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A novel natural phenyl alkene with cytotoxic activity.

ABSTRACT: A novel phenyl alkene (1) was isolated from a mixture of three Florida sponges, Smenospongia aurea, Smenospongia cerebriformis, and Verongula rigida. Unlike terpenoids or amino acid derivatives, which are commonly known classes of secondary metabolites from these genera, the chemical structure of 1 showed an unprecedented linear phenyl alkene skeleton. Through comprehensive analyses of NMR and MS data, the gross structure of 1 was determined to be (E)-10-benzyl-5,7-dimethylundeca-1,5,10-trien-4-ol. The absolute configuration at C-4 was established as R by a modified Mosher's method. Based on the relative configuration between C-4 and C-7, the absolute configuration at C-7 was assigned as S. Compound 1 showed in vitro cytotoxic activity against HL-60 human leukemia cancer cells with an IC50 value of 8.1 µM. Molecular docking study suggests that the structure of compound 1 matches the pharmacophore of eribulin required to display cytotoxic activity through the inhibition of microtubule activity.

SUBMITTER: Hwang IH

PROVIDER: S-EPMC5085269 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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A novel natural phenyl alkene with cytotoxic activity.

Hwang In Hyun IH Oh Joonseok J Kochanowska-Karamyan Anna A Doerksen Robert J RJ Na MinKyun M Hamann Mark T MT

Tetrahedron letters 20130518 29

A novel phenyl alkene (1) was isolated from a mixture of three Florida sponges, Smenospongia aurea, Smenospongia cerebriformis, and Verongula rigida. Unlike terpenoids or amino acid derivatives, which are commonly known classes of secondary metabolites from these genera, the chemical structure of 1 showed an unprecedented linear phenyl alkene skeleton. Through comprehensive analyses of NMR and MS data, the gross structure of 1 was determined to be (E)-10 ...[more]

PMID: 27795588

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Project description:BackgroundPMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder.ObjectiveTo evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors.MethodsWe studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay.ResultsWe found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules.ConclusionsOur results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types.

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A novel natural phenyl alkene with cytotoxic activity.

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A novel natural phenyl alkene with cytotoxic activity.

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