Design and synthesis of novel chloropyridazine hybrids as promising anticancer agents acting by apoptosis induction and PARP-1 inhibition through a molecular hybridization strategy.

Guided by the molecular hybridization principle, a novel series of 4-chloropyridazinoxyphenyl conjugates (3a-h, 4a-e, and 5) was designed and synthesized as proposed apoptotic inducers and PARP-1 inhibitors. The growth inhibition % of the designed hybrids was investigated in eleven cancer cell lines, where the anticancer activities were found to be in the following order: 4-chloropyridazinoxyphenyl-aromatic ketones hybrids (3a-h) > 4-chloropyridazinoxyphenyl-benzyloxyphenylethan-1-one hybrids (4a-e) > 4-chloropyridazinoxyphenyl-thiazolidine-2,4-dione hybrid (5). Further, the most sensitive three cancer cell lines (HNO97, FaDu, and MDA-MB-468) were selected to measure the IC50 values of the new hybrids. Moreover, the frontier three members (3c, 3e, and 4b) were selected for the measurements of apoptotic protein markers (p53, BAX, caspase 3, caspase 6, BCL-2, and CK 18). Besides, the impact of compounds 3a-e and 4b on the activity of PARP-1 was investigated, where 3c, 3d, and 3e demonstrated comparable efficiencies to olaparib. Furthermore, γ-H2Ax, a well-established marker for double-strand DNA breaks, was examined and the occurrence of DNA damage was observed. In addition, a significant inhibition of cell proliferation and a remarkable 15 to 50-fold reduction in the number of colonies compared to the control group were recorded. Finally, the PARP-1 inhibitory potential of the novel hybrids was compared to the co-crystal of the target receptor (PDB ID: 6NTU) using molecular docking.

Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays.

Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.

Anticancer effect and laser photostability of ternary graphene oxide/chitosan/silver nanocomposites on various cancer cell lines.

Aims: The development of nanocomposites (NCs) of antitumor activity provides a new paradigm for fighting cancer. Here, a novel NC of green synthetic silver nanoparticles (AgNPs), graphene oxide (GO) and chitosan (Cs) NPs was developed. Materials & methods: The prepared GO/Cs/Ag NCs were analyzed using various techniques. Cytotoxicity of the NCs was evaluated against different cancer cell lines by Sulforhodamine B (SRB) assay. Results: GO/Cs/Ag NCs are novel and highly stable. UV-Vis showed two peaks at 227 and 469 nm, indicating the decoration of AgNPs on the surface of GO/Cs NPs. All tested cell lines were affected by GO/Cs NPs and GO/Cs/Ag NCs. Conclusion: The results indicate that GO/Cs/Ag NCs were present on tested cell lines and are a promising candidate for cancer therapy.

Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells.

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 µM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.

Multi-target rational design and synthesis of novel diphenyl-tethered pyrazolopyrimidines targeting EGFR and topoisomerase II with potential DNA intercalation and apoptosis induction.

Herein, we envisioned the design and synthesis of novel pyrazolopyrimidines (confirmed by elemental analysis, 1H and 13C NMR, and mass spectra) as multitarget-directed drug candidates acting as EGFR/TOPO II inhibitors, DNA intercalators, and apoptosis inducers. The target diphenyl-tethered pyrazolopyrimidines were synthesized starting from the reaction of phenyl hydrazine and ethoxymethylenemalononitrile to give aminopyrazole-carbonitrile 2. The latter hydrolysis with NaOH and subsequent reaction with 4-chlorobenzaldhyde afforded the corresponding pyrazolo[3,4-d]pyrimidin-4-ol 4. Chlorination of 4 with POCl3 and sequential reaction with different amines afforded the target compounds in good yields (up to 73 %). The growth inhibition % of the new derivatives (6a-m) was investigated against different cancer and normal cells and the IC50 values of the most promising candidates were estimated for HNO97, MDA-MB-468, FaDu, and HeLa cancer cells. The frontier derivatives (6a, 6i, 6k, 6l, and 6m) were pursued for their EGFR inhibitory activity. Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib as a reference standard. On the other side, compounds (6a, 6i, 6k, 6l, and 6m) underwent topoisomerase II (TOPO II) inhibitory assay. In particular, compounds 6a and 6l exhibited IC50s of 17.89 and 19.39 µM, respectively, surpassing etoposide with IC50 of 20.82 µM. Besides, the DNA fragmentation images described the great potential of both candidates 6a and 6l in inducing DNA degradation at lower concentrations compared to etoposide and doxorubicin. Moreover, compound 6l, with the most promising EGFR/TOPO II inhibition and DNA intercalation, was selected for further investigation for its apoptosis induction ability by measuring caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 proteins. Additionally, molecular docking was used to explain the SAR results based on the differences in the molecular features of the investigated congeners and the target receptors' topology.

SIRT1 as a potential key regulator for mediating apoptosis in oropharyngeal cancer using cyclophosphamide and all-trans retinoic acid.

Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.

Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer.

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.

Lead Optimization of BIBR1591 To Improve Its Telomerase Inhibitory Activity: Design and Synthesis of Novel Four Chemical Series with In Silico, In Vitro, and In Vivo Preclinical Assessments.

Herein, modifications to the previously reported BIBR1591 were conducted to obtain bioisosteric candidates with improved activities. The % inhibition of the newly afforded candidates against the telomerase target was investigated. Notably, 6f achieved superior telomerase inhibition (63.14%) compared to BIBR1532 and BIBR1591 (69.64 and 51.58%, respectively). In addition, 8a and 8b showed comparable promising telomerase inhibition with 58.65 and 55.57%, respectively, which were recorded to be frontier to that of BIBR1591. 6f, 8a, and 8b were tested against five cancer cell lines related to the lung and liver subtypes. Moreover, 6f was examined on both cell cycle progression and apoptosis induction in HuH7 cancer cells. Furthermore, the in vivo antitumor activity of 6f was further assessed in female mice with solid Ehrlich carcinoma. In addition, molecular docking and molecular dynamics simulations were carried out. Collectively, 6f, 8a, and 8b could be considered potential new telomerase inhibitors to be subjected to further investigation and/or optimization.

Niosomes loading N-acetyl-L-cysteine for cancer treatment in vivo study.

Scientists are seeking to find an effective treatment for tumors that has no side effects. N-Acetyl-l-cysteine (NAC) is a thiol compound extracted from garlic. Current study explores the potential of NAC-loaded niosomes (NAC-NIO) for tumor treatment in mice. NAC-loaded niosomes' efficiency, morphology, UV absorption, size distribution, zeta potential, release, and FTIR analysis were evaluated. For vivo study, 25 male BALB/c mice were divided to five groups: gp1 negative control (receive saline), gp2 positive control (tumor group), gp3 treated with NAC, gp4 treated with NAC-NIO at the same time of tumor injection, and gp5 treated with NAC-NIO after tumor growth (day 14). The impact of NAC-NIO on the tumor treatment was evaluated by measuring tumor size progress, comet assay, oxidative stress parameters (GSH, nitric oxide, MDA), western blot analysis, and histopathological investigation of tissues. NAC-NIO showed 72 ± 3% encapsulation efficiency and zeta potential - 5.95 mV with spherical shape. It was found that oral administration of NAC-NIO in a dose of 50 mg/kg provided significant protection against tumor cells. Our formulation decreases DNA injury significantly (P < 0.05). It was noticed that NAC-NIO can increase oxidative stress levels in tumor tissue. On the other hand, the caspase 3 and caspase 9 gene expression were upregulated significantly (P < 0.001) in mice administrated NAC-NIO compared with all other groups. Histological studies confirmed the protective effect of NAC-NIO against tumor especially for treatment during tumor growth protocol. The results suggested that oral delivery of NAC-NIO formulation improved antioxidant effect.

Physico-chemical properties of curcumin nanoparticles and its efficacy against Ehrlich ascites carcinoma.

Curcumin is a bioactive component with anticancer characteristics; nevertheless, it has poor solubility and fast metabolism, resulting in low bioavailability and so restricting its application. Curcumin loaded in nano emulsions (Cur-NE) was developed to improve water solubility and eliminate all the limitations of curcumin. Size distribution, zeta potential, transmission electron microscopy (TEM) measurements, UV-Visible spectra, IR spectra and thermogravimetric analysis (TGA), were used to characterize the prepared Cur-NE. Cancer therapeutic efficacy was assessed by oxidative stress (superoxide dismutase (SOD), Glutathione-S-Transferase (GST), malondialdehyde (MDA) and nitric oxide (NO), DNA damage, apoptotic proteins (caspase-3 and 9), besides investigating tumor histology and monitoring tumor growth. Additionally, the cytotoxicity and genotoxicity of the liver, kidney, heart, and spleen tissues were examined to gauge the adverse effects of the treatment method's toxicity. The results showed that Cur-NE is more effective than free curcumin at slowing the growth of Ehrlich tumors while significantly increasing the levels of apoptotic proteins. On the other hand, Cur-NE-treated mice showed some damage in other organs when compared to mice treated with free curcumin. Cur-NE has a higher efficacy in treating Ehrlich tumor.

Yttrium Oxide nanoparticles induce cytotoxicity, genotoxicity, apoptosis, and ferroptosis in the human triple-negative breast cancer MDA-MB-231 cells.

BACKGROUND: Triple-negative breast cancer (TNBC) is a lethal mammary carcinoma subtype that affects females and is associated with a worse prognosis. Chemotherapy is the only conventional therapy available for patients with TNBC due to the lack of therapeutic targets. Yttrium oxide (Y2O3) is a rare earth metal oxide, whose nanoparticle (NPs) formulations are used in various applications, including biological imaging, the material sciences, and the chemical synthesis of inorganic chemicals. However, the biological activity of Y2O3-NPs against TNBC cells has not been fully explored. The current study was conducted to assess Y2O3-NPs' anticancer activity against the human TNBC MDA-MB-231 cell line. METHODS: Transmission electron microscopy (TEM), X-ray diffraction, Zeta potential, and dynamic light scattering (DLS) were used to characterize the Y2O3-NPs. SRB cell viability, reactive oxygen species (ROS) measurement, single-cell gel electrophoresis (comet assay), qPCR, flow cytometry, and Western blot were employed to assess the anticancer activity of the Y2O3-NPs. RESULTS: Our results indicate favorable physiochemical properties of Y2O3-NPs (with approximately average size 14 nm, Zeta Potential about - 53.2 mV, and polydispersity index = 0.630). Y2O3-NPs showed a potent cytotoxic effect against MDA-MB-231 cells, with IC50 values of 74.4 µg/mL, without cytotoxic effect on the normal retina REP1 and human dermal fibroblast HDF cell lines. Further, treatment of MDA-MB-231 cells with IC50 Y2O3-NPs resulted in increased oxidative stress, accumulation of intracellular ROS levels, and induced DNA damage assessed by Comet assay. Upon Y2O3-NPs treatment, a significant increase in the early and late phases of apoptosis was revealed in MDA-MB-231 cells. qPCR results showed that Y2O3-NPs significantly upregulated the pro-apoptotic genes CASP3 and CASP8 as well as ferroptosis-related gene heme oxygenase-1 (HO-1), whereas the anti-apoptotic gene BCL2 was significantly downregulated. CONCLUSION: This study suggests that Y2O3-NPs are safe on normal REP1 and HDF cells and exhibited a potent selective cytotoxic effect against the TNBC MDA-MB-231 cells through increasing levels of ROS generation with subsequent DNA damage, and induction of apoptosis and ferroptosis.

Design and synthesis of novel pyrazolopyrimidine candidates as promising EGFR-T790M inhibitors and apoptosis inducers.

Aim: Our objective was to design and synthesize a new range of pyrazolopyrimidines while maintaining the key pharmacophoric features of EGFR tyrosine kinase inhibitors. Materials & methods: Percentage inhibition in 14 human cancer cell lines and IC50 values were recorded. Compounds 6c, 7e and 7f were examined against both wild and mutant (T790M) EGFR subtypes. Apoptosis markers, cell cycle arrest, apoptosis assay and molecular docking were performed. Results: Compounds 6c, 7e and 7f demonstrated superior inhibitory potentials against wild and mutant (T790M) EGFR subtypes. A molecular docking study showed that compounds 6c and 7e had the best fit. Conclusion: The designed candidates demonstrated superior inhibitory potential as promising EGFR-T790M inhibitors that agrees with the proposed rationale.

Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments.

Nowadays, diabetes mellitus has emerged as a significant global public health concern with a remarkable increase in its prevalence. This review article focuses on the definition of diabetes mellitus and its classification into different types, including type 1 diabetes (idiopathic and fulminant), type 2 diabetes, gestational diabetes, hybrid forms, slowly evolving immune-mediated diabetes, ketosis-prone type 2 diabetes, and other special types. Diagnostic criteria for diabetes mellitus are also discussed. The role of inflammation in both type 1 and type 2 diabetes is explored, along with the mediators and potential anti-inflammatory treatments. Furthermore, the involvement of various organs in diabetes mellitus is highlighted, such as the role of adipose tissue and obesity, gut microbiota, and pancreatic ß-cells. The manifestation of pancreatic Langerhans ß-cell islet inflammation, oxidative stress, and impaired insulin production and secretion are addressed. Additionally, the impact of diabetes mellitus on liver cirrhosis, acute kidney injury, immune system complications, and other diabetic complications like retinopathy and neuropathy is examined. Therefore, further research is required to enhance diagnosis, prevent chronic complications, and identify potential therapeutic targets for the management of diabetes mellitus and its associated dysfunctions.

Investigating the superiority of chitosan/D-alpha-tocopheryl polyethylene glycol succinate binary coated bilosomes in promoting the cellular uptake and anti-SARS-CoV-2 activity of polyphenolic herbal drug candidate.

The evolution of a safe and effective therapeutic system to conquer SAR-CoV-2 infection deemed to be a crucial worldwide demand. Curcumin (CUR) is a phytomedicinal polyphenolic drug that exhibited a well-reported anti-SAR-CoV-2. However, the therapeutic activity of CUR is hindered by its poor intestinal permeability and diminished aqueous solubility. Therefore, this study strived to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) bilosomes (TPGS-Bs) adopting 23 full factorial designs to improve solubility and intestinal permeability of CUR, hence boosting its anti-SARS-CoV-2 activity. Eight experimental runs were attained considering three independent variables: soybean phosphatidylcholine amount (mg) (SPC amount), bile salt amount (mg) (BS amount), and TPGS amount (mg). The optimum formula (F4) exhibited EE % (88.5 ± 2.4 %), PS (181.5 ± 21.6 nm), and ZP (-34.5 ± 3.7 mV) with desirability value = 0.739 was picked as an optimum formula. Furthermore, the optimum formula (F4) was extra coated with chitosan (CS) to improve permeability and anti-SAR-CoV-2 activity. Caco-2 cell uptake after 2 hr revealed the superiority of CS-F4 and F4 by 6 and 5 folds relative to CUR dispersion, respectively. Furthermore, CS-F4 exhibited a significantly higher anti-SARS-CoV-2 activity with IC50 (0.24 µg/ml) by 8.3 times than F4 (1.99 µg/ml). Besides, the mechanistic study demonstrated that the two formulae imparted antiviral activity by inhibiting the spike protein by virucidal potentialities. In addition, the conducted molecular docking and MD simulations towards the SARS-CoV-2 Mpro enzyme confirmed the interaction of CUR with key residues of the virus enzymes. Based on the preceded, CS-F4 could be assumed to be used to effectively eradicate SARS-CoV-2 infection.

Antioxidant and Anticancer Assessment and Phytochemical Investigation of Three Varieties of Date Fruits.

Date palm (Phoenix dactylifera L.) fruits contain high concentrations of phenolic compounds, particularly flavonoids and other micronutrients, which impact human health due to their potent antioxidant, anti-inflammatory, and anticancer characteristics. In the present study, the effect of ethyl acetate, hydroethanol, hydromethanol, and aqueous extract from three date palm varieties (i.e., Ajwa, Siwi, and Sukkari) on phytochemical profiles and antioxidant and anticancer activities was investigated. Fruit extracts were screened for their antioxidant activity using the DPPH· method. Phenolic constituents were quantified and identified using HPLC-DAD. Extracts (ethyl acetate, hydroethanol, and hydromethanol) were assessed for cytotoxicity on nine human cancer cell lines, i.e., MG-63, HCT116, MCF7, MDA-MB-231, HEPG2, HUH7, A549, H460, and HFB4, using the sulphorhodamine-B (SRB) assay. Results showed that the ethyl acetate extract of the Sukkari fruits has the greatest antioxidant potential with an IC50 value of 132.4 ± 0.3 µg·mL-1, while the aqueous extract of Ajwa date fruits exhibited the lowest antioxidant effect with an IC50 value of 867.1 ± 0.3 µg·mL-1. The extracts exhibited potent to moderate anticancer activities against the investigated cancer cell line in a source-dependent manner. Methanol extract of Siwi fruits exhibited the most potent anticancer activity (IC50 = 99 ± 1.6 µg·mL-1), followed by the same extract of Sukkari fruits with an IC50 value of 119 ± 3.5 µg·mL-1 against the cell line of human breast cancer (MDA-MB-231). Additionally, principal component analysis (PCA) was investigated to determine the relationship among the investigated traits and treatments. Our findings reveal that date palm fruit-derived extracts are excellent sources of biologically active constituents and substantiate their potential use in new anticancer strategies from natural resources.

Novel fused imidazotriazines acting as promising top. II inhibitors and apoptotic inducers with greater selectivity against head and neck tumors: Design, synthesis, and biological assessments.

Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell carcinoma (HNSCC) subtype which is attributed to its reported multiple drug resistance (MDR). In the current study, we considered the essential pharmacophoric features of Dox as an effective Top. II inhibitor and sought to develop a novel set of imidazo[1,2-a] [1,3,5]triazin-2-amines (2a-2p) as a suggested anticancer option that could intercalate the DNA base pairs. We evaluated the % inhibition of the newly synthesized compounds on thirteen cancer cell lines and the analysis of structure-activity relationships revealed that the human head and neck cancer cell line (HNO97) was the most sensitive to their growth inhibition effect. Then, the IC50 values were recorded against the most sensitive cancer cell lines (HNO97, MDA-MB-231, and HEPG2), and compared to the normal cell line OEC (human oral epithelial cells). Compounds 2f and 2g showed very strong activities against HNO97 with IC50 values of (4 ± 1 and 3 ± 1.5 µg/mL), respectively, compared to that of Dox (9 ± 1.6 µg/mL). Next, a quantitative determination of human DNA Top. II concentrations in the most sensitive cell line (HNO97) were recorded for the most active anticancer derivatives. Again, compound 2f showed a superior Top. II inhibition with 87.86% compared to that of Dox (86.44%), while compound 2g achieved an inhibition of 81.37% which was close to the effect of Dox. To further investigate their effects on cell cycle progression and apoptosis induction in HNO97 cells, both 2f and 2g were selected for analysis. Both candidates arrested cell cycle progression at both the S and G2-M phases, as well as increased the early and late apoptosis phase ratios. Besides, both 2f and 2g were subjected to protein expression analysis of apoptosis-related genes (p53, BAX, IL-6, and BCL2). Moreover, the antioxidant effect of 2f and 2g was evaluated by measuring GSH, MDA, and NO markers in HNO97 cells. Furthermore, molecular docking for the newly designed tricyclic derivatives against both the Top. II and DNA double helix was carried out.

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N-(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies.

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC50 and inhibitory concentration 50 (IC50) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with an IC50 value of 0.73 µg/mL. Moreover, F3e was selected for further elucidation of a possible mode of action where the results showed that it exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition. Besides, molecular docking and MD simulations towards the SARS-CoV-2 Mpro were performed. Finally, a structure-activity relationship (SAR) study focussed on studying the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide in addition to compound contraction on SARS-CoV-2 activity.HighlightsEmulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g).The most potent 3e-loaded EMLs (F3e) showed an IC50 value of 0.73 µg/mL against SARS-CoV-2.F3e exhibited a combination of virucidal (>90%), viral adsorption (>80%), and viral replication (>60%) inhibition.Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA calculations were performed.Structure-activity relationship (SAR) study was discussed to study the influence of altering the size, type, and flexibility of the α-substituent to the carboxamide on the anti-SARS-CoV-2 activity.

Biological evaluation, docking studies, and in silico ADME prediction of some pyrimidine and pyridine derivatives as potential EGFRWT and EGFRT790M inhibitors.

Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds 8 and 14 displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds 8 and 14 were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates.

Enhanced cytotoxic effect of doxorubicin conjugated gold nanoparticles on breast cancer model.

BACKGROUND: The difficulty of achieving targeted drug delivery following administration of presently marketed anticancer therapeutics is still a concern. Metallic nanoparticles (NPs) appear to be promising in this regard. The present study focused on the use of gold nanoparticles (AuNPs) as a drug carrier for anticancer Doxorubicin (DOX) forming DOX-AuNPs nanocomposite. The anticancer effect of the prepared nanocomposite was evaluated using SRP essay on breast cancer cell line (MCF7) for different incubation times (24 h,48, and72hr). The prepared DOX-AuNPs nanocomposite was investigated by UV-visible spectroscopy, TEM, fluorescence spectroscopy, and FTIR spectroscopy. RESULTS: Our results showed that the prepared AuNPs and DOX-AuNPs nanocomposite have spherical and small size10 ± 2 nm and 12 ± 2 nm respectively. The potential cytotoxicity of the DOX-AuNPs nanocomposite on the MCF7 cell line was significantly increased compared to free DOX. The 20 µM DOX- AuNPs nanocomposite produced a similar decrease in cell survival as 80 µM free DOX. CONCLUSION: Future work is in progress to investigate the positive effects of the prepared nanocomposite for chemo-photothermal combination treatment.

Pivotal Role of Copper Nanoparticles Shelled by Turmeric or Sumac on Huh-7 Cell Line Cytotoxicity, Apoptosis and Antioxidant Capacity.

<b>Background and Objective:</b> Cancer is a complex interaction among multiple signalling pathways involving a variety of target molecules. Nanoparticles were used in cancer treatment because of their intrinsic anticancer properties. The use of plant extracts in the preparation of metallic nanoparticles as a convenient substitute has been proposed. This study assessed the cytotoxic, antioxidant and apoptotic effects of copper nanoparticles shelled with either turmeric or sumac biosynthesized as core-shell nanostructures on the liver tumour cell line (Huh-7). <b>Materials and Methods:</b> The nanostructures were synthesized by sonochemical method and characterization was done to confirm the successful synthesis within the nanoscale. Cytotoxicity of nanostructures was investigated on Huh-7 and normal kidney epithelial cell lines (VERO). Malondialdehyde, nitric oxide, reduced glutathione and superoxide dismutase were estimated in cell lysate to assess the antioxidant properties of nanostructures. Caspase-3 was also measured as an apoptotic marker. <b>Results:</b> Both nanostructures had low IC₅₀ on Huh-7 cells and a non-toxic effect on VERO cells. The cytotoxic effect was coupled with a significant increase in antioxidant activities and apoptotic efficiency compared to control. <b>Conclusion:</b> The findings summarized here support the utilization of biosynthesized copper with turmeric or sumac as core-shell nanostructures as a novel chemotherapeutic drug for cancer treatment that improves antioxidant effect that modulates the side effect of cytotoxicity. Also, it is obvious that copper nanostructure biosynthesized with turmeric has a more advanced effect than that of sumac.