Publications by authors named "Safwat A Ahmed"

50 Publications

VEGFR-Mediated Cytotoxic Activity of Isolated Metabolites: A Biological Evaluation and In Silico Study.

Life (Basel) 2021 Jul 28;11(8). Epub 2021 Jul 28.

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

Natural products play a remarkable role not only in the synthesis, design, and discovery of new drugs but also as the most prominent source of drugs and bioactive substances. Adding to the search for new sources of safe innovative antitumor drugs, here we reported a phytochemical study on   which revealed promising antiangiogenic agents. Six compounds were isolated and identified as xanthoxyline (), stigmasterol (), oleanolic acid (), salvigenin () rhamnetin () and dihydroquercetin-4'-methyl ether () using nuclear magnetic resonance (NMR) spectroscopic techniques. Compound and are first reported in genus. Both the extract and isolated compounds were evaluated for in vitro antiproliferative activity against breast cancer cell line (MCF-7). In vivo antiproliferative activity against Ehrlich's ascites carcinoma (EAC) were also assessed. The extract and isolates showed significant reduction in tumor weight, decreased both serum vascular endothelial growth factor B (VEGF-B) levels and vascular endothelial growth factor receptor 2 (VEGFR-2) expression significantly compared to the control EAC group, suggesting an antiangiogenic activity through the inhibition of VEGF signaling. Besides, they displayed reduction in CD34 expression, confirming their antiangiogenic effect. Moreover, the potential affinity of isolated compounds to human estrogen nuclear receptor-alpha (ER-α), the most recognized modulator of VEGFR-2 expression, was virtually estimated through molecular modeling studies. The most promising activity profiles were assigned to the investigated flavonoids, compounds -, as well as the alkyl-phenylketone, compound . Additionally, these four top active compounds showed respective high to intermediate docking scores while possessing preferential binding with ER-α critical pocket residues. Based on the provided data, these isolated compounds illustrated promising inhibitors of VEGF-stimulated angiogenesis, which could be a possible mechanism for their anticancer activity.
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http://dx.doi.org/10.3390/life11080759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398779PMC
July 2021

Chemical profiling, cytotoxic activities through apoptosis induction in MCF-7 cells and molecular docking of bark nonpolar extract.

J Biomol Struct Dyn 2021 Jun 2:1-12. Epub 2021 Jun 2.

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

The chemical constituents of the nonpolar fractions of the bamboo shoot skin were extensively studied. The phytochemical study was divided into two parts: the first deals with isolation of the chemical constituents using different chromatographic techniques that resulted in isolation of four compounds. The chemical structures of the pure isolated compounds were elucidated using different spectroscopic data. The second part deals with identification of the rest of the constituents using the GC technique. Additionally, both crude extract and the pure isolated compounds were investigated for cytotoxic activity. One of the isolated compounds; namely glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC = 19.78 µM) compared to 5-FU (26.98 µM), and it remarkably stimulated apoptotic breast cancer cell death with 31.6-fold (16.13% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Moreover, the identified compounds especially were found to have high binding affinity towards both TPK and VEGFR-2 through the molecular docking studies which highlight its mode of action. HighlightsChemical profiling of bark nonpolar extract was fully identified.Glyceryl 1-monopalmitate showed highly promising effect against the MCF-7 cells with (IC = 19.78 µM) compared to 5-FU (26.98 µM).Glyceryl 1-monopalmitate significantly stimulated apoptotic breast cancer cell death with 31.6-fold by arresting cell cycle at G2/M and preG1 phases.Molecular docking simulation showed good binding affinities towards TPK and VEGFR-2 proteins.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1932599DOI Listing
June 2021

The Antioxidant DC. Ethanolic Extract Counteracts Cisplatin Triggered Hepatic and Renal Toxicities.

Antioxidants (Basel) 2021 May 21;10(6). Epub 2021 May 21.

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

Cisplatin is a powerful anti-neoplastic drug that displays multi-organ toxicity, especially to the liver and kidneys. Consumption of phytomedicines is a promising strategy to overcome the side effects of chemotherapy. extract proved to possess potent antioxidant activity. Its protective potential against cisplatin-induced hepato-nephrotoxicity was scrutinized. Moreover, a phytochemical study was conducted on ethyl acetate fraction which led to the isolation of five known phenolic compounds. Structure determination was achieved utilizing H- and C-NMR spectral analyses. The isolated phytochemicals were -ferulic acid (), kaempferol (), -coumaric acid (), luteolin () and quercetin (). Regarding our biological study, has improved liver and kidney deteriorated functions caused by cisplatin administration and attenuated the histopathological injury in their tissues. Serum levels of ALT, AST, blood urea nitrogen and creatinine were significantly decreased. has modulated the oxidative stress mediated by cisplatin as it lowered MDA levels while enhanced reduced-GSH concentrations. More importantly, the plant has alleviated cisplatin triggered inflammation, apoptosis via reduction of INFγ, IL-1β and caspase-3 production. Moreover, mitochondrial injury has been ameliorated as remarkable increase of mtDNA was noted. Furthermore, the MTT assay proved the combination of cisplatin- extract led to growth inhibition of MCF-7 cells in a notable additive way. Additionally, we have investigated the binding affinity of constituents with caspase-3 and IFN-γ proteins using molecular simulation. All the isolated compounds exhibited good binding affinities toward the target proteins where quercetin possessed the most auspicious caspase-3 and IFN-γ inhibition activities. Our results put forward that is a promising candidate to counteract chemotherapy side effects and the observed activity could be attributed to the synergism between its phytochemicals.
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http://dx.doi.org/10.3390/antiox10060825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224350PMC
May 2021

Molecular Docking and Dynamics Simulation Study of   Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors.

Biology (Basel) 2021 May 1;10(5). Epub 2021 May 1.

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

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge  , as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target's crucial residues than those of reference ligands. Compounds , , , and , were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds and , within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand's binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds and , as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.
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http://dx.doi.org/10.3390/biology10050389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147222PMC
May 2021

Microbial Biotransformation of Cannabidiol (CBD) from Cannabis sativa.

Planta Med 2021 Apr 26. Epub 2021 Apr 26.

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.

Microbial biotransformation of cannabidiol was assessed using 31 different microorganisms. Only (ATCC 9628), (ATCC 7195), and (ATCC 22 752) were able to metabolize cannabidiol. (ATCC 9628) yielded five metabolites, namely, 7,4″-dihydroxycannabidiol (1: ), 6,4″-dihydroxycannabidiol (2: ), 6,2″-dihydroxycannabidiol (3: ), 6,3″-dihydroxycannabidiol (4: ), and 6,7,4″-trihydroxycannabidiol (5: ). (ATCC 7195) metabolized cannabidiol to afford six metabolites identified as 7,3″-dihydroxycannabidivarin (6: ), 7-hydroxycannabidivarin-3″-carboxylic acid (7: ), 3″-hydroxycannabidivarin (8: ), 4″-hydroxycannabidiol (9: ), and cannabidivarin-3″-carboxylic acid (10: ) along with compound 1: . Incubation of cannabidiol with (ATCC 22 752) yielded three metabolites, 6,3″-dihyroxycannabidivarin (11: ), 6,3″-dihyroxycannabidivarin (12: ), and compound 6: . All compounds were evaluated for their antimicrobial and antiprotozoal activity.
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http://dx.doi.org/10.1055/a-1468-3781DOI Listing
April 2021

Holospiniferoside: A New Antitumor Cerebroside from The Red Sea Cucumber In Vitro and In Silico Studies.

Molecules 2021 Mar 12;26(6). Epub 2021 Mar 12.

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

Chemical investigation of the methanolic extract of the Red Sea cucumber led to the isolation of a new cerebroside, holospiniferoside (), together with thymidine (), methyl--d-glucopyranoside (), a new triacylglycerol (), and cholesterol (). Their chemical structures were established by NMR and mass spectrometric analysis, including gas chromatography-mass spectrometry (GC-MS) and high-resolution mass spectrometry (HRMS). All the isolated compounds are reported in this species for the first time. Moreover, compound exhibited promising in vitro antiproliferative effect on the human breast cancer cell line (MCF-7) with IC of 20.6 µM compared to the IC of 15.3 µM for the drug cisplatin. To predict the possible mechanism underlying the cytotoxicity of compound , a docking study was performed to elucidate its binding interactions with the active site of the protein Mdm2-p53. Compound displayed an apoptotic activity via strong interaction with the active site of the target protein. This study highlights the importance of marine natural products in the design of new anticancer agents.
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http://dx.doi.org/10.3390/molecules26061555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001240PMC
March 2021

Chemical Constituent Profiling of var. Pubescens with Selective Cytotoxic Polar Fraction through EGFR Inhibition in HepG2 Cells.

Molecules 2021 Feb 10;26(4). Epub 2021 Feb 10.

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

Different extracts of the Bamboo shoot skin var. pubescens were screened against panel of cancer cell lines and normal one. The cell viability results exhibited that the ethyl acetate extract showed the least vitality percentage of 2.14% of HepG2 cells. Accordingly, it was subjected to chromatographic separation, which resulted in the isolation of a new natural product; 7-hydroxy, 5-methoxy, methyl cinnamate (), together with four known compounds. The structures of the pure isolated compounds were deduced based on different spectroscopic data. The new compound () was screened against the HepG2 and MCF-7 cells and showed IC values of 7.43 and 10.65 µM, respectively. It induced apoptotic cell death in HepG2 with total apoptotic cell death of 58.6% (12.44-fold) compared to 4.71% in control by arresting cell cycle progression at the G1 phase. Finally, compound was validated as EGFR tyrosine kinase inhibitor in both enzymatic levels (IC = 98.65 nM compared to Erlotinib (IC = 78.65 nM). Finally, in silico studies of compound through the molecular docking indicated its high binding affinity towards EGFR protein and the ADME pharmacokinetics indicated it as a drug-like.
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http://dx.doi.org/10.3390/molecules26040940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916669PMC
February 2021

New Antiproliferative Triflavanone from -Isolation, Structure Elucidation and Molecular Docking Studies.

Molecules 2021 Jan 31;26(3). Epub 2021 Jan 31.

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

In this study isolates from , a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in : daphnoretin methyl ether (), rutamontine (), neodaphnoretin (), acetyldaphnoretin (), and edgeworthin (); two flavonoids: genkwanin () and -tiliroside (); -hydroxy benzoic acid () and sitosterol glucoside (). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds , and exhibited remarkable cytotoxic activities against HepG2 cells, with IC values of 8.6, 12.3 and 9.4 μM, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC values of 4.26 and 9.6 μM, respectively. Compound significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.
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http://dx.doi.org/10.3390/molecules26030739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867015PMC
January 2021

Chemical Profiling, Antioxidant, Cytotoxic Activities and Molecular Docking Simulation of DC. (Cruciferae).

Antioxidants (Basel) 2020 Dec 16;9(12). Epub 2020 Dec 16.

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

Our investigation intended to analyze the chemical composition and the antioxidant activity of and to evaluate the antiproliferative effect of crude and phenolics extracts by MTT assay on a panel of cancerous and non-cancerous breast and liver cell lines. The total flavonoid and phenolic contents of were 47.3 ± 17.9 mg RE/g and 83.8 ± 5.3 mg respectively. extract exhibited remarkable antioxidant capacity (50.92 ± 5.64 mg GAE/g) in comparison with BHT (74.86 ± 3.92 mg GAE/g). Moreover, the extract exhibited promising reduction ability (1.17 mMol Fe/g) in comparison to the positive control (ascorbic acid with 2.75 ± 0.91) and it displayed some definite radical scavenging effect on DPPH (IC values of 211.9 ± 3.7 µg/mL). Chemical profiling of extract was achieved by LC-ESI-TOF-MS/MS analysis. Forty-nine hits mainly polyphenols were detected. Flavonoid fraction of was more active than the crude extract. It demonstrated selective cytotoxicity against the MCF-7 and HepG2 cells (IC = 13.04 and 19.3 µg/mL respectively), induced cell cycle arrest at pre-G1 and G2/M-phases and displayed apoptotic effect. Molecular docking studies supported our findings and revealed that kaempferol-L-rhamnoside and kaempferol-3-rutinoside were the most active inhibitors of Bcl-2. Therefore, herb seems to be a promising candidate to further advance anticancer research. In extrapolation, the intake of phenolics might be adventitious for alleviating breast and liver malignancies and tumoral proliferation in humans.
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http://dx.doi.org/10.3390/antiox9121286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766671PMC
December 2020

Cytotoxic, Apoptosis-Inducing Activities, and Molecular Docking of a New Sterol from Bamboo Shoot Skin var. pubescens.

Molecules 2020 Nov 30;25(23). Epub 2020 Nov 30.

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

Phytochemical screening of nonpolar fractions from the methanol extract of the Bamboo shoot skin var. pubescens resulted in the isolation of a new sterol-glucoside-fatty acid derivative (6'--octadeca-8'',11''-dienoyl)-sitosterol-3---d-glucoside (), together with six known compounds. The chemical structures of the pure isolated compounds were deduced based on different spectral data. The isolated compounds were assessed to determine their cytotoxic activity, and the results were confirmed by determining their apoptotic activity. Compound was more cytotoxic against the MCF-7 cells (IC = 25.8 µM) compared to Fluorouracil (5-FU) (26.98 µM), and it significantly stimulated apoptotic breast cancer cell death with 32.6-fold (16.63% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Additionally, RT-PCR results further confirmed the apoptotic activity of compound by the upregulation of proapoptotic genes (P53; Bax; and caspases 3, 8, and 9) and downregulation of the antiapoptotic genes (BCL2). Finally, the identified compounds, especially , were found to have high binding affinity towards both tyrosine-specific protein kinase (TPK) and vascular endothelial growth factor receptor (VEGFR-2) through the molecular docking studies that highlight its mode of action.
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http://dx.doi.org/10.3390/molecules25235650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731115PMC
November 2020

Jaceidin Flavonoid Isolated from Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies.

Plants (Basel) 2020 Aug 14;9(8). Epub 2020 Aug 14.

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

Phytochemical study of aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-β-eudesmol (2), 5,7-dihydroxy-3,3',4'-trimethoxyflavone (3), 5,7,4'-trihydroxy-3,6,3'-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1β,4β,7α-triol (5) and 1β,4β,7β,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and extract were evaluated for their in vivo anti-tumor activity against Ehrlich's ascites carcinoma (EAC). Compared to control group, jaceidin and extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.
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http://dx.doi.org/10.3390/plants9081031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464537PMC
August 2020

New Cytotoxic Cerebrosides from the Red Sea Cucumber Supported by Studies.

Mar Drugs 2020 Aug 1;18(8). Epub 2020 Aug 1.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia 61111, Egypt.

Bioactivity-guided fractionation of a methanolic extract of the Red Sea cucumber and LC-HRESIMS-assisted dereplication resulted in the isolation of four compounds, three new cerebrosides, spiniferosides A (), B (), and C (), and cholesterol sulfate (). The chemical structures of the isolated compounds were established on the basis of their 1D NMR and HRMS spectral data. Metabolic profiling of the extract indicated the presence of diverse secondary metabolites, mostly hydroxy fatty acids, diterpenes, triterpenes, and cerebrosides. The isolated compounds were tested for their in vitro cytotoxicities against the breast adenocarcinoma MCF-7 cell line. Compounds , , , and displayed promising cytotoxic activities against MCF-7 cells, with IC values of 13.83, 8.13, 8.27, and 35.56 µM, respectively, compared to that of the standard drug doxorubicin (IC 8.64 µM). Additionally, docking studies were performed for compounds , , , and to elucidate their binding interactions with the active site of the SET protein, an inhibitor of protein phosphatase 2A (PP2A), which could explain their cytotoxic activity. This study highlights the important role of these metabolites in the defense mechanism of the sea cucumber against fouling organisms and the potential uses of these active molecules in the design of new anticancer agents.
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http://dx.doi.org/10.3390/md18080405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460232PMC
August 2020

Anti-inflammatory effect of methoxyflavonoids from ( growing in Egypt.

Nat Prod Res 2020 Aug 4:1-5. Epub 2020 Aug 4.

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.

is a medicinal plant that grows in Sinai Peninsula in Egypt. Phytochemical investigation of methanolic extract led to the isolation of five methoxy flavonoids; Chrysosplenol-D 5,7,4'-trihydroxy- 3,3'-dimethoxy flavone , 5,7-dihydroxy -3,3',4'-trimethoxyflavone , Bonanzin , 3,5,6,7,4'-pentamethoxy flavone a sesquiterpene, Cryptomeridiol and stigmast-5,22-dien-3-O-β-D-glucopyranoside . The anti-inflammatory activity of compounds and was assessed on CaCo2 cells stimulated by lipopolysaccharide (LPS). Both compounds downregulated LPS-induced expression of inflammatory cytokines; tumor necrosis factor alpha (TNFα), interleukin 1β (IL1β), nuclear factor kappa B (NFκB), cyclooxygenase 1 (Cox1), cyclooxygenase 2 (Cox2), and 5-lipoxygenase (5Lox). In vivo, both compounds significantly decreased paw edema thickness in rats relative to carrageenan, showing better anti-inflammatory activity than celecoxib (36.98%) after 1 h (46.60% and 48.11%, respectively). An study was performed, where both compounds were docked into the active site of the crystal structure of the human Cox2 enzyme.
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http://dx.doi.org/10.1080/14786419.2020.1802272DOI Listing
August 2020

Thalassosterol, a New Cytotoxic Aromatase Inhibitor Ergosterol Derivative from the Red Sea Seagrass .

Mar Drugs 2020 Jul 8;18(7). Epub 2020 Jul 8.

Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.

(Forssk.) Den Hartog is a seagrass belonging to the plant family Cymodoceaceae with ubiquitous phytoconstituents and important pharmacological potential, including antioxidant, antiviral, and cytotoxic activities. In this work, a new ergosterol derivative named thalassosterol () was isolated from the methanolic extract of growing in the Red Sea, along with two known first-reported sterols, namely ergosterol () and stigmasterol (), using different chromatographic techniques. The structure of the new compound was established based on 1D and 2D NMR spectroscopy and high-resolution mass spectrometry (HR-MS) and by comparison with the literature data. The new ergosterol derivative showed significant in vitro antiproliferative potential against the human cervical cancer cell line (HeLa) and human breast cancer (MCF-7) cell lines, with IC values of 8.12 and 14.24 µM, respectively. In addition, docking studies on the new sterol explained the possible binding interactions with an aromatase enzyme; this inhibition is beneficial in both cervical and breast cancer therapy. A metabolic analysis of the crude extract of using liquid chromatography combined with high-resolution electrospray ionization mass spectrometry (LC-ESI-HR-MS) revealed the presence of an array of phenolic compounds, sterols and ceramides, as well as di- and triglycerides.
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http://dx.doi.org/10.3390/md18070354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401251PMC
July 2020

Ergosterol Peroxide from the Egyptian Red Lingzhi or Reishi Mushroom, Ganoderma resinaceum (Agaricomycetes), Showed Preferred Inhibition of MCF-7 over MDA-MB-231 Breast Cancer Cell Lines.

Int J Med Mushrooms 2020 ;22(4):389-396

Chemistry Department, Faculty of Science, Damietta University, New Damietta City, Egypt; Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.

Ergosterol peroxide and ganoderic acid AMI were isolated for the first time from the mycelium of the Egyptian Ganoderma resinaceum mushroom. The structure of these two metabolites was established by detailed analysis of 1D and 2D NMR. The isolated compounds were tested for their antitumor in vitro activities in MCF-7 and MDA-MB-231 breast cancer cell lines. Ergosterol peroxide showed preferred inhibition of MCF-7 (ER +ve) cell lines relative to MDA-MB-231 (ER -ve) cell lines with an IC50 of 1.18 μM and 12.82 μM respectively. Our data suggest that ergosterol peroxide targets estrogen receptors.
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http://dx.doi.org/10.1615/IntJMedMushrooms.2020034223DOI Listing
February 2021

New Cytotoxic Natural Products from the Red Sea Sponge .

Mar Drugs 2020 May 3;18(5). Epub 2020 May 3.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia 61111, Egypt.

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (), and a cerebroside, stylissoside A (), from the methanol extract of the Red Sea sponge . Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, and , displayed strong cytotoxicity against the MCF-7 cell line, with IC values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC at 36.8 ± 0.16 µM for and IC 30.5 ± 0.23 µM for compared to the standard drug cisplatin. Molecular docking experiments showed that and displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.
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http://dx.doi.org/10.3390/md18050241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281077PMC
May 2020

Isolates From Inhibit Progression Of Hepatocellular Carcinoma And .

Nat Prod Res 2021 Jun 17;35(11):1799-1807. Epub 2019 Jul 17.

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.

Herein, we investigated effect of Thymelaea hirsuta isolates on hepatocellular carcinoma. Methanolic extract of led to isolation of two new compounds [6` hydroxyDaphnoretin (9) and Mithnin (15)], seven compounds reported for the first time from genus Thymelaea [Dotriacontanol (1), and 3-ketopentatriacontanoic (2), Docosylcoumarate (5), Docosylcaffeate (6), Daphnodorin B (11), 3`` -epi-dihydrodaphnodorin B (12) and Wikstaiwanone B (14)], and six known compounds. Eight compounds (5, 6, 9, 10, 11, 12, 14, and 15) showed significant anti-proliferative activity on HepG2 cells. These compounds caused significant reduction (p < 0.05) in serum levels of AST, ALT, ALP, total bilirubin, GGT, and AFP, a significant increase in and expression, and a significant decrease in gene in liver as compared to the HCC group. These results indicate that isolates inhibited HCC progression, possibly through induction of apoptosis and therefore they could be used as a beneficial source for treating HCC.
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http://dx.doi.org/10.1080/14786419.2019.1643859DOI Listing
June 2021

Analysis of Terpenes in Cannabis sativa L. Using GC/MS: Method Development, Validation, and Application.

Planta Med 2019 Mar 15;85(5):431-438. Epub 2019 Jan 15.

National Center for Natural Products Research, University of Mississippi, University, MS, USA.

Terpenes are the major components of the essential oils present in various L. varieties. These compounds are responsible for the distinctive aromas and flavors. Besides the quantification of the cannabinoids, determination of the terpenes in strains could be of importance for the plant selection process. At the University of Mississippi, a GC-MS method has been developed and validated for the quantification of terpenes in cannabis plant material, viz., -pinene, -pinene, myrcene, limonene, terpinolene, linalool, -terpineol, -caryophyllene, -humulene, and caryophyllene oxide. The method was optimized and fully validated according to AOAC (Association of Official Analytical Chemists) guidelines against reference standards of selected terpenes. Samples were prepared by extraction of the plant material with ethyl acetate containing -tridecane solution (100 µg/mL) as the internal standard. The concentration-response relationship for all analyzed terpenes using the developed method was linear with values > 0.99. The average recoveries for all terpenes in spiked indoor cultivated samples were between 95.0 - 105.7%, with the exception of terpinolene (67 - 70%). The measured repeatability and intermediate precisions (% relative standard deviation) in all varieties ranged from 0.32 to 8.47%. The limit of detection and limit of quantitation for all targeted terpenes were determined to be 0.25 and 0.75 µg/mL, respectively. The proposed method is highly selective, reliable, and accurate and has been applied to the simultaneous determination of these major terpenes in the biomass produced by our facility at the University of Mississippi as well as in confiscated marijuana samples.
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http://dx.doi.org/10.1055/a-0828-8387DOI Listing
March 2019

Isolated compounds from Cuscuta pedicellata ameliorate oxidative stress and upregulate expression of some energy regulatory genes in high fat diet induced obesity in rats.

Biomed Pharmacother 2018 Dec 2;108:1253-1258. Epub 2018 Oct 2.

Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.

Background: Cuscuta pedicellata and some of its isolated compounds were suggested previously to have an anti-obesity effect in rats. This study aimed to investigate the effect of ten isolated compounds from C. pedicellata on insulin resistance, some oxidative stress markers and expression of the mitochondrial uncoupling protein-1 (UCP-1) and Carnitine palmitoyltransferase-I (CPT-1) genes in brown adipose tissue of high fat diet (HFD) rats.

Methods: One hundred and four male albino rats were divided into 13 groups. Group (1) was considered as normal untreated rats. Obesity was induced in all other groups by HFD. Group (2) served as obese control group and groups (3-11) were treated for four weeks with C. pedicellata extract or one of its isolated compounds (naringenin, kaempferol, aromadenderin, quercetin, 3,5,7,30,50-pentahydroxy flavanone, naringenin-7-O-b-d-glucoside, aromadenderin-7-O-b-d-glucoside, taxifolin 7-O-b-d-glucoside, kaempferol-3-O-b-d-glucoside [astragalin], and quercitin-3-O-b-d-glucoside [isoquercitrin]). At the end of the experiment, rats were then sacrificed under anesthesia and their brown adipose tissues were dissected out for determination of UCP-1 and CPT-1 genes using quantitative PCR. Blood samples were collected for determination of blood glucose, insulin, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase.

Results: A significant reduction in homeostasis model assessment-insulin resistance (HOMA-IR) and TBARS levels was observed in rats treated with C. pedicellata crude extract and some of its isolated compounds, with a significant increase in SOD and catalase levels and upregulation of UCP-1 and CPT-1 genes expression compared to the obese control group.

Conclusions: This study suggests a beneficiary role of C. pedicellata in reducing insulin resistance, oxidative stress and enhancing energy expenditure.
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http://dx.doi.org/10.1016/j.biopha.2018.09.126DOI Listing
December 2018

Anti-Helicobacter, Antitubercular and Cytotoxic Activities of Scalaranes from the Red Sea Sponge Hyrtios erectus.

Molecules 2018 Apr 23;23(4). Epub 2018 Apr 23.

Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

The Red Sea specimen of the marine sponge (order Dictyoceratida) was found to contain scalarane-type sesterterpenes. 12--deacetyl-12,19-di--scalarin (), a new scalarane sesterterpenoid, along with fourteen previously-reported scalarane-type sesterterpenes (⁻ and ) have been isolated. The chemical structures of the isolated compounds were elucidated on the basis of detailed 1D and 2D NMR spectral data and mass spectroscopy, as well as by comparison with reported data. The anti-, antitubercular and cytotoxic activities of all fifteen compounds were evaluated to reveal the potency of Compounds , , , , , and . Amongst these, Compounds , , , and displayed a promising bioactivity profile, possessing potent activities in the antitubercular and anti- bioassay. Compounds and showed the most promising cytotoxic profile, while Compounds and showed a moderate cytotoxic profile against MCF-7, HCT-116 and HepG2 cell lines.
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http://dx.doi.org/10.3390/molecules23040978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017761PMC
April 2018

Determination of Acid and Neutral Cannabinoids in Extracts of Different Strains of Cannabis sativa Using GC-FID.

Planta Med 2018 Mar 13;84(4):250-259. Epub 2017 Dec 13.

National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, Mississippi, United States of America.

Cannabis ( L.) is an annual herbaceous plant that belongs to the family Cannabaceae. -Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the two major phytocannabinoids accounting for over 40% of the cannabis plant extracts, depending on the variety. At the University of Mississippi, different strains of with different concentration ratios of CBD and Δ-THC, have been tissue cultured via micropropagation and cultivated. A GC-FID method has been developed and validated for the qualitative and quantitative analysis of acid and neutral cannabinoids in extracts. The method involves trimethyl silyl derivatization of the extracts. These cannabinoids include tetrahydrocannabivarian, CBD, cannabichromene, -Δ-tetrahydrocannabinol, Δ-THC, cannabigerol, cannabinol, cannabidiolic acid, cannabigerolic acid, and Δ-tetrahydrocannabinolic acid-A. The concentration-response relationship of the method indicated a linear relationship between the concentration and peak area ratio with R > 0.999 for all 10 cannabinoids. The precision and accuracy of the method were found to be ≤ 15% and ± 5%, respectively. The limit of detection range was 0.11 - 0.19 µg/mL, and the limit of quantitation was 0.34 - 0.56 µg/mL for all 10 cannabinoids. The developed method is simple, sensitive, reproducible, and suitable for the detection and quantitation of acidic and neutral cannabinoids in different extracts of cannabis varieties. The method was applied to the analysis of these cannabinoids in different parts of the micropropagated cannabis plants (buds, leaves, roots, and stems).
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http://dx.doi.org/10.1055/s-0043-124088DOI Listing
March 2018

Antiproliferative Scalarane-Based Metabolites from the Red Sea Sponge Hyrtios erectus.

Mar Drugs 2016 Jul 8;14(7). Epub 2016 Jul 8.

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

Two new sesterterpenes analogs, namely, 12-acetoxy,16-epi-hyrtiolide (1) and 12β-acetoxy,16β-methoxy,20α-hydroxy-17-scalaren-19,20-olide (2), containing a scalarane-based framework along with seven previously reported scalarane-type sesterterpenes (3-9) have been isolated from the sponge Hyrtios erectus (order Dictyoceratida) collected from the Red Sea, Egypt. The structures of the isolated compounds were elucidated on the basis of their spectroscopic data and comparison with reported NMR data. Compounds 1-9 exhibited considerable antiproliferative activity against breast adenocarcinoma (MCF-7), colorectal carcinoma (HCT-116) and hepatocellular carcinoma cells (HepG2). Compounds 3, 5 and 9 were selected for subsequent investigations regarding their mechanism of cell death induction (differential apoptosis/necrosis assessment) and their influence on cell cycle distribution.
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http://dx.doi.org/10.3390/md14070130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962020PMC
July 2016

A New Bioactive Metabolite Isolated from the Red Sea Marine Sponge Hyrtios erectus.

Molecules 2016 Jan 15;21(1):82. Epub 2016 Jan 15.

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

Chemical investigation of the lipophilic fraction of Hyrtios erectus, a Red Sea sponge, yielded a new pentacyclic nitrogen-containing scalarane; 24-methoxypetrosaspongia C (1), together with the previously reported scalaranes sesterstatin 3 (2), 12-deacetyl-12-epi-scalaradial (3) and 12-deacetyl-12,18-di-epi-scalaradial (4). The compounds were identified using HRESIMS, 1D and 2D NMR experiments. The isolated compounds showed growth inhibitory activity against hepatocellular carcinoma (HepG2), colorectal carcinoma (HCT-116) and breast adenocarcinoma cells (MCF-7).
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http://dx.doi.org/10.3390/molecules21010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273094PMC
January 2016

Mechanism of action of antiepileptic ceramide from Red Sea soft coral Sarcophyton auritum.

Bioorg Med Chem Lett 2015 Dec;25(24):5819-24

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of a new ceramide N-((2S,3R,4E,6E)-1,3-dihydroxyhenicosa-4,6-dien-2-yl)tridecanamide (1). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The anticonvulsant activity of the isolated ceramide was measured in vivo using the pentylenetetrazole (PTZ)-induced seizure model, where it successfully antagonized the lethality of pentylenetetrazole in mice. In addition, the isolated ceramide showed good anxiolytic activity when used in the light–dark transition box and the elevated plus maze compared to diazepam. The molecular modeling studies for the antiepileptic and antianxiety mechanism of the isolated ceramide suggested a CNS depressing activity possibly through GABA and serotonin receptors modulation. The pharmacological activity of the ceramide involved agonistic activity on GABA-A receptors but not 5HT3 receptors.
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http://dx.doi.org/10.1016/j.bmcl.2015.08.039DOI Listing
December 2015

Minor oxygenated cannabinoids from high potency Cannabis sativa L.

Phytochemistry 2015 Sep 17;117:194-199. Epub 2015 Jun 17.

National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, United States. Electronic address:

Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC-MS. These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, Δ(9)-THC aldehyde A, 8-oxo-Δ(9)-THC, 10aα-hydroxy-10-oxo-Δ(8)-THC, 9α-hydroxy-10-oxo-Δ(6a,10a)-THC, and 1'S-hydroxycannabinol, respectively. The latter compound showed moderate anti-MRSa (IC50 10.0 μg/mL), moderate antileishmanial (IC50 14.0 μg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50 values of 3.4 and 2.3 μg/mL, respectively.
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http://dx.doi.org/10.1016/j.phytochem.2015.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883105PMC
September 2015

Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa.

J Nat Prod 2015 Jun 22;78(6):1271-6. Epub 2015 May 22.

†National Center for Natural Products Research, ‡Department of Pharmaceutics and Drug Delivery, and §Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, United States.

Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ(9)-tetrahydrocannabinol (1), 8β-hydroxy-Δ(9)-tetrahydrocannabinol (2), 10α-hydroxy-Δ(8)-tetrahydrocannabinol (3), 10β-hydroxy-Δ(8)-tetrahydrocannabinol (4), 10α-hydroxy-Δ(9,11)-hexahydrocannabinol (5), 9β,10β-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ(9)-tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1-8, Δ(9)-tetrahydrocannabinol, and Δ(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880513PMC
June 2015

Antichlamydial sterol from the Red Sea sponge Callyspongia aff. implexa.

Planta Med 2015 Mar 17;81(5):382-7. Epub 2015 Mar 17.

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.

Marine sponges are rich sources of natural products exhibiting diverse biological activities. Bioactivity-guided fractionation of the Red Sea sponge Callyspongia aff. implexa led to the isolation of two new compounds, 26,27-bisnorcholest-5,16-dien-23-yn-3β,7α-diol, gelliusterol E (1) and C27-polyacetylene, callimplexen A (2), in addition to the known compound β-sitosterol (3). The structures of the isolated compounds were determined by 1D- and 2D-NMR techniques as well as high-resolution tandem mass spectrometry and by comparison to the literature. The three compounds (1-3) were tested against Chlamydia trachomatis, an obligate intracellular gram-negative bacterium, which is the leading cause of ocular and genital infections worldwide. Only gelliusterol E (1) inhibited the formation and growth of chlamydial inclusions in a dose-dependent manner with an IC50 value of 2.3 µM.
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http://dx.doi.org/10.1055/s-0035-1545721DOI Listing
March 2015

Evaluation of Phytocannabinoids from High Potency using Bioassays to Determine Structure-Activity Relationships for Cannabinoid Receptor 1 and Cannabinoid Receptor 2.

Med Chem Res 2014 Sep;23(9):4295-4300

Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA ; National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University Mississippi 38677, USA.

has been around for thousands of years and has been used recreationally, medicinally, and for fiber. Over 500 compounds have been isolated from with approximately 105 being cannabinoids. Of those 105 compounds, Δ-tetrahydrocannabinol has been determined as the primary constituent, which is also responsible for the psychoactivity associated with . Cannabinoid receptors belong to the large superfamily of G protein-coupled receptors. Targeting the cannabinoid receptors has the potential to treat a variety of conditions such as pain, neurodegeneration, appetite, immune function, anxiety, cancer, and others. Developing bioassays to determine binding and functional activity of compounds has the ability to lead researchers to develop a safe and effective drug that may target the cannabinoid receptors. Using radioligand binding and functional bioassays, a structure-activity relationship for major and minor cannabinoids was developed.
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http://dx.doi.org/10.1007/s00044-014-0972-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235762PMC
September 2014

New antibacterial xanthone from the marine sponge-derived Micrococcus sp. EG45.

Bioorg Med Chem Lett 2014 Nov 22;24(21):4939-42. Epub 2014 Sep 22.

Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt. Electronic address:

Microluside A [4 (19-para-hydroxy benzoyloxy-O-β-D-cellobiosyl), 5 (30-para-hydroxy benzoyloxy-O-β-D-glucopyranosyl) xanthone (1)] is a unique O-glycosylated disubstituted xanthone isolated from the broth culture of Micrococcus sp. EG45 cultivated from the Red Sea sponge Spheciospongia vagabunda. The structure of microluside A was determined by 1D- and 2D-NMR techniques as well as high resolution tandem mass spectrometry. The antimicrobial activity evaluation showed that 1 exhibited antibacterial potential against Enterococcus faecalis JH212 and Staphylococcus aureus NCTC 8325 with MIC values of 10 and 13 μM, respectively.
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http://dx.doi.org/10.1016/j.bmcl.2014.09.040DOI Listing
November 2014

Evaluation of anti-melanoma activities of (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol from the Red Sea soft coral Sarcophyton glaucum.

Nat Prod Commun 2014 Aug;9(8):1143-6

Three natural cembranoids from the Red Sea soft coral Sarcophyton glaucum namely (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol, (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were evaluated for their inhibitory effects on mouse melanoma B16F10 cell growth. Results show that all the cembranoids strongly inhibit viability of melanoma cells particularly during 48 -72 hrs treatment and also inhibit de novo DNA synthesis and PARP activity and stimulate fragmentation of DNA. (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol was not cytotoxic to monkey kidney CV-1 cells at the concentration that produces the anti-melanoma effects which indicates that this compound may be a good candidate for further development. (1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol were found to be cytotoxic to healthy cells.
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August 2014
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