28 day repeated oral administration in Wistar rats with three different doses (250, 500, and 1000 mg/kg). The MgO particles were characterised systematically in order to get more insights of the toxicological behaviour. MgO NPs induced significant DNA damage and aberrations in chromosomes. Moreover, hepatic enzymes released into the systemic circulation caused significant elevated levels of physiological enzymes in blood. NPs could interfere with proteins and enzymes and alter the redox balance in cell environment. Significant accumulation of Mg in all tissues and clearance via urine and faeces was noted in size dependent kinetics. Oral administration of MgO NPs altered the biochemical and genotoxic parameters in dose dependent and gender independent manner.

Biochemical alterations induced by nickel oxide nanoparticles in female Wistar albino rats after acute oral exposure.

CONTEXT: Nickel oxide (NiO) nanoparticles (NPs) with appropriate surface chemistry have been widely used for their potential new applications in biomedical industry. Increased usage of these NPs enhances the chance of exposure of personnel involved in the work place. OBJECTIVE: This study was designed to assess the ability of NiO NPs to cause biochemical alterations post-acute oral exposure in female Wistar rats. MATERIALS AND METHODS: Rats were administered with 125, 250, and 500 mg/kg doses of NiO NPs for haematological, biochemical, and histopathological studies. Biodistribution patterns of NiO NPs in female Wistar rats were also monitored. RESULTS: NiO NPs caused significant (p < 0.01) inhibition of RBC and brain AchE of treated rats at the high dose. Activation of the hepatotoxicity marker enzymes, aminotransferases, was recorded in serum and liver, whereas inhibition was observed in kidney. The activity of antioxidant enzymes was also altered by NiO NPs in a dose-dependent manner and found to be significant at the high dose of exposure. CONCLUSIONS: This study revealed that exposure to nanosized NiO particles at acute doses may cause adverse changes in animal biochemical profiles. Further, the in vivo studies on toxicity evaluation help in biomonitoring of the potential contaminants.

Acute oral toxicity study of magnesium oxide nanoparticles and microparticles in female albino Wistar rats.

Advancements in nanotechnology have led to the development of the nanomedicine, which involves nanodevices for diagnostic and therapeutic purposes. A key requirement for the successful use of the nanoparticles (NPs) in biomedical applications is their good dispensability, colloidal stability in biological media, internalization efficiency, and low toxicity. Therefore, toxicological profiling is necessary to understand the mechanism of NPs and microparticles (MPs). MgO NPs have attracted wide scientific interest due to ease of synthesis, chemical stability and unique properties. However, their toxic effects on humans should also be of concern with the increased applications of nano MgO. The present study was aimed to assess the toxicological potential of MgO NPs in comparison to their micron counterparts in female Wistar rats. Toxicity was evaluated using genotoxicity, histological, biochemical, antioxidant and biodistribution parameters post administration of MgO particles to rats through oral route. The results obtained from the investigation revealed that the acute exposure to the high doses of MgO NPs produced significant (p < 0.01) DNA damage and biochemical alterations. Antioxidant assays revealed prominent oxidative stress at the high dose level for both the particles. Toxicokinetic analysis showed significant levels of Mg accumulation in the liver and kidney tissues apart from urine and feces. Further, mechanistic investigational reports are warranted to document safe exposure levels and health implications post exposure to high levels of NPs.

Assessment of genotoxicity and biodistribution of nano- and micron-sized yttrium oxide in rats after acute oral treatment.

The increasing use of yttrium oxide (Y2 O3 ) nanoparticles (NPs) entails an improved understanding of their potential impact on the environmental and human health. In the present study, the acute oral toxicity of Y2 O3 NPs and their microparticles (MPs) was carried out in female albino Wistar rats with 250, 500 and 1000 mg kg-1 body weight doses. Before the genotoxicity evaluation, characterization of the particles by transmission electron microscopy, dynamic light scattering and laser Doppler velocimetry was performed. The genotoxicity studies were conducted using micronucleus and comet assays. Results showed that Y2 O3 NP-induced significant DNA damage at higher dose (1000 mg kg-1 body weight) in peripheral blood leukocytes and liver cells, micronucleus formation in bone marrow and peripheral blood cells. The findings from biochemical assays depicted significant alterations in aspartate transaminase, alanine transaminase, alkaline phosphatase, malondialdehyde, superoxide dismutase, reduced glutathione, catalase and lactate dehydrogenase levels in serum, liver and kidneys at the higher dose only. Furthermore, tissue biodistribution of both particles was analyzed by inductively coupled plasma optical emission spectrometry. Bioaccumulation of yttrium (Y) in all tissues was significant and dose-, time- and organ-dependent. Moreover, Y2 O3 NP-treated rats exhibited higher tissue distribution along with greater clearance through urine whereas Y2 O3 MP-dosed animals depicted the maximum amount of Y in the feces. Hence, the results indicated that bioaccumulation of Y2 O3 NPs via its Y ions may induce genotoxic effects.

Toxicological assessment of nano and micron-sized tungsten oxide after 28days repeated oral administration to Wistar rats.

Tungsten oxide (WO3) nanoparticles (NPs) are being used in various applications. However, the health consequences of WO3 NPs exposure have not been explored extensively. Hence, the goal of this study was to evaluate the toxicity of WO3 NPs and their microparticles (MPs) after 28days repeated oral administration in Wistar rats. The particles were characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), laser Doppler velocimetry (LDV), Brunner-Emmett-Teller (BET), X- ray diffraction (XRD), and inductively coupled plasma optical emission spectrometer (ICP-OES). Genotoxicity was determined using comet assay in blood and liver and micronucleus test in bone marrow. Biochemical parameters such as aspartate aminotransferase and alanine aminotransferase in serum and reduced glutathione content, catalase and lipid peroxidation in liver tissue were determined. Histopathological changes in tissues were documented. Biodistribution of tungsten (W) in rat's blood, urine, feces and tissues were analysed. The mean size of WO3 NPs and MPs by TEM was 52±2.97nm, and 5.73±7.58µm and morphology were spherical in both the particles. DLS of NPs was 195.6nm. XRD and BET data of WO3 NPs and MPs showed a hexagonal and tetragonal crystal structure and surface area of 19.33 and 15.15(m2/g), respectively. The results revealed a significant increase in DNA damage and micronuclei, a difference in biochemical levels and histopathological alterations after exposure to 1000mg/kg dose of WO3 NPs. W biodistribution was detected in all the tissues in a dose and organ-dependent manner in both the particles. The highest amount of W was found in the liver and lowest in the brain of the treated rats. The tested NPs were found to have little toxicity hazard.

Toxicological assessment of tungsten oxide nanoparticles in rats after acute oral exposure.

Advances in and the rapid growth of the nanotechnology sector have escalated manufacture of nanoparticles (NPs), resulting in a significant increase in the probability of exposure of humans and wildlife to these materials. Many NPs have been found to exert genotoxicity. Therefore, genotoxicity studies are mandatory to assess the toxicity of NPs as a concern of succumbing to genetic diseases and cancers are universal. Tungsten oxide (WO3) NPs are being explored extensively in various fields. However, the toxicological data of WO3 NPs by oral route in mammals is limited. Hence, the goal of the current investigation was to evaluate the acute toxicity of WO3 NPs and microparticles (MPs) after single oral administration with 100, 500 and 1000 mg/kg body weight doses in female Wistar rats. TEM, dynamic light scattering and laser Doppler velocimetry techniques were used to characterise the particles. The genotoxicity studies were conducted using comet, micronucleus and chromosomal aberration assays. Alterations in biochemical indices and metal distribution in various organs were also evaluated. The mean size of WO3 NPs and MPs by TEM was 53.2 ± 1.91 nm and 5.17 ± 3.18 µm, respectively. The results revealed a significant increase in DNA damage and micronuclei and chromosomal aberrations after exposure to 1000 mg/kg dose of WO3 NPs. Significant alterations in aspartate transaminase, alanine transaminase, reduced glutathione, catalase and malondialdehyde levels in serum and liver were found only at the higher dose of WO3 NPs. Tungsten (W) biodistribution was observed in all the tissues in a dose-, time- and organ-dependent manner. In addition, the maximum concentration of W was found in the liver and the least in the brain was observed. The test substances were found to have a relatively low acute toxicity hazard. The data obtained gives preliminary information on the potential toxicity of WO3 NPs and MPs.

Genotoxicity study of nickel oxide nanoparticles in female Wistar rats after acute oral exposure.

Nanoparticles (NPs) apart from their widespread advantages and increased utilisation, have aroused concerns over their safe use. Nickel (II) oxides (NiO) NPs are used as catalysts, biosensors and in many of the consumer products. The increasing use of NiO NPs necessitates an improved understanding of their potential impact on the environment and human health. In this study, we investigated the acute genotoxic effects of NiO NPs by oral route administration with three different doses (125, 250 and 500 mg/kg bw). Before the in vivo toxicological evaluation, characterisation of particles by Transmission Electron Microscopy, X-ray diffraction, Dynamic Light Scattering (DLS) and Laser Doppler Velocimetry analysis was performed. Genotoxicity biomarkers such as comet, micronucleus and chromosomal aberrations (CAs) assays were utilised in this study. To document the uptake, retention and elimination of the NPs, biodistribution studies were also performed. The particle size obtained from Transmission Electron Microscopy analysis for NiO NPs was 15.62 ± 2.59 nm. The mean hydrodynamic diameter and PdI of NiO NPs in Milli-Q water suspension obtained by DLS was 168.9 ± 17.13 nm and 0.375, respectively. Comet assay revealed significant (P < 0.001) DNA damage at 500 mg/kg bw dose in the PBL, liver and kidney cells of rats at the 24-h sampling time. The result of micronucleus and CAs tests was in agreement with the comet assay data. Biodistribution of NiO NPs revealed a maximum accumulation of Ni in the liver tissue at the 24-h sampling time. Our study showed significant DNA damage at the high dose level and the effect was more prominent at 24-h sampling time, providing preliminary evidence that the NiO NPs are capable of inducing genotoxicity when administered through the oral route. However, mechanistic investigations are needed before drawing any firm conclusion regarding the toxicology of NiO NPs.