Publications by authors named "Mohamed A Tantawy"

21 Publications

  • Page 1 of 1

Synthesis, antimicrobial, anti-cancer and in silico studies of new urea derivatives.

Bioorg Chem 2021 Jul 29;112:104953. Epub 2021 Apr 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt.

The reaction of an alkyl or aryl isocyanates with some primary amines in acetonitrile at room temperature afforded the corresponding alkyl- and aryl-urea derivatives. All the prepared urea compounds have been elucidated by FTIR, NMR, and elemental analysis. The compounds 1 and 3 were confirmed by single-crystal X-ray diffraction. The 4-tolylsulfonyl isocyanate reacted with the aryl amines 1, 2, 3, and 2,4-dichloroaniline to afford the corresponding sulfonylurea derivatives 5-8. Likewise, the reaction of the isocyanates with 2,4-dichloroaniline, 5-methyl isoxazole-3-amine, and 2-aminothiazole derivatives gave the corresponding urea derivatives 9-17. All the prepared compounds 5-17 were tested in vitro as anti-microbial and anti-HepG2 agents. Moreover, analyzing gene expression of TP53-exon4 and TP53-exon7, DNA damage values, and DNA fragmentation percentages have been discussed. The compounds 5 and 8 recorded the highest activity against the tested microbial strains with maximum activity against C. albicans (50 mm) and B. mycoides (40 mm), respectively. The compounds 5 inhibited the growth of E. coli, S. aureus, and C. Albicans at the MIC level of 0.0489 µM, while the compound 8 was able to inhibit the visible growth of E. coli and C. albicans at MIC value of 3.13 µM and S. aureus at 0.3912 µM. In the same line, compound 5 showed the best cytotoxic activity against the HepG2 cell line (IC = 4.25 µM) compared to 5 fluorouracil with IC = 316.25 µM. Expression analysis of liver cancer related to a gene including TP53-exon4 and TP53-exon7 was used in HepG2 Liver cancer cell lines using RT-qPCR. The expression values of TP53-exon4 and TP53-exon7 genes were decreased. The DNA damage values and DNA fragmentation percentages were increased significantly (P < 0.01) in the treated HepG2 (5) sample compared with the negative control. Docking studies were performed for the synthetic compounds against 2 bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics, and one cell division protein kinase 2 (CDK2) as target for anticancer drugs.
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http://dx.doi.org/10.1016/j.bioorg.2021.104953DOI Listing
July 2021

5-Aryl-1-Arylideneamino-1-Imidazole-2(3)-Thiones: Synthesis and In Vitro Anticancer Evaluation.

Molecules 2021 Mar 18;26(6). Epub 2021 Mar 18.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt.

A novel series of arylidene amino imidazole-2-thiones were synthesized, identified using IR, H-NMR, and C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles and exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds and displayed good inhibitory activity compared with reference drug erlotinib.
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http://dx.doi.org/10.3390/molecules26061706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003321PMC
March 2021

Evaluation of antioxidant and anticancer activity of crude extract and different fractions of Chlorella vulgaris axenic culture grown under various concentrations of copper ions.

BMC Complement Med Ther 2021 Feb 5;21(1):51. Epub 2021 Feb 5.

Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza, 12613, Egypt.

Background: Chlorella vulgaris is a microalga potentially used for pharmaceutical, animal feed, food supplement, aquaculture and cosmetics. The current study aims to study the antioxidant and prooxidant effect of Chlorella vulgaris cultivated under various conc. of copper ions.

Methods: The axenic green microalgal culture of Chlorella vulgaris was subjected to copper stress conditions (0.00, 0.079, 0.158, 0.316 and 0.632 mg/L). The growth rate was measured at OD nm and by dry weight (DW). Moreover, the Antioxidant activity against DPPH and ABTS radical, pigments and phytochemical compounds of the crude extracts (methylene chloride: Methanol, 1:1) were evaluated. The promising Cu crude extract (0.316 mg/L) further fractionated into twenty-one fractions by silica gel column chromatography using hexane, chloroform and ethyl acetate as a mobile phase.

Results: The obtained results reported that nine out of these fractions exhibited more than 50% antioxidant activity and anticancer activity against Hela cancer cell lines. Based on IC, fraction No. 7 was found to be the most effective fraction possessing a significant increase in both antioxidant and anticancer potency. Separation of active compound (s) in fraction No 7 was performed using precoated silica gel plates (TLC F) with ethyl acetate: hexane (9:1 v/v) as mobile phase. Confirmation of active compound separation was achieved by two-dimensional TLC and visualization of the separated compound by UV lamp. The complete identification of the separated active compound was performed by UV- Vis- spectrophotometric absorption, IR, MS, H-NMRT C-NMR. The isolated compound ((2E,7R,11R)-3,7,11,15-Tetramethyl-2-hexadecenol) have high antioxidant activity with IC (10.59 μg/ml) against DPPH radical assay and comparable to the capacities of the positive controls, Butylated hydroxy toluene [BHT] (IC 11.2 μg/ml) and Vitamin C (IC 12.9 μg/ml). Furthermore, pure isolated compound exhibited a potent anticancer activity against Hela cell line with IC (4.38 μg/ml) compared to Doxorubicin (DOX) as synthetic drug (13.3 μg/ml). In addition, the interaction of the pure compound with Hela cancer cell line and gene expression were evaluated.

Conclusions: The authors recommend cultivation of Chlorella vulgaris in large scale under various stress conditions for use the crude extracts and semi purified fractions for making a pharmaco-economic value in Egypt and other countries.
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http://dx.doi.org/10.1186/s12906-020-03194-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863377PMC
February 2021

Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein.

Pharmaceuticals (Basel) 2021 Feb 1;14(2). Epub 2021 Feb 1.

Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.

Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax's pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds , and with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while and depicted noticeable activities against A549/lung adenocarcinoma cells (IC = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, , showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; , , , , and through RT-PCR assay. Improving the compound's pharmaceutical profile was undertaken by introducing within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound's cytotoxic activity. In conclusion, is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.
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http://dx.doi.org/10.3390/ph14020113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912796PMC
February 2021

Cytotoxicity, predictions and molecular studies for androstane heterocycle compounds revealed potential antitumor agent against lung cancer cells.

J Biomol Struct Dyn 2020 Dec 10:1-14. Epub 2020 Dec 10.

Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.

The IL6/JAK2/STAT3 axis dysregulation and the related downstream pathways are a major contributor to the progression of non-small-cell lung carcinoma (NSCLC) and mainly affect apoptosis. Furthermore, tubulin inhibitors are potential chemotherapeutic agents against NSCLC. In this study, we have provided new molecular insights into the antiproliferative activity of six 3β-acetoxy-5α-androstane heterocycle compounds against NSCLC. The cell line A549, which represents a good model of NSCLC, was used to evaluate the antitumour activity of tested androstane derivatives, and non-cancerous gingival mesenchymal stem cell line (GMSC) were used to assess the specificity and toxicity of the tested compounds. Further on, molecular docking predictions were used to determine the molecular targets for the most promising cytotoxic compound. To assess apoptosis and cell cycle progression in treated A549 cells, flow cytometry was used. RT-qPCR and ELISA analyses were used to gain deep insights into cellular and molecular mechanisms. Results revealed that compound has potential cytotoxicity on A549 cells, with lower IC value (27.36 μM). Moreover, , compound showed a good binding affinity to JAK2 and tubulin-colchicine soblidotin molecular targets. This was further confirmed on the molecular level. Compound has also led to apoptosis and increased fragmentation of DNA, and mitochondrial dysfunction. Our findings have provided good evidence that compound may be a dual inhibitor of IL6/JAK2/STAT3 and tubulin formation in lung cancer. These findings support further molecular exploration of this androstane derivative as promising anti-lung cancer agent.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1856188DOI Listing
December 2020

Antimicrobial evaluation and docking study of some new substituted benzimidazole-2yl derivatives.

Bioorg Chem 2020 08 26;101:103972. Epub 2020 May 26.

Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, 12622, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza 12622, Egypt.

Benzimidazoles incorporated biologically active heterocycles such as quinoline, triazine-3-thione, thiazole and thiadiazole, were synthesized utilizing 2-acetylbenzimidazole as a building block. The structures of the newly synthesized benzimidazoles were assured by their spectral data (IR, H NMR, C- NMR and MS spectra). Most of the synthesized candidates were screened for their in vitro antimicrobial activity against Staphylococcus aureus, Escherichia coli, Bacillus pumilus and antifungal activity against (Saccharomyces cerevisiae). As a result, 2-(2-(1-(1H-benzo[d]imidazol-2-yl)ethylidene)hydrazineyl)-5-(furan-2-yl)-1,3,4-thiadiazole (14) had the most potent inhibitory activity against all tested bacteria with no antifungal inhibition. Furthermore, to gain insight into the mode of action of the synthesized compounds as antibacterial agents, docking studies were performed for the synthesized compounds in order to evaluate their activity as anti-bacterial agents. Virtual screening of the most promising compounds was performed against two bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics.
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http://dx.doi.org/10.1016/j.bioorg.2020.103972DOI Listing
August 2020

Thymoquinone-chemotherapeutic combinations: new regimen to combat cancer and cancer stem cells.

Naunyn Schmiedebergs Arch Pharmacol 2020 09 26;393(9):1581-1598. Epub 2020 May 26.

Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, 12144, USA.

Cancer is a worldwide disease that causes millions of cases of mortality and morbidity. The major problem associated with the cancer is its resistance to conventional therapy and a high relapse rate. The use of chemotherapy to treat cancer began at the start of the twentieth century with attempts to control cancer. In time advance, many cancer chemotherapeutic agents have been developed for cancer treatment with different mechanisms of action including the alkylating agents, antimetabolites, antimicrotubule, topoisomerase inhibitors, and cytotoxic antibiotics, all of which have toxic effects toward normal cells in the body. Here, we reviewed chemotherapeutics' anticancer role potentiation and safety by thymoquinone (TQ) alone or in combination with the most common therapeutic drugs. Our search was done through PubMed, Science Direct, Springer Link, Taylor & Francis Online, Wiley Online Library, Nature publication group, SAGE Journals, and Web of Science databases. We recognized that TQ-chemotherapeutics combination increased chemo-modulation to the anticancer effect of different chemotherapeutics and protected the normal body cells from the toxic injuries that are induced by chemotherapeutics based on its antioxidant power. Moreover, the current study investigates the possible combinatory effect of TQ and chemotherapeutics to control cancer stem cells through molecular docking targeting of wingless/integrated (Wnt) and Hedgehog (Hh). We found that TQ modulates the Wnt and Hh pathways, by binding with tankyrase-2 and smoothened 7TM receptor, respectively, more efficiently than most chemotherapeutics drugs, while methotrexate showed high-binding affinity compared with TQ. Therefore, we encourage researchers to investigate the chemo-modulatory potential and protective effects of TQ in combination with chemotherapeutics for either cancer or cancer stem cell treatment.
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http://dx.doi.org/10.1007/s00210-020-01898-yDOI Listing
September 2020

Synthetic antiprotozoal thiazolide drug induced apoptosis in colorectal cancer cells: implications of IL-6/JAK2/STAT3 and p53/caspases-dependent signaling pathways based on molecular docking and in vitro study.

Mol Cell Biochem 2020 Jun 30;469(1-2):143-157. Epub 2020 Apr 30.

Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt.

Colorectal cancer (CRC) is a global pressing healthcare priority. Dysregulation of the IL6/JAK2/STAT3 and p53/caspase downstreaming pathways are significantly involved in the progression of CRC, and mainly affecting apoptosis. Discovery of new anti-cancer agents is laborious, time consuming, and costly with obvious socioeconomic burden. In the present study, we are proposing new molecular insights on the anti-proliferative and apoptotic therapeutic effects of nitazoxanide (NTZ) on CRC. NTZ is FDA-approved thiazolide antiparasitic agent, which has excellent safety and pharmacokinetic profiles. The molecular docking study revealed that NTZ has better binding affinity and docking score against JAK2 and BCL2 proteins compared to 5-Fluorouracil, which is the standard drug for treatment of CRC. The current in vitro work on a human HCT116 cell line displayed that NTZ had lower IC value (11.20 µM) than 5-flurouracil (23.78 µM), and NTZ induced a statistically significant down-regulation of IL6/JAK2/STAT3. NTZ also modulated significantly the p53/caspases-dependent signaling pathways, leading to enhancement of apoptosis and an increase of DNA fragmentation. Moreover, NTZ regulated the Bcl-2 gene family and promoted the loss of mitochondrial function which was depicted by release of cytochrome c (Cyt c), and caspase activation in apoptotic HCT116 cells. Additionally, NTZ was able to reduce the expression of VEGF in CRC cell line, which needs future thorough molecular investigations. In conclusion, our findings provided a novel evidence that NTZ could be a dual potential IL6/JAK2/STAT3 signaling inhibitor and p53/caspases-dependent pathway activator in CRC cell line. These potentials support further exploratory molecular researches targeting the therapeutic roles of NTZ in CRC; individually and simultaneously with current approved chemotherapeutic regimens.
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http://dx.doi.org/10.1007/s11010-020-03736-4DOI Listing
June 2020

Molecular docking, anti-proliferative activity and induction of apoptosis in human liver cancer cells treated with androstane derivatives: Implication of PI3K/AKT/mTOR pathway.

J Steroid Biochem Mol Biol 2020 04 23;198:105604. Epub 2020 Jan 23.

Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt. Electronic address:

Worldwide, cancer is still an area with high unmet medical need. Lead optimization efforts towards structure-based drug design were employed to discover newly synthesized hetero-steroid derivatives with promising anticancer effects against hepatocellular carcinoma (HCC). The aim of our study is to evaluate the anti-proliferative activity and the mechanism, a dual PI3K/mTOR inhibitor, and mechanism of action of a series of heterocylic androstane derivatives as anti-HCC agent. The cytotoxic effects of different heterocylic androstanes and 5FU as single agents, were assessed against both HepG2 cells and Non-malignant MDCK cell line to assess the toxicity. Then the underlying mechanism of compound 4 as most promising compound was evaluated using molecular docking, MTT assay, cell cycle analysis, DNA fragmentation, and real-time PCR. The results of MTT assay showed potential cytotoxic effect for compound 4 and 5 against liver cancer cell line with IC value 39.81 and 57.54 μM, respectively. Inhibition of the PI3K/AKT/mTOR pathway was achieved by compound 4, which was documented by molecular docking and augmented by gene expression analysis. Detailed mechanism revealed that compound 4 induced cell cycle arrest, DNA fragmentation, and induction of apoptosis by inhibition of anti-apoptotic genes, and upregulation of apoptotic genes. Our results shed a light on aminopyrazoloandrostane derivative 4 as an inhibitor of the PI3K/AKT/mTOR pathway, which might be acting as promising anti-liver cancer agent. Our data support further investigation of agents targeting the PI3K/AKT/mTOR.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105604DOI Listing
April 2020

Role of nanoparticles in osteogenic differentiation of bone marrow mesenchymal stem cells.

Cytotechnology 2020 Feb 13;72(1):1-22. Epub 2019 Nov 13.

Hormones Department, Medical Research Division, National Research Centre, 33 EL Bohouth St. (former EL -Tahrir st.), Dokki, Giza, P.O. 12622, Egypt.

The present study aimed to investigate the osteoinductive potentiality of some selected nanostructures; Hydroxyapatite (HA-NPs), Gold (Au-NPs), Chitosan (C-NPs), Gold/hydroxyapatite (Au/HA-NPs) and Chitosan/hydroxyapatite (CH-NPs) on bone marrow- derived mesenchymal stem cells (BM-MSCs). These nanostructures were characterized using transmission electron microscope and Zetasizer. MSCs were isolated from bone marrow of rat femur bones and their identity was documented by morphology, flow cytometry and multi-potency capacity. The influence of the selected nanostructures on the viability, osteogenic differentiation and subsequent matrix mineralization of BM-MSCs was determined by MTT assay, molecular genetic analysis and alizarin red S staining, respectively. MTT analysis revealed insignificant toxicity of the tested nanostructures on BM-MSCs at concentrations ranged from 2 to 25 µg/ml over 48 h and 72 h incubation period. Notably, the tested nanostructures potentiate the osteogenic differentiation of BM-MSCs as evidenced by a prominent over-expression of runt-related transcription factor 2 (Runx-2) and bone morphogenetic protein 2 (BMP-2) genes after 7 days incubation. Moreover, the tested nanostructures induced matrix mineralization of BM-MSCs after 21 days as manifested by the formation of calcium nodules stained with alizarin red S. Conclusively, these data provide a compelling evidence for the functionality of the studied nanostructures as osteoinductive materials motivating the differentiation of BM-MSCs into osteoblasts with the most prominent effect observed with Au-NPs and Au/HA-NPs, followed by CH-NPs.
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http://dx.doi.org/10.1007/s10616-019-00353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002803PMC
February 2020

Molecular Docking Study, Cytotoxicity, Cell Cycle Arrest and Apoptotic Induction of Novel Chalcones Incorporating Thiadiazolyl Isoquinoline in Cervical Cancer.

Anticancer Agents Med Chem 2020 ;20(1):70-83

Chemistry Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.

Background: Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities.

Objective: The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer.

Methods: An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline was developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines.

Results: Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s 66.1, 51.3, and 85.1μM, respectively. Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding.

Conclusion: We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.
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http://dx.doi.org/10.2174/1871520619666191024121116DOI Listing
January 2021

Synthesis of novel hybrid hetero-steroids: Molecular docking study augmented anti-proliferative properties against cancerous cells.

Steroids 2020 02 30;154:108527. Epub 2019 Oct 30.

Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt. Electronic address:

Hetero-steroids, hybrid anticancer agents, have received much interest in view of their numerous and promising biological activities. In this study, a novel class of hetero-steroids were synthesized, analytical and spectral data proved the validity of the novel synthesized steroid derivatives. The cytotoxicity of the synthesized compounds 2, 5, 6, 7, 10, 11, 12, 14, 15, 17 were evaluated using human hepatocellular carcinoma cell lines (HepG2 and Huh-7) and non-small cell lung cancer (A549) cell lines. The synthesized compounds reported a remarkable gradual decrease in the cell viability of the three tested cancer cell lines. It was observed that compounds 2 and 12 had the lowest IC and the highest cytotoxic effects against all tested cell lines. As attempt to explain the cytotoxic activity achieved by the tested compounds in the in vitro study, molecular simulation was done to reveal the activity of the tested compounds against four different proteins (CDK2, CYP19, JAK2, and BCL2) which are highly implicated in cancer regulation and progression. We found that compound 2, and 12 were the best docked compounds against all tested receptors, which was indicated by lowest binding energy compared to reference ligand. Interestingly enough, our molecular study was in agreement with the cytotoxic activity. As future prospective, we are recommending further study on compounds 2, and 12 against the four different proteins to prove their mode of action.
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http://dx.doi.org/10.1016/j.steroids.2019.108527DOI Listing
February 2020

Screening of different drug design tools to predict the mode of action of steroidal derivatives as anti-cancer agents.

Steroids 2019 12 3;152:108485. Epub 2019 Sep 3.

Hormones Department, Medical Research Division, National Research Centre, Cairo, Egypt.

There is a pressing need to discover and develop novel drugs against cancer. With the new era of bioinformatics, which integrates different aspects, drug development has been tremendously improved. Recently, extensive research was directed towards the rational modification of steroid molecules against different disease especially cancer. Moreover, heterocyclic steroid derivatives have shown a lot of different biological activities such as antimicrobial, anti-inflammatory, and anti-cancer activities. Molecular docking methods can be used to explore how the steroid derivatives conformations can adopt within the binding sites of specific macromolecular targets involved in cancer progression. We conducted this study to investigate the accuracy of different molecular docking calculations using different steroidal molecular targets, and to define the most accurate one to study the mode of action of steroid derivatives as potential anti-cancer drugs. Our results revealed that the Dock6, PLANTS, AutoDock, GLIDE (SP and XP), and GOLD (ASP, Chemscore, and PLP) software were able to maintain the binding mode of the co-crystallized ligands inside their proteins by achieving RMSD values lower than two. Moreover, molecular docking study revealed that compound 4, and 5 are promising steroidal derivatives as anti-cancer drugs. Further on, the cytotoxic activity of the selected steroidal derivatives were tested against leukemia cell line using MTT assay. The results revealed that compound 4, and 5 were potential cytotoxic agents against THP-1 cells (ICs were 44.67 µM, and 46.77 µM, respectively), these results are in agreement with the molecular docking study.
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http://dx.doi.org/10.1016/j.steroids.2019.108485DOI Listing
December 2019

Deregulated MicroRNA Signature Following Glioblastoma Irradiation.

Cancer Control 2019 Jan-Dec;26(1):1073274819847226

4 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.

Glioblastoma (GBM), the most common and aggressive brain tumor in adults, shows resistance to treatment, particularly radiotherapy. One method for effective treatment is using a group of radiosensitizers that make tumor cells responsive to radiotherapy. A class of molecules whose expression is affected by radiotherapy is the microRNAs (miRNAs) that present promising regulators of the radioresponse. Eighteen miRNAs (miR-26a, -124, -128, -135b, -145, -153, -181a/b, -203, -21, -210, -212, -221/222, -223, -224, -320, and -590), involved in the pathogenesis of GBM and its radioresponsive state, were reviewed to identify their role in GBM and their potential as radiosensitizing agents. MicroRNAs-26a, -124, -128, -145, -153, -181a/b, -203, -221/222, -223, -224, -320, and -590 promoted GBM radiosensitivity, while microRNAs-135b, -21, -210, and -212 encouraged radioresistance. Ectopic overexpression of the radiosensitivity promoting miRNAs and knockdown of the radioresistant miRNAs represent a prospective radiotherapy enhancement opportunity. This offers a glimmer of hope for a group of the most unfortunate patients known to medicine.
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http://dx.doi.org/10.1177/1073274819847226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501491PMC
November 2019

Comprehensive data analysis for development of custom qRT-PCR miRNA assay for glioblastoma: a prevalidation study.

Epigenomics 2019 02 22;11(4):367-380. Epub 2019 Feb 22.

Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.

Aim: Glioblastoma (GB) is one notable example of miRNA-modulated neoplasms. Given its unique expression signature, proper miRNA profiling can help discriminate between GB and other types of brain tumors. The current work aimed to develop a more GB-specific and applicable custom designed quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) miRNA assay.

Materials & Methods: A comprehensive data analysis of bioinformatics databases, previous literature and commercially available pre-designed miRNA PCR arrays within the market.

Results: A highly enriched panel of 84 deregulated and GB-specific miRNAs has been developed.

Conclusion: After validation of this newly developed array, it can not only save the researcher's time and effort, but can also have a potential diagnostic and/or prognostic role in GB, paving the road toward personalized medicine.
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http://dx.doi.org/10.2217/epi-2018-0134DOI Listing
February 2019

Synthesis and Evaluation of Novel Cholestanoheterocyclic Steroids as Anticancer Agents.

Appl Biochem Biotechnol 2019 Jul 6;188(3):635-662. Epub 2019 Jan 6.

Hormones Department, National Research Centre, Dokki, Giza, 12622, Egypt.

Modification of steroid molecules by introducing heterocyclic ring into the core structure of steroids has been utilized as an attractive approach for either cancer prognosis or diagnosis. Several new cholestanoheterocyclic steroids were synthesized, and analytical and spectral data proved the validity of the novel synthesized steroid derivatives. The cytotoxicity of synthesized compounds 3, 4, 5, 7, 9, 10, 13, 15b, and 16b was evaluated using human colorectal cancer HCT 116 and Caco-2, cervical cancer HeLa, hepatoma HepG2, and breast cancer MCF7 cell lines. Intriguingly, compound 13 has the highest cytotoxic effect when applied on the majority of cancer cells. In conclusion, compound 13 may be considered as a promising anticancer candidate against all cancer cell lines, because it recorded the lowest IC of the majority of the cancer cell lines used. Furthermore, a molecular docking study was employed to determine the binding modes against aromatase cytochrome P450 (CYP19), cyclin-dependent kinase 2 (CDK2), and B-cell lymphoma (BCL-2) proteins, which are major proteins involved in the pathogenesis of cancer. Molecular docking analyses revealed that compounds 13, 3, and 5 (free energy of binding = - 9.2, - 9.1, and - 9.0 kcal/mol, respectively) were the best docked ligand against aromatase CYP19; compounds 16b, 3, 9, and 10 (free energy of binding = - 9.6, - 9.3, and - 9.2 kcal/mol, respectively) were the best docked ligand against CDK2, while compounds 15b, 16b, and 13 (free energy of binding = - 9.1, - 9.0, and- 8.7 kcal/mol, respectively) were the best docked ligand against BCL2. In conclusion, compounds 3, 13, and 16b were the most promising compounds with the lowest ICs against most of the tested cancer cell lines, and they displayed the lowest binding energies, critical hydrogen bonds, and hydrophobic interactions with the three molecular targets compared to other tested compounds.
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http://dx.doi.org/10.1007/s12010-018-02943-6DOI Listing
July 2019

NS Segment of a 1918 Influenza A Virus-Descendent Enhances Replication of H1N1pdm09 and Virus-Induced Cellular Immune Response in Mammalian and Avian Systems.

Front Microbiol 2018 22;9:526. Epub 2018 Mar 22.

Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany.

The 2009 pandemic influenza A virus (IAV) H1N1 strain (H1N1pdm09) has widely spread and is circulating in humans and swine together with other human and avian IAVs. This fact raises the concern that reassortment between H1N1pdm09 and co-circulating viruses might lead to an increase of H1N1pdm09 pathogenicity in different susceptible host species. Herein, we explored the potential of different NS segments to enhance the replication dynamics, pathogenicity and host range of H1N1pdm09 strain A/Giessen/06/09 (Gi-wt). The NS segments were derived from (i) human H1N1- and H3N2 IAVs, (ii) highly pathogenic- (H5- or H7-subtypes) or (iii) low pathogenic avian influenza viruses (H7- or H9-subtypes). A significant increase of growth kinetics in A549 (human lung epithelia) and NPTr (porcine tracheal epithelia) cells was only noticed for the reassortant Gi-NS-PR8 carrying the NS segment of the 1918-descendent A/Puerto Rico/8/34 (PR8-wt, H1N1), whereas all other reassortants showed either reduced or comparable replication efficiencies. Analysis using tracheal organ cultures of turkeys (TOC-Tu), a species susceptible to IAV H1N1 infection, demonstrated increased replication of Gi-NS-PR8 compared to Gi-wt. Also, Gi-NS-PR8 induced a markedly higher expression of immunoregulatory and pro-inflammatory cytokines, chemokines and interferon-stimulated genes in A549 cells, THP-1-derived macrophages (dHTP) and TOC-Tu. , Gi-NS-PR8 induced an earlier onset of mortality than Gi-wt in mice, whereas, 6-week-old chickens were found to be resistant to both viruses. These data suggest that the specific characteristics of the PR8 NS segments can impact on replication, virus induced cellular immune responses and pathogenicity of the H1N1pdm09 in different avian and mammalian host species.
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http://dx.doi.org/10.3389/fmicb.2018.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874506PMC
March 2018

Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs.

Bioorg Chem 2017 08 20;73:128-146. Epub 2017 Jun 20.

Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.

Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically important properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and many structure-activity relationships have been confirmed by such synthetic modifications. Several studies demonstrate that steroidal heterocyclic derivatives can be effective in the prevention and treatment of many types of hormone-dependent cancers. The present review is a concise report on steroidal heterocyclic derivatives, with special emphasis on steroid heterocyclic derivatives with 5 membered rings or six-membered rings having interesting therapeutic potential as enzyme inhibitors and cytotoxic drugs to be used as candidates for anti-cancer drug development.
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http://dx.doi.org/10.1016/j.bioorg.2017.06.006DOI Listing
August 2017

The interferon-induced gene Ifi27l2a is active in lung macrophages and lymphocytes after influenza A infection but deletion of Ifi27l2a in mice does not increase susceptibility to infection.

PLoS One 2014 3;9(9):e106392. Epub 2014 Sep 3.

Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, Germany; University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

Interferons represent one of the first and essential host defense mechanisms after infection, and the activation of the IFN-pathway results in the transcriptional activation of hundreds of interferon-stimulated genes. The alpha-inducible protein 27 like 2A (Ifi27l2a) gene (human synonym: ISG12) is strongly up-regulated in the lung after influenza A infection in mice and has been shown in gene expression studies to be highly correlated to other activated genes. Therefore, we investigated the role of Ifi27l2a for the host defense to influenza A infections in more detail. RT-PCR analyses in non-infected mice demonstrated that Ifi27l2a was expressed in several tissues, including the lung. Detailed analyses of reporter gene expression in lungs from Ifi27l2a-LacZ mice revealed that Ifi27l2a was expressed in macrophages and lymphocytes but not in alveolar cells or bronchiolar epithelium cells. The number of macrophages and lymphocyte strongly increased in the lung after infection, but no significant increase in expression levels of the LacZ reporter gene was found within individual immune cells. Also, no reporter gene expression was found in bronchiolar epithelial cells, alveolar cells or infiltrating neutrophils after infection. Thus, up-regulation of Ifi27l2a in infected lungs is mainly due to the infiltration of macrophages and lymphocytes. Most surprisingly, deletion of Ifi27l2a in mouse knock-out lines did not result in increased susceptibility to infections with H1N1 or H7N7 influenza A virus compared to wild type C57BL/6N mice, suggesting a less important role of the gene for the host response to influenza infections than for bacterial infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106392PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153650PMC
May 2015

Infection- and procedure-dependent effects on pulmonary gene expression in the early phase of influenza A virus infection in mice.

BMC Microbiol 2013 Dec 17;13:293. Epub 2013 Dec 17.

Institute for Experimental Infection Research, TWINCORE Center for Experimental and Clinical Infection Research, Feodor-Lynen-Str, 7, Hannover 30625, Germany.

Background: Investigating the host response in the early stage of influenza A virus (IAV) infection is of considerable interest. However, it is conceivable that effects due to the anesthesia and/or intranasal infection procedure might introduce artifacts. We therefore aimed to evaluate the effects of anesthesia and/or intranasal infection on transcription of selected pulmonary mRNAs in two inbred mouse strains with differential susceptibility to IAV infection.

Results: DBA/2J and C57BL/6J mice were evaluated in a time course experiment in which lung tissue was sampled after 6, 12, 18, 24, 48 and 120 h. After anesthesia with ketamine and xylazine, a suspension of mouse-adapted IAV strain PR8_Mun in 20 μl sterile buffer, or 20 μl sterile buffer only, was instilled intranasally. The mice receiving anesthesia and PBS only were designated the "mock treatment" group. Pulmonary expression of 10 host mRNAs (Fos, Retnla, Irg1, Il6, Il1b, Cxcl10, Stat1, Ifng, Ifnl2, and Mx1) and viral hemagglutinin (HA) mRNA were determined at the designated time points. As expected, weight loss and viral replication were greater in the DBA/2J strain (which is more susceptible to IAV infection). Four mRNAs (Retnla, Irg1, Il6, and Cxcl10) were procedure-dependently regulated in DBA/2J mice between 6 and 24 h, and two (Retnla and Il6) in C57BL/6J mice, although to a lesser extent. All 10 mRNAs rose after infection, but one (Fos) only in DBA/2J mice. These infection-dependent effects could be separated from procedure-dependent effects beginning around 12 h in DBA/2J and 18 h in C57BL/6J mice. The interferon-related mRNAs Stat1, Ifng, Infl2, and Mx1 were unaffected by mock treatment in either mouse strain. Mx1 and Infl2 correlated best with HA mRNA expression (r = 0.97 and 0.93, respectively, in DBA/2J).

Conclusions: These results demonstrate effects of the anesthesia and/or intranasal infection procedure on pulmonary gene expression, which are detectable between approximately 6 and 24 h post procedure and vary in intensity and temporal evolution depending on the mouse strain used. Mock infection controls should be included in all studies on pulmonary gene expression in the early phase of infection with IAV and, likely, other respiratory pathogens.
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http://dx.doi.org/10.1186/1471-2180-13-293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880568PMC
December 2013

Novel modified steroid derivatives of androstanolone as chemotherapeutic anti-cancer agents.

Eur J Med Chem 2009 Oct 17;44(10):3936-46. Epub 2009 Apr 17.

Division of Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt.

The aim of the present study is to synthesize and evaluate new potential chemotherapeutic anti-tumor agents. Several thiazolo-, pyrido-, pyrano- and lactam steroid derivatives were obtained using 17beta-hydroxy-5alpha-androstan-3-one (androstanolone) 1 as starting steroid. The structure of the novel steroid derivatives was confirmed using the analytical and spectral data. The most pure and structurally promising compounds 7a, 10a, 12b, 18 and 23 were evaluated as anti-tumor agents. The in vitro cytotoxic activity was evaluated against hepatoma cell lines using MTT assay. Also the in vivo anti-tumor activity was evaluated against Ehrlich ascites carcinoma (EAC). The results of the in vitro study showed that at incubation time 72h, in olive oil, compound 7a was the most effective cytotoxic compound with IC(50) of 30 microM, while the effects of compounds 18 and 23 were approximately similar with IC(50) of 37 microM and 35 microM respectively. While the tested compounds when dissolved in DMSO showed approximately the same IC(50) at both 48 and 72h incubation period, compound 23 was the most effective cytotoxic with IC(50) 42 microM at 48h and 40 microM at 72h. The results of the in vivo study showed that all the tested novel compounds at 25mg/kg were effective against EAC. Our novel steroid derivatives are promising candidates as anti-cancer agents, none of the mice treated with our novel derivatives showed any toxic symptoms, but they also completely inhibited tumor growth and retained the hemoglobin content, body weight, and WBCs near normal values and similar to what obtained for the standard drug 5-flurouracil.
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http://dx.doi.org/10.1016/j.ejmech.2009.04.020DOI Listing
October 2009
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