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Compounds from Simarouba berteroana which inhibit proliferation of NF1-defective cancer cells.

ABSTRACT: A neurofibromatosis type 1 (NF1) based bioassay-guided phytochemical investigation on Simarouba berteroana led to the isolation of one new canthin-6-one-9-methoxy-5-O-?-D-glucopyranoside (1), seven known canthine alkaloids (2-8), two known quassinoids (9-10) and a known neo-lignan (11). The structures of all compounds were established by HRMS, 1D- and 2D-NMR analysis and comparison with previously reported data. Most of the compounds inhibited the proliferation of an Nf1- and p53-deficient mouse glioma cell line at non-cytotoxic concentrations.

SUBMITTER: Devkota KP

PROVIDER: S-EPMC3891785 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Compounds from Simarouba berteroana which inhibit proliferation of NF1-defective cancer cells.

Devkota Krishna P KP Wilson Jennifer A JA Henrich Curtis J CJ McMahon James B JB Reilly Karlyne M KM Beutler John A JA

Phytochemistry letters 20140201

A neurofibromatosis type 1 (NF1) based bioassay-guided phytochemical investigation on Simarouba berteroana led to the isolation of one new canthin-6-one-9-methoxy-5-O-β-D-glucopyranoside (1), seven known canthine alkaloids (2-8), two known quassinoids (9-10) and a known neo-lignan (11). The structures of all compounds were established by HRMS, 1D- and 2D-NMR analysis and comparison with previously reported data. Most of ...[more]

PMID: 24443661

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Project description:Fucosylation is one of the most prevalent modifications on N- and O-glycans of glycoproteins, and it plays an important role in various cellular processes and diseases. Small molecule inhibitors of fucosylation have shown promise as therapeutic agents for sickle cell disease, arthritis, and cancer. We describe here the design and synthesis of a panel of fluorinated l-fucose analogs bearing fluorine atoms at the C2 and/or C6 positions of l-fucose as metabolic fucosylation inhibitors. Preliminary study of their effects on cell proliferation revealed that the 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6) showed significant inhibitory activity against proliferation of human colon cancer cells and human umbilical vein endothelial cells. In contrast, the previously reported 2-deoxy-2-fluoro-l-fucose (1) had no apparent effects on proliferations of all the cell lines tested. To understand the mechanism of cell proliferation inhibition by the fluorinated l-fucose analogs, we performed chemoenzymatic synthesis of the corresponding GDP-fluorinated l-fucose analogs and tested their inhibitory activities against the mammalian α1,6-fucosyltransferase (FUT8). Interestingly, the corresponding GDP derivatives of 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6), which are the stronger proliferation inhibitors, showed much weaker inhibitory activity against FUT8 than that of the 2-deoxy-2-fluoro-l-fucose (1). These results suggest that FUT8 is not the major target of the 6-fluorinated fucose analogs (3 and 6). Instead, other factors, such as the key enzymes involved in the de novo GDP-fucose biosynthetic pathway and/or other fucosyltransferases involved in the biosynthesis of tumor-associated glyco-epitopes are most likely the targets of the fluorinated l-fucose analogs to achieve cell proliferation inhibition. To our knowledge, this is the first comparative study of various fluorinated l-fucose analogs for suppressing the proliferation of human cancer and primary endothelial cells required for angiogenesis.

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Compounds from Simarouba berteroana which inhibit proliferation of NF1-defective cancer cells.

Publications

Compounds from <i>Simarouba berteroana</i> which inhibit proliferation of <i>NF1</i>-defective cancer cells.

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