Publications by authors named "Gamal A Elmegeed"

29 Publications

  • Page 1 of 1

Synthesis and cytotoxic evaluation of novel hybrid estrane heterocycles as chemotherapeutic anti-cancer agents.

Steroids 2021 Feb 27;169:108813. Epub 2021 Feb 27.

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

New synthesized hybrid steroidal heterocyclic compounds have received a lot of attention in view of their biological activities as anticancer agents. In this study, a novel class of hybrid estrane heterocyclic compounds were synthesized and evaluated by analytical and spectral data which proved the validity of these derivatives. The cytotoxicity of synthesized compounds 2a, 2b, 2c, 3b, 8, 10a, 10b, 13, 14, 16a and 19 against three human cell lines: breast cancer cells (MCF-7), prostate cancer cells (PC3), and liver cancer cells (HepG2) has been tested using MTT assay. Compounds 10a, 10b, 2c, and 14 revealed more inhibitory influence on MCF7, PC3 and HepG2 growth than the reference drug doxorubicin (Dox) after 24 h incubation. Noteworthy, the tested compounds 10a, 10b, 2c, and 14 exhibited the most pronounced effect in this respect. The results were confirmed by morphology study.
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http://dx.doi.org/10.1016/j.steroids.2021.108813DOI Listing
February 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

Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study.

Asian Pac J Cancer Prev 2019 Oct 1;20(10):3057-3070. Epub 2019 Oct 1.

Department of Hormones, Medical Research Division, National Research Centre, Dokki, Giza, Egypt.

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa -fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.
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http://dx.doi.org/10.31557/APJCP.2019.20.10.3057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982653PMC
October 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

The Effect of Newly Synthesized Heterosteroids on miRNA34a, 98, and 214 Expression Levels in MCF-7 Breast Cancer Cells.

Indian J Clin Biochem 2018 Jul 26;33(3):328-333. Epub 2017 Jul 26.

1Hormones Department, National Research Centre, Dokki, Giza, 12622 Egypt.

Hybrid anticancer drugs have emerged as great therapeutic options that can effectively overcome most obstacles facing conventional anticancer drugs. miRNAs are considered as class of non-coding RNAs that can negatively regulate protein coding gene expression. miRNA expression is commonly altered in cancer cells. The current work aimed to test the effect of new pro-apoptotic heterosteroids on some drug resistance related miRNAs expression levels (miRNA34a, 98, and 214) in MCF-7 breast cancer cells. After cell treatment with these compounds , , , , , , and , miRNAs were extracted and subjected to reverse transcription and subsequent PCR amplification using Real Time-PCR technique. The expression levels of miR-34a, miR-98 and miR-214 were quantitatively determined. The study revealed that the expression levels of miR-34a, miR-98 and miR-214 were up-regulated upon treatment with tamoxifen, which was used as a positive control drug, as compared to control cells,. Strikingly, the levels of miR-34a, miR-98 and miR-214 expression were significantly down-regulated when treated with most of the new heterosteroids as compared to control cells. These results could indicate the promising effects of these new heterosteroids on reducing drug resistance as compared to tamoxifen drug. As well established, cells develop drug resistance to tamoxifen.
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http://dx.doi.org/10.1007/s12291-017-0681-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052734PMC
July 2018

Novel pregnenolone derivatives modulate apoptosis via Bcl-2 family genes in hepatocellular carcinoma in vitro.

J Steroid Biochem Mol Biol 2018 10 10;183:125-136. Epub 2018 Jun 10.

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

A series of pregnenolone derivatives were synthesized and assessed for anti-cancer activity against hepatocellular carcinoma cell line (HepG2). The synthesized hetero-steroids (compounds 3, 4, 5, 6, 7, 8a and 8b) were evaluated for their cytotoxic activities using MTT (3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assay. Apoptotic activity was assessed using dual acridine orange/ethidium bromide staining method and DNA fragmentation assay. Pro-apoptotic genes (Bax and Bak) and anti-apoptotic genes (Bcl-2 and Bcl-xL) were analyzed using quantitative real time PCR. The results revealed that compounds 4 and 6 displayed cytotoxic activity (IC, 36.97 ± 2.18 and 18.46 ± 0.64 μM, respectively), while compounds 5 and 7 exhibited weak cytotoxic activity (IC, 93.87 ± 8.30 μM and 93.48 ± 4.14 μM, respectively). All synthesized heterocyclic pregnenolone derivatives induced apoptosis through DNA fragmentation. Compounds 4 and 6 increased early and late apoptotic cell percentages while compounds 3, 5, 7 and 8b increased either early or late apoptotic cell percentage. Moreover, compounds 3, 6 and 8b up-regulated the expression level of Bak gene. On the other hand, compounds 4, 5, 7 and 8a down-regulated the Bcl-2 expression level, besides, compounds 5, 7 and 8a down-regulated the Bcl-xL expression level. Compounds 5, 7, 8a and 8b increased the Bak/Bcl-xL ratio, besides, compound 8a raised the Bax/Bcl-xL ratio whereas compound 5 elevated Bax/Bcl-2 and Bak/Bcl-2 ratios. The present work introduced novel pro-apoptotic pregnenolone derivatives that acted against HepG2 cells through DNA fragmentation, apoptotic morphological changes and were able to increase the pro-apoptotic/anti-apoptotic ratios of Bcl-2 family genes. This study particularly revealed that the cytotoxic compound 4 is the most promising pro-apoptotic compound among other synthesized derivatives where it induced apoptosis (late and early) through the down-regulation of Bcl-2 gene expression level.
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http://dx.doi.org/10.1016/j.jsbmb.2018.06.006DOI Listing
October 2018

Synthesis, Characterization, and Evaluation of Cytotoxic Effects of Novel Hybrid Steroidal Heterocycles as PEG Based Nanoparticles

Asian Pac J Cancer Prev 2017 07 27;18(7):1937-1946. Epub 2017 Jul 27.

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

Anticancer agents featuring hybrid molecules can improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized heterocyclic steroids of promising anticancer effects loaded in polyethylene glycol (PEG)•based nanoparticles form. Several heterocyclic steroids (1-9) were synthesized via multicomponent reactions (MCRs) and confirmed via the analytical and spectral data. Compounds 1, 2, 3, 4, 5, 6, 7 and 9, were investigated individually in their free and PEG based nano-size hybrid forms as anticancer agents against three human cell lines: hepatocellular carcinoma cells (HepG2); breast cancer cells (MCF-7); and colon cancer cells (HCT116). The neutral red supravital dye uptake assay was employed. Compound 6 in its PEG based nano-size form exhibited the best cytotoxic effects against HepG2 and HCT116 cell lines, with IC50 values of 2.44 μmol/l and 2.59 μmol/l, respectively. In addition, it demonstrated a low IC50 value against MCF-7 (3.46μmol/l) cells. This study introduced promising anticancer agents acting through conversion into PEG-based nanoparticles.
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http://dx.doi.org/10.22034/APJCP.2017.18.7.1937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648402PMC
July 2017

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

Evaluation of heterocyclic steroids and curcumin derivatives as anti-breast cancer agents: Studying the effect on apoptosis in MCF-7 breast cancer cells.

Steroids 2016 11 21;115:80-89. Epub 2016 Aug 21.

Hormones Department, National Research Centre, Dokki, Giza, Egypt (ID:60014618).

Anticancer agents consisting of hybrid molecules are used to improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized hetero-steroids of promising anticancer effects. Besides, the pro-apoptotic effects of new compounds were investigated extensively. Several pyrimidino-, triazolopyrimidino-, pyridazino-, and curcumin-steroid derivatives were synthesized, elucidated and confirmed using the spectral and analytical data. The synthesized hetero-steroids, compounds 9, 10, 11, 12, 13, 14, 15, 18, 20, 21, 22 and 24, were tested for their cytotoxic effects versus human breast cancer cells (MCF-7) using neutral red supravital dye uptake assay. Compound 24 (IC50=18μM) showed more inhibitory influence on MCF-7 growth. Using QRT-PCR (Quantitative real time-polymerase chain reaction), CCND1, Survivin, BCL-2, CDC2, P21 and P53, genes expression levels were investigated. The study results disclose that compounds 4, 7, 18, 24 knocked down the expression levels of CCND1, Survivin, BCL-2 and CDC2. However, P21 and P53 were up-regulated by compounds 21, 22. This study introduced promising pro-apoptotic anticancer agents acting through the modulation of key regulators of apoptosis and cell cycle genes.
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http://dx.doi.org/10.1016/j.steroids.2016.08.014DOI Listing
November 2016

Synthesis of novel steroidal curcumin derivatives as anti-Alzheimer's disease candidates: Evidences-based on in vivo study.

Steroids 2015 Sep 13;101:78-89. Epub 2015 Jun 13.

Hormones Department, National Research Centre, Dokki, Giza, Egypt(1).

Alzheimer's disease (AD) is a complex disease in which a single monofunctional 'targeted' drug is uneffective for management. Hybrid drugs that impact multiple targets simultaneously are better at controlling such complex disease systems. Hybrid agents were synthesized through the combination of the steroid moiety with curcumin molecule. Also novel curcumin analogues containing promising heterocyclic nucleus fused to the essential pharmacophoric feature of the curcumin moiety, were synthesized. The aim of the present study was extended to elucidate the efficacy of these novel synthesized compounds in the regression of AD induced in adult female albino rats. The results revealed that treatment of AD groups with compounds 3, 5, 8c or rivastigmin experienced significant increase in brain Ach, GSH, paraoxenase and BCL2 levels with respect to untreated group associated with significant decrease in brain AchE activity, urinary 8-OHG level, serum Caspase-3 level and brain P53 level relative to the untreated group. Immunohistochemical investigation revealed that the selected treatments caused marked increase in ChAT positive cells. These findings were documented by the histological investigation of the brain tissue. The activity of tested compounds showed gradual increase from compound b followed by compound 8c then compound 5. The anti-cholinesterase potential, anti-oxidant properties and anti-apoptotic activity are responsible for the anti-Alzheimer's disease potential of these compounds.
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http://dx.doi.org/10.1016/j.steroids.2015.06.003DOI Listing
September 2015

Heterocyclizations of pregnenolone: novel synthesis of thiosemicarbazone, thiophene, thiazole, thieno[2,3-b]pyridine derivatives and their cytotoxicity evaluations.

Steroids 2012 Dec 12;77(14):1560-9. Epub 2012 Oct 12.

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

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring D modification of 1 through its reaction with 4-phenyl-3-thiosemicarbazide gave the thiosemicarbazone derivative 3. The latter compound underwent heterocyclization reactions to give the thiazolyl hydrazonoandrostane and pyrazolyl semicarbazidoandrostane derivatives 5a-d, and 9a-d, respectively. On the other hand compound 1 reacted with either malononitrile or ethyl cyanoacetate to give the Knoevenagel condensated products 11a and 11b, respectively. Compounds 11a,b afforded the thiophenyl pregnane derivatives 12a and 12b, respectively, their reactivity toward some chemical reagents was studied. The cytotoxicity of the newly synthesized heterocyclic steroids against three human tumor cell lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) were studied. Some of tested compounds were found to exhibit much higher inhibitory effects toward the three tumor cell lines than the reference drug, doxorubicin.
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http://dx.doi.org/10.1016/j.steroids.2012.09.004DOI Listing
December 2012

One-pot three-component synthesis of novel heterocyclic steroids as a central antioxidant and anti-inflammatory agents.

Steroids 2012 Nov 20;77(13):1469-76. Epub 2012 Sep 20.

Photochemistry Department, National Research Centre, Dokki, Cairo, Egypt.

Oxidative stress and inflammation have been implicated in several neurodegenerative and developmental brain disorders. The present work was devoted to the design and synthesis of novel steroid derivatives bearing promising heterocyclic moiety that would act to reduce neuro-inflammation and oxidative stress in brain. The novel heterocyclic steroids were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The tested compounds were assayed in the model of neuro-inflammation produced in rats by cerebral lipopolysaccharide injection. The intracerebral administration of bacterial endotoxin resulted in cerebral inflammatory state evidenced by increased malondialdehyde (MDA), decreased reduced glutathione (GSH) level, increased nitric oxide as well as increased acetylcholinesterase (AChE) activity in the brain. Compounds 6, 10, 8b and 13a markedly increased reduced glutathione. Malondialadehyde and nitric oxide levels were reduced to normal values after treatment with all tested compounds. AChE activity was normalized by compound 8b and reduced to below normal values by compounds 10 and 14a. These results are exciting in that these agents might be useful candidates in treatment of cerebral inflammation.
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http://dx.doi.org/10.1016/j.steroids.2012.09.001DOI Listing
November 2012

Sterol C24-methyltransferase: Physio- and stereo-chemical features of the sterol C3 group required for catalytic competence.

Arch Biochem Biophys 2012 May 14;521(1-2):43-50. Epub 2012 Mar 14.

Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.

Sterol C24-methyltransferases (24-SMTs) catalyze the electrophilic alkylation of Δ(24)-sterols to a variety of sterol side chain constructions, and the C3- moiety is the primary determinant for substrate binding by these enzymes. To determine what specific structural features of the C3-polar group ensure sterol catalysis, a series of structurally related C3-analogs of lanosterol that differed in stereochemistry, bulk and electronic properties were examined against the fungal 24-SMT from Paracoccidioides brasiliensis (Pb) which recognize lanosterol as the natural substrate. Analysis of the magnitude of sterol C24-methylation activity (based on the kinetic constants of V(max)/K(m) and product distributions determined by GC-MS) resulting from changes at the C3-position in which the 3β-OH was replaced by 3α-OH, 3β-acetyl, 3-oxo, 3-OMe, 3β-F, 3β-NH(2) (protonated species) or 3H group revealed that lanosterol and five substrate analogs were catalyzed and yielded identical side chain products whereas neither the 3H- or 3α-OH lanosterol derivatives were productively bound. Taken together, our results demonstrate a chemical complementarity involving hydrogen bonding formation of specific active site contacts to the nucleophilic C3-group of sterol is required for proper orientation of the substrate C-methyl intermediate in the activated complex.
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http://dx.doi.org/10.1016/j.abb.2012.03.002DOI Listing
May 2012

Cytotoxicity and gene expression profiles of novel synthesized steroid derivatives as chemotherapeutic anti-breast cancer agents.

Bioorg Med Chem 2011 Nov 22;19(22):6860-72. Epub 2011 Sep 22.

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

Anti-cancer agents which combine two biologically active compounds in one such as steroidal heterocyclic derivatives attain both hormone and cytotoxic effects on cancer cells. The aim of the present study is to synthesize and evaluate new potential chemotherapeutic anti-breast cancer agents. Several pyridazino-, pyrimido-, quinazolo-, oxirano- and thiazolo-steroid derivatives were synthesized. The structure of the novel steroid derivatives was confirmed using the analytical and spectral data. The most structurally promising of the novel synthesized steroid derivatives, compounds 8, 12, 17, 20, 22c, 24c, 30a and 30b, were investigated individually as anti-breast cancer agents against human breast cancer cells (MCF-7) using sulforhodamine B (SRB) assay. The tested compounds 17, 20, 22c and 8 showed potent broad spectrum cytotoxic activity in vitro after 48 h incubation. Compound 17 (IC(50)=2.5 μM) exhibited more inhibitory influence on MCF-7 growth than the reference drug doxorubicin (Dox) (IC(50)=4.5 μM) after 48 h incubation. Also, the present study showed that all the tested steroid derivatives exhibited significant depletion with various intensities in gene expression of breast cancer related genes (VEGF, CYP19 and hAP-2γ). Noteworthy, compounds 17, 20 and 22c showed the most pronounced effect in this respect.
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http://dx.doi.org/10.1016/j.bmc.2011.09.033DOI Listing
November 2011

Evaluation of anti-inflammatory, anti-nociceptive, and anti-ulcerogenic activities of novel synthesized thiazolyl and pyrrolyl steroids.

Arch Pharm (Weinheim) 2011 Sep 25;344(9):595-604. Epub 2011 Aug 25.

Organic Chemistry Department, October University of Modern Sciences and Arts (MSA), Egypt.

Developing new therapeutic agents that can overcome gastrointestinal injury and at the same time could lead to an enhanced anti-inflammatory effect becomes an urgent need for inflammation patients. Thiazolyl and pyrrolyl steroids were synthesized via straight forward and efficient methods and their structures were established based on their correct elemental analysis and compatible IR, (1) H-NMR, (13) C-NMR, and mass spectral data. The dihydrothiazolyl-hydrazonoprogesterone 12 and the aminopyrrolylprogesterone 16a showed anti-inflammatory, antinociceptive, and anti-ulcerogenic activity with various intensities. Edema were significantly reduced by both doses of tested compounds (25 and 50 mg/kg) at 2, 3, and 4 h post-carrageenan. The high dose of compound 16a was the most effective in alleviating thermal pain. Gastric mucosal lesions, caused in the rats by the administration of ethanol or indomethacin (IND), were significantly inhibited by each of the two tested compounds. These results provide a unique opportunity to develop new anti-inflammatory drugs which devoid the ulcerogenic liabilities associated with currently marketed drugs.
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http://dx.doi.org/10.1002/ardp.201000366DOI Listing
September 2011

Synthesis of modified steroids as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agents.

Steroids 2011 Sep-Oct;76(10-11):1190-203. Epub 2011 May 31.

Organic Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts, Elwahaat Road, October City, Egypt.

The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study.
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http://dx.doi.org/10.1016/j.steroids.2011.05.011DOI Listing
November 2011

Development of new indole-derived neuroprotective agents.

Bioorg Med Chem 2011 May 21;19(9):2966-74. Epub 2011 Mar 21.

Organic Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts, October City, Egypt.

There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. The present study aimed at synthesizing new functionalized indole derivatives with structures justifying neuroprotective activity using L-tryptophan (TRP) as starting material. The potential neuroprotective effect of these newly synthesized agents against acrylamide (ACR) induced neurotoxicity was investigated in adult female rats. The novel indole derivatives, indolylmethyl pyridine derivatives 9a,b, pyrimidinylindolyl propanone derivatives 12a-c, pyrazolylindolyl propanone derivatives 14a,b, and indolyl tetrazolopropanoic acid derivative 17 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [ip, 50mgkg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with the indole derivatives 9b, 12c, 14a, and 17 (ip, 50mgkg(-1) b. wt.) prior to ACR produced neuroprotective activity with various intensities depending on the structure of each compound. Compound 17 in which the tetrazole ring was attached to the TRP moiety ranked as the strongest neuroprotective agent. All the tested compounds have been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by ACR administration.
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http://dx.doi.org/10.1016/j.bmc.2011.03.031DOI Listing
May 2011

Potent neuroprotective role of novel melatonin derivatives for management of central neuropathy induced by acrylamide in rats.

Eur J Med Chem 2010 Nov 17;45(11):5452-9. Epub 2010 Sep 17.

Hormones Department, National Research Centre, Dokki, Cairo, Egypt.

Acrylamide (ACR) has been shown to be a neurotoxic agent for both laboratory animals and human. The present study aimed at synthesizing new functionalized melatonin derivatives bearing promising heterocyclic moiety that could be expected to have protective effect against ACR-induced neurotoxicity in adult female rats. The novel melatonin derivatives 4, 6, 7 and 11 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [i.p., 50 mg kg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with melatonin derivatives 4, 6, 7 and 11 (i.p., 50 mg kg(-1) b. wt) prior to ACR produced significant decrease in brain MDA level and LDH activity with concomitant significant increase in brain monoamines and antioxidant enzymes activity. It could be concluded that the new synthesized melatonin derivatives exhibited promising protective activity against ACR-induced neurotoxicity.
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http://dx.doi.org/10.1016/j.ejmech.2010.09.017DOI Listing
November 2010

Synthesis and antidepressant evaluation of five novel heterocyclic tryptophan-hybrid derivatives.

Arch Pharm (Weinheim) 2010 May;343(5):261-7

Pharmacology Department, National Research Centre, Dokki, Cairo, Egypt.

This study aimed at evaluating the reactivity of L-Tryptophan (TRP) 1 towards various chemical reagents to produce new bi- and tri-heterocyclic systems providing basic pharmacological activities. Indol-3-yl hydroxyoxazol-2-yl acetonitrile derivatives 5 and 6, indol-3-yl-hydroxyoxazol-2-yl-1,2,4-triazine derivatives 8 and 9, indol-3-yl-hydroxyoxazol-2-yl-aminopyrazole derivatives 11a, b, and indol-3-yl-hydroxyoxazol-2-yl-aminoisoxazole derivative 12 were synthesized via straightforward and efficient methods. The structures were characterized by spectral data (IR, (1)H-NMR, (13)C-NMR, and MS) and the purity was ascertained by microanalysis. Also, this work was extended to study the potential role of the novel synthesized TRP derivatives 5, 6, 9, 11a, and 12 as antidepressant and sedative agents in comparison with TRP. All compounds showed significant antidepressant activity in the forced-swimming test at two doses (50 or 100 mg/kg). Also, all tested compounds (at 50 or 100 mg/kg) produced a significant decrease in locomotor activity of mice during a 30 min observation period. The most potent antidepressant and sedative effect was produced by the tri-heterocyclic compounds 9 and 12, followed by 11a and TRP.
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http://dx.doi.org/10.1002/ardp.200900244DOI Listing
May 2010

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

Androgenic profile and genotoxicity evaluation of testosterone propionate and novel synthesized heterocyclic steroids.

J Steroid Biochem Mol Biol 2008 Jun 22;110(3-5):284-94. Epub 2008 Apr 22.

Hormones Department, National Research Center, 12622 Dokki, Cairo, Egypt.

In this study, we tested the androgenic activity of three structurally promising novel synthesized heterocyclic steroids compared with testosterone propionate in male mice. Additionally, the possible genotoxic effects of the novel synthesized heterocyclic steroids in comparison with testosterone propionate on male mice using chromosomal analysis of somatic and germ cells as well as RAPD-PCR were investigated. Male mice were administered with two doses of testosterone propionate, pyridoandrostene derivative 4b, pyrimidinoandrostene derivative 9a and thienoandrostene derivative 12 (200 and 400mg/kg b.w.) daily for 2 weeks. Results indicated that compounds 4b and 12 have androgenic activity as well as testosterone propionate. There were no significant differences in the frequencies of total chromosomal aberrations in both somatic and germ cells as well as no alteration in the DNA bands patterns between control, testosterone propionate and pyridoandrostene 4b treated animals. However, the pyrimidinoandrostene derivative 9a caused significant increase in the mean value of total chromosomal aberrations of both somatic and germ cells (P< or =0.01) as well as enhanced the polymorphic bands patterns as compared to the control and the other tested compounds. On the other hand, thienoandrostene derivative 12 induced significant decrease in the mean values of chromosomal aberrations in both somatic and germ cells, decreased sperm morphological abnormalities, increased the sperm count and motility than control. Our data indicate that testosterone propionate; pyridoandrostene 4b and thienoandrostene derivative 12 have no genotoxic activity. However, pyrimidinoandrostene derivative 9a has genotoxic activity possibly due to a modulation of the different expression of the catalyzing enzyme systems which will be investigated in the nearly future.
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http://dx.doi.org/10.1016/j.jsbmb.2007.11.006DOI Listing
June 2008

Screening for antidepressant, sedative and analgesic activities of novel fused thiophene derivatives.

Acta Pharm 2008 Mar;58(1):1-14

National Organization for Drug Control and Research, P.O. 29 Cairo, Egypt.

This study was aimed at the synthesis of fused benzothiophene derivatives containing heterocyclic moiety. The reaction of the tetrahydrobenzo[b]thiophene derivatives 1a,b with ethoxycarbonylisothiocyanate afforded the thiourea derivatives 2a,b. Cyclization of the latter products gave the annulated benzo[b]thienopyrimidine derivatives 3a,b. Compounds 2a,b and 3a underwent a series of heterocyclization reactions through the reaction with some chemical reagents to give the new benzo[b]thienopyrimidine derivatives 5a,b to 8a-c. Also, this work was extended to study the potential role of the novel synthesized thiourea derivative 2a and benzo[b]thienopyrimidine derivatives 3a, 5b, 6a and 8b as antidepressant, sedative or analgesic agents at two doses (15 or 30 mg kg(-1) body mass). Some compounds (2a, 3a and 5b) showed mild antidepressant activity in the forced-swimming test. No compound showed sedative effect. Visceral pain evoked by i.p. injection of acetic acid in mice was significantly inhibited by all compounds at a high doses.
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http://dx.doi.org/10.2478/v10007-007-0041-5DOI Listing
March 2008

Synthesis and in vivo anti-mutagenic activity of novel melatonin derivatives.

Eur J Med Chem 2008 Apr 5;43(4):763-70. Epub 2007 Jul 5.

Hormones Department, National Research Center, Dokki, Cairo, Egypt.

Extensive literature suggests that melatonin play a role against the degenerative effect of central neurotoxins by its acting as free radical scavenger. This study aimed at evaluation of the anti-mutagenic activity of novel synthesized indole derivatives 2, 4a, and 8 in albino male mice in comparison with the parent melatonin. Efficacy of melatonin and its derivatives to influence cyclophosphamide (CP)-induced genotoxicity was tested using micronuclei (MN) formation in the bone marrow cells and determination of DNA, RNA and protein levels as well as cholinesterase and peroxidase activities in several organs of male mice. Following intragastrical injection of melatonin or one of its derivatives daily for 1 week, CP was given intraperitoneally, i.p., as a single dose of 25mg/kg BW. Pyridazin-4-yl thiadiazoloindole derivative 8, diaminothiophen-5-yl thiadiazoloindole derivative 4a and melatonin were significantly able to reduce the number of micronucleated polychromatic erythrocytes (MnPCEs) in the bone marrow cells induced by CP (P<0.0001, P<0.001, P<0.01, respectively). However, reduction of MN formation in the bone marrow cells was not significant when thiadiazoloindole derivative 2 was administered (P=0.14). Examination of the protective effect of melatonin and its derivatives on the levels of DNA, RNA and protein as well as enzyme activities showed that compound 8 had the ability to inhibit the clastogenic effect of CP in several organs of male mice. These findings suggest that compounds 4a, 8 and melatonin were able to reduce the mutagenicity effect of CP in male mice. The ability of compounds 4a, 8 and melatonin to reduce CP-related genotoxicity is possibly attributed to their antioxidant activity.
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http://dx.doi.org/10.1016/j.ejmech.2007.06.003DOI Listing
April 2008

Evaluation of the anti-inflammatory and anti-nociceptive activities of novel synthesized melatonin analogues.

Eur J Med Chem 2007 Oct 23;42(10):1285-92. Epub 2007 Feb 23.

Hormone Department, National Research Centre, Dokki, Giza 12622, Cairo, Egypt.

This study aimed at evaluation of the reactivity of melatonin (1) towards various chemical reagents to produce new melatonin analogues containing heterocyclic moieties which would provide basic pharmacological activities. The pyrrolo[1,2-a]indole derivatives 3, 5, 12, 14 and pyrido[1,2-a]indole derivatives 9a, b were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. Also, this work was extended to study the potential role of the novel synthesized melatonin analogues 3, 5, 9a and 12 as anti-inflammatory and anti-nociceptive agents in comparison with melatonin. After s.c. administration all compounds induced significant anti-inflammatory activity, inhibiting the paw oedema response compared with the control group at all time points in the test. Compound 5 has the strongest anti-inflammatory activity which exceeds that of the parent reference, melatonin, followed by compounds 9a and 12, at the first 2h of administration. Effect of melatonin analogues on thermal pain, acetic acid-induced writhing and gastric lesions caused by indomethacin was also investigated. Compounds 5 and 12 were more potent as anti-nociceptive drugs; they are more potent in this respect than melatonin.
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http://dx.doi.org/10.1016/j.ejmech.2007.01.027DOI Listing
October 2007

Synthesis of novel steroidal heterocyclic derivatives as antibacterial agents.

Steroids 2007 May 13;72(5):459-65. Epub 2007 Feb 13.

Hormones Department, National Research Center, 12622 Dokki, Giza, Cairo, Egypt.

This study aimed at the synthesis of novel structurally promising steroidal heterocycles and to elucidate the potential role of these compounds as antibacterial agents. Epi-androsterone 1 reacted with CS2 and sodium hydride in dimethylsulfoxide to yield alpha-oxoketene dithiodisodium salt 2. The non-isolable salt 2 reacted with acetyl chloride, benzoyl chloride, phenacyl bromide and iodomethane to afford the corresponding alpha-oxodithioacetal derivatives 4a,b, 6 and 7, respectively. Interaction of 2 with the alkyl halide reagents 8a-d yielded the corresponding thiophene derivatives 10a-d. Alpha-oxoketene dithioacetal 7 reacted with urea and thiourea to furnish the pyrimidinoandrostane derivatives 12a,b. Compound 7 also reacted with ortho-phenylene diamine and ortho-aminophenol 13a,b to produce the dinucleophilic adducts 15a,b. The in vitro antibacterial evaluation of some newly prepared compounds showed that all compounds have high significant antibacterial activity against the used strains of gram positive and gram negative bacteria.
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http://dx.doi.org/10.1016/j.steroids.2007.01.003DOI Listing
May 2007

Novel synthesized aminosteroidal heterocycles intervention for inhibiting iron-induced oxidative stress.

Eur J Med Chem 2005 Dec 9;40(12):1283-94. Epub 2005 Sep 9.

Hormones Department, National Research Center, Dokki, Giza, Egypt.

The objective of this study was to elucidate the potential role of novel synthesized aminosteroidal heterocyclic compounds 2, 5, 9b and 10c against iron-induced oxidative stress with particular insight on erythrocyte ghosts in male rats. Chronic iron supplementation (3000 mg kg(-1) diet) for 6 weeks significantly increased plasma iron and ferritin levels. It also produced significant increase in plasma TNF-alpha and NO levels. Lipid metabolism was also affected by excess iron, so that plasma and erythrocyte membrane total cholesterol, triglycerides, phospholipids and total lipid levels were significantly elevated. In consequence, a significant increase in plasma leptin level was detected. Iron overload clearly induces oxidative stress as indicated by the significant increase in both plasma and erythrocyte membrane lipid peroxidation levels. Noteworthy, excess iron not only decreased the mean value of erythrocyte membrane protein but also caused marked alterations in the membrane protein fractions with concomitant inhibition in erythrocyte membrane ATPases activity. On the other hand, treatment with the aminosteriodal heterocyclic compounds especially compounds 5, 2, and 10c in an oral dose of 5 mg kg(-1) B.W. per day could ameliorate almost all of the changes in plasma and erythrocyte ghosts components induced by iron overload. The efficacious role of these novel synthesized aminosteriods in preventing iron-induced oxidative stress may be mediated through their iron chelating properties, anti-lipid peroxidation activities and membrane stabilizing actions. The encouraging results obtained in the present study lend credence to substantial investigation to assess the use of these compounds as a potent line of therapy to retard the pathogenesis of iron overload diseases.
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http://dx.doi.org/10.1016/j.ejmech.2005.07.012DOI Listing
December 2005

Synthesis of biologically active steroid derivatives by the utility of Lawesson's reagent.

Steroids 2005 Mar;70(3):131-6

Photochemistry Department, National Research Centre, Dokki, Giza, Egypt.

Steroid derivatives V, VI, VII and VIII reacted with Lawesson's reagent (LR) to produce spiro-oxazaphosphole-4',17-androstene derivative XI, diazaphospholoandrostane XIV and the thionated derivatives XVI and XVII, respectively. The structures of the new compounds were confirmed by analytical and spectroscopic evidence. A mechanism accounting for the formation of the new compounds was given. The in vitro antimicrobial activity of the new compounds were tested.
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http://dx.doi.org/10.1016/j.steroids.2004.11.001DOI Listing
March 2005

Cardioprotective activity of melatonin and its novel synthesized derivatives on doxorubicin-induced cardiotoxicity.

Bioorg Med Chem 2005 Mar;13(5):1847-57

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

This study aimed at evaluation of melatonin and some of its novel synthesized derivatives 3, 4, 9 and 10b as cardioprotective agents against doxorubicin-induced acute cardiac toxicity in rats. Also, this work was extended to study the potential role of each synthesized derivative in comparison with the parent compound melatonin. Intraperitoneal injection of a single dose (15mg/kg B.W.) of doxorubicin resulted in significant increase in serum troponin I, leptin, triglycerides, cholesterol and LDL-cholesterol levels with concomitant decrease in serum T(3), T(4) and IL-1alpha levels. In contrast, intraperitoneal injection of melatonin or its synthesized derivatives especially compounds 3 and 10b in a dose of 5mg/kg B.W./day for 10days reversed doxorubicin-induced changes in the above mentioned parameters towards the normal values. The present data revealed that doxorubicin exerts its action mainly through the oxidative stress. This appeared from the significant elevation in serum nitric oxide level and cardiac lipid peroxidation level with concomitant decrease in cardiac antioxidative enzymes activity. Treatment with melatonin and its derivatives 3 and 10b could reduce the markers of oxidative stress and restore the activity of the antioxidative enzymes in the heart tissue. In conclusion, the cardioprotective effect of melatonin and its derivatives may be mediated through the antioxidant and free radical scavenging activity of these compounds.
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http://dx.doi.org/10.1016/j.bmc.2004.10.066DOI Listing
March 2005

Synthesis and antimicrobial evaluation of some novel cholestane heterocyclic derivatives.

Arch Pharm (Weinheim) 2004 Mar;337(3):140-7

Hormone Department, National Research Centre, Dokki, Giza, Egypt.

This study was performed to investigate the reactivity of 5alpha-cholestan-3-one (1) towards various chemical reagents to produce new steroidal heterocyclic derivatives. The aminothieno[2, 3:2, 3]cholestane derivative 2 was synthesized according to Gewald's conditions. The diazonium salt of compound 2 coupled with malononitrile to afford dicyanomethylenhydrazinothieno[2', 3':2, 3]cholestane derivative 5. The behavior of compound 5 towards nitrogen nucleophiles and several active methylene reagents was investigated. Additionally, a variety of steroidal heterocyclic derivatives like compounds 15a, b-22a, b were synthesized starting with 5alpha-cholestan-3-one (1). The structures of the compounds were established based on the analytical and spectral data. The in vitro antimicrobial activity of some newly synthesized compounds against bacteria and fungi was studied.
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http://dx.doi.org/10.1002/ardp.200300825DOI Listing
March 2004