Asymmetric Synthesis of (+)-Hypusine

Jain, Rajni; Albrecht, Brian K.; DeMong, Duane E.; Williams, Robert M.

doi:10.1021/ol016959o

Cited by 12 publications

(6 citation statements)

References 23 publications

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“…[α] D 23 +7.6 ( c 0.5, 6 M HCl), [α] D 25 +7.3 ( c 0.52, 6 M HCl)). The analytical data for this substance matched those reported in the literature …”

supporting

confidence: 81%

“…Over the past decade, eIF5A and hypusination have attracted increasing attention as a potential diagnostic marker and a drug target. , Synthetic hypusinated peptides are of great interest in order to elucidate the physiological functions of eIF5A. Although several synthetic methods for free hypusine have been reported, the orthogonal protection of the side-chain functionalities remains as a challenge for the incorporation of hypusine into peptide sequences. In 1997, Bergeron et al developed a protected hypusine reagent ( 2 , Figure ) for peptide synthesis .…”

mentioning

confidence: 99%

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Development of Orthogonally Protected Hypusine for Solid-Phase Peptide Synthesis

Song¹,

Tom²,

et al. 2015

J. Org. Chem.

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An orthogonally protected hypusine reagent was developed for solid-phase synthesis of hypusinated peptides using the Fmoc/t-Bu protection strategy. The reagent was synthesized in an overall yield of 27% after seven steps from Cbz-Lys-OBzl and (R)-3-hydroxypyrrolidin-2-one. The side-chain protecting groups (Boc and t-Bu) are fully compatible with standard Fmoc chemistry and can be readily removed during the peptide cleavage step. The utility of the reagent was demonstrated by solid-phase synthesis of hypusinated peptides.

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“…[α] D 23 +7.6 ( c 0.5, 6 M HCl), [α] D 25 +7.3 ( c 0.52, 6 M HCl)). The analytical data for this substance matched those reported in the literature …”

supporting

confidence: 81%

mentioning

confidence: 99%

Development of Orthogonally Protected Hypusine for Solid-Phase Peptide Synthesis

Song¹,

Tom²,

et al. 2015

J. Org. Chem.

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“…A number of approaches have been reported in the literature for the stereoselective synthesis of hypusine (Tice and Ganem 1983;Bergeron et al 1993, Jain et al 2001). Due to the readily available starting materials, a method employing protected lysine and (S)-(+)-epichlorohydrin was chosen (Bergeron et al 1993).…”

Section: Synthesis Of (+)-Hypusinementioning

confidence: 99%

New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential

et al. 2015

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Deoxyhypusine hydroxylase (DOHH) is a dinuclear iron enzyme required for hydroxylation of the aminobutyl side chain of deoxyhypusine in eukaryotic translation initiation factor 5A (eIF-5A), the second step in hypusine biosynthesis. DOHH has been recently identified in P. falciparum and P. vivax. Both enzymes have very peculiar features including E-Z type HEAT-like repeats and a diiron centre in their active site. Both proteins share only 26 % amino acid identity to the human paralogue. Hitherto, no X-ray structure exists from either enzyme. However, structural predictions based on the amino acid sequence of the active site in comparison to the human enzyme show that four conserved histidine and glutamate residues provide the coordination sites for chelating the ferrous iron ions. Recently, we showed that P. vivax DOHH is inhibited by zileuton (N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea), a drug that is known for inhibiting human 5-lipoygenase (5-LOX) by the complexation of ferrous iron. A novel discovery program was launched to identify inhibitors of the P. falciparum DOHH from the Malaria Box, consisting of 400 chemical compounds, which are highly active in the erythrocytic stages of Malaria infections. In a first visual selection for potential ligands of ferrous iron, three compounds from different scaffold classes namely the diazonapthyl benzimidazole MMV666023 (Malaria Box plate A, position A03), the bis-benzimidazole MMV007384 (plate A, position B08), and a 1,2,5,-oxadiazole MMV665805 (plate A, position C03) were selected and subsequently evaluated in silico for their potential to complex iron ions. As a proof of principle, a bioanalytical assay was performed and the inhibition of hypusine biosynthesis was determined by GC-MS. All tested compounds proved to be active in this assay and MMV665805 exhibited the strongest inhibitory effect. Notably, the results were in accordance with the preliminary quantum-mechanical calculations suggesting the strongest iron complexation capacity for MMV665805. This compound might be a useful tool as well as a novel lead structure for inhibitors of P. falciparum DOHH.

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“…63 Finally, the total synthesis of (+)-hypusine dihydrochloride (175) was achieved starting from both 149a and 149b. 64…”

Section: Scheme 32mentioning

confidence: 99%

Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

Wijtmans¹,

Vink²,

Schoemaker³

et al. 2004

Synthesis

105

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Asymmetric Synthesis of (+)-Hypusine

Cited by 12 publications

References 23 publications

Development of Orthogonally Protected Hypusine for Solid-Phase Peptide Synthesis

Development of Orthogonally Protected Hypusine for Solid-Phase Peptide Synthesis

New insights into novel inhibitors against deoxyhypusine hydroxylase from plasmodium falciparum: compounds with an iron chelating potential

Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

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