MetAP-2 Inhibitors Based on the Fumagillin Structure. Side-Chain Modification and Ring-Substituted Analogues

Rodeschini, Vincent; Boiteau, Jean‐Guy; Weghe, Pierre van de; Tarnus, Céline; Eustache, Jacques

doi:10.1021/jo035065+

Cited by 49 publications

(27 citation statements)

References 27 publications

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“…Liotta showed that a non‐complexed, and hence more nucleophilic anion is formed by reduction of diphenyl diselenide by sodium metal, or deprotonation of benzeneselenol with sodium hydride . Pleasingly exposure of the enantioenriched γ‐lactone (+)‐ 36 to phenylselanyl anion prepared by reduction of diphenyl diselenide with sodium hydride allowed reaction at room temperature to give the fully substituted pyrrolidinone 39 after acid base extraction (Scheme ). Reduction of the carboxylic acid in 39 to the corresponding primary alcohol 40 proved problematic with direct reduction using borane resulting in substrate decomposition and attempted reduction of the corresponding mixed anhydride with sodium borohydride resulting in numerous uncharacterized products being formed.…”

Section: Resultsmentioning

confidence: 99%

A Total Synthesis of Salinosporamide A

Marx

Burton

2018

Chemistry A European J

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Section: Resultsmentioning

confidence: 99%

A Total Synthesis of Salinosporamide A

Marx

Burton

2018

Chemistry A European J

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“…Fumagillin inhibits HUVEC proliferation at low nM concentration, and it has partial or no effect on non-endothelial cells at concentrations up to 1 µM (J. . It was proposed that fumagillin inhibits angiogenesis by covalently binding to the His-231 position of the enzyme MetAP2 (Griffith et al 1997;Sin et al 1997), and this finding provided a starting point for the rational design of fumagillin analogs (Rodeschini et al 2004). …”

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confidence: 99%

Early Genetic Mechanisms Underlying the Inhibitory Effects of Endostatin and Fumagillin on Human Endothelial Cells

et al. 2004

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A tumor needs to initiate angiogenesis in order to develop its own blood supply, to grow, to invade, and to spread. Angiogenesis, under normal conditions, is a tightly regulated balance between endogenous pro- and antiangiogenic factors. In this study, we investigated, by microarray analysis, the effects of two known antiangiogenic agents (endostatin and fumagillin) on the gene expression profiles of human umbilical vein endothelial cells (HUVEC) in order to elucidate pathways common to the effects of these agents. We observed a majority of gene expression changes within 1 and 2 h of treatment. The genes demonstrating these early expression changes are involved in cell proliferation, gene transcription, and a number have unknown functions. We selected four genes (DOC1, KLF4, TC-1, ID1) from the microarray profile that showed a similar pattern of expression for both of the antiangiogenic agents we tested. We then used small interfering RNAs (siRNA) in an attempt to better understand the role of these selected genes in the inhibitory activity of these agents. Because the gene expression changes occurred within 1 and 2 h of treatment, these genes might be involved in the initial pathways of angiogenesis inhibition

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“…Epoxidation of the enone moiety by TBHP in the presence of benzyltrimethylammonium hydroxide (triton B)18 furnished stereoselectively epoxide ( 14 ), in 65% yield for three steps from 13 19. The regioselective opening of the epoxide moiety20 found within 14 was established by PhSeNa (generated in situ from diphenyl diselenide and NaBH 4 ) in 86% yield followed by silylation of 15 with SEMCl, which led to disilyl ether ( 16 ) in 85% yield from 14 (Scheme 1). …”

Section: Resultsmentioning

confidence: 99%

Toosendanin: Synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II)

Nakai

Pellett

Tepp

et al. 2010

Bioorganic & Medicinal Chemistry

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Botulinum neurotoxins (BoNTs) are the etiological agents responsible for botulism, a disease characterized by peripheral neuromuscular blockade and a characteristic flaccid paralysis of humans. The natural product toosendanin, a limonoid, is a traditional Chinese medicine that has reported antibotulinum properties in animal models. Toosendanin effectively inhibits the biological activity of BoNT/A in neuronal cells at concentrations of 200 nM, and partial inhibition can be observed with concentrations as low as 8 nM. Mechanistically, toosendanin's inhibition is due to prevention of transduction of the BoNT LC through the HC channel. Intriguing questions as to the molecular architecture of toosendanin as related to its anti-botulinum properties have focused our attention on a synthesis of toosendanin's unusual AB-ring, containing a unique bridged hemi-acetal. Within the current work, a synthetic strategy allowing access to the AB-fragment of toosendanin was achieved from a trans-decalin system. In addition, this fragment was examined for its modulation of BoNT/A intoxication in a rat spinal cord cellular assay.

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MetAP-2 Inhibitors Based on the Fumagillin Structure. Side-Chain Modification and Ring-Substituted Analogues

Cited by 49 publications

References 27 publications

A Total Synthesis of Salinosporamide A

A Total Synthesis of Salinosporamide A

Early Genetic Mechanisms Underlying the Inhibitory Effects of Endostatin and Fumagillin on Human Endothelial Cells

Toosendanin: Synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II)

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