Sugar Amino Acid Containing Somatostatin Analogues that Induce Apoptosis in Both Drug-Sensitive and Multidrug-Resistant Tumor Cells

Gruner, Sibylle A. W.; Kéri, Gÿorgý; Schwab, Richárd; Venetianer, and Aniko; Kessler, Horst

doi:10.1021/ol0166698

Cited by 57 publications

(54 citation statements)

References 26 publications

(18 reference statements)

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“…Consequently, one cannot find a comparative estimate of the published data which would establish the most reasonable and economic conditions for the synthesis of either the 3-azido-3-deoxy-allofuranose or the epimeric glucofuranose derivatives. In addition, although the synthesis of the N-protected sugar amino acid is described (Gruner 2001;Gruner, Truffault et al 2002;, the important intermediate free sugar amino acid 1 was not yet isolated and characterized. Hence, we accomplished alternative routes with different sulfonate esters and under various reaction conditions, then we evaluated the results to choose the most advantageous protocol for producing both the 3-azido-3-deoxy-allo compound 4 (A, B, C, D) and the 3-azido-3-deoxy-gluco epimer 5 (E, F, G, H) (Scheme 2 and Scheme 3) in multigram scale.…”

Section: Resultsmentioning

confidence: 99%

“…Among β-furanoid sugar amino acids, 1,2-O-isopropylidene-3-amino-3-deoxy-α-D-ribofuranuronic acid (H-RibAFU(ip)-OH, -tX-, 1) and its C-3 epimer, H-XylAFU(ip)-OH, (-cX-, 2) have attracted special attention (Figure 1). The small scale synthesis of the N-protected derivatives of 1 and 2 from diaceton-glucofuranose (3) was described in various quantities (Gruner 2001;Gruner, Truffault et al 2002;Chandrasekhar 2004). Conditions of these syntheses are different and the results are sometimes poor.…”

Section: Introductionmentioning

confidence: 99%

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C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

et al. 2016

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To obtain key sugar derivatives of making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-tX-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-cX-OH) from D-glucose is described here. The present synthetic route elaborated is i) appropriate for large-scale synthesis, ii) reagent costs reduced (e.g. by a factor of 400), iii) yields optimized are ~80% or higher for all six consecutive steps concluding -tX-or -cX-and iv) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-riboamino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous flow reactor). Multigram scale syntheses of these β-sugar amino acids, β-SAAs, now available on a larger scale made possible to test and optimize coupling reactions and conditions of making α/β-chimera peptides. Our study encompasses necessary building blocks (e.g. -X-OMe, -X-O i Pr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-tX-Aaa-or -Aaa-tX-tXAaa-type "inserts". Completed for both stereoisomers of X, including the newly synthetized FmoccX-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish. 2Graphical abstract: From D-glucose in 6 (7) steps both C-3 epimers of an azido-furanuronic acid (cAFU and tAFU) are obtained. Yield optimized, scalable and robust reactions made possible to get β-sugar amino acids in a more environment-friendly way. Useful derivatives were synthesized and probed as key intermediates of foldameric "Lego element" now ready to be built in into α/β-chimera peptides supporting drug design and discovery.3

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

et al. 2016

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“…1) and their homooligomers are part of several bioactive macromolecules (Gruner et al 2001(Gruner et al , 2002aChandrasekhar et al 2009). Among them, H-RibAFU(ip)-OH, (1a) (Gruner et al 2002b) and its xylo epimer H-XylAFU(ip)-OH (2a) (Chandrasekhar et al 2004) as hydrophilic analogs of cisand trans-ACPC monomers were incorporated into β-peptidic heterooligomers.…”

Section: Introductionmentioning

confidence: 99%

Origin of problems related to Staudinger reduction in carbopeptoid syntheses

et al. 2016

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We report the solid phase synthesis of -GG-X-GG-type α/β-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc deriva-tive (e.g., Fmoc-RibAFU(ip)-OH) and the azido deriva-tive (e.g., N 3 -RibAFU(ip)-OH) via Staudinger reaction with nBu 3 P can be successfully applied. Both X-ray dif-fraction, 1 H-and 31 P-NMR, and theoretical (QM) data support and explain why the application of Ph 3 P as Staudinger reagent is "ineffective" in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (-CONH-) bond. The failure of the poly-peptide chain elongation with N 3 -cX originates from the "coincidence" of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack dur-ing the hydrolysis of a quasi penta-coordinated triph-enylphosphinimine. Nevertheless, the synthesis of the above α/β-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo-and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

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“…In line with this, Gruner and coworkers 53 have prepared a selection of somatostatin analogues, originally based on the sequence cyclo-(SAA)-Phe-D-Trp-LysThr-. Inhibition of growth hormone release has been demonstrated, as well as antiproliferative and apoptotic activity.…”

Section: Figurementioning

confidence: 99%

Carbohydrates in peptide and protein design

Jensen¹,

Brask²

2005

Biopolymers

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Monosaccharides and amino acids are fundamental building blocks in the assembly of nature's polymers. They have different structural aspects and, to a significant extent, different functional groups. Oligomerization gives rise to oligosaccharides and peptides, respectively. While carbohydrates and peptides can be found conjoined in nature, e.g., in glycopeptides, the aim of this review is the radical redesign of peptide structures using carbohydrates, particularly monosaccharides and cyclic oligosaccharides, to produce novel peptides, peptidomimetics, and abiotic proteins. These hybrid molecules, chimeras, have properties arising largely from the combination of structural characteristics of carbohydrates with the functional group diversity of peptides. This field includes de novo designed synthetic glycopeptides, sugar (carbohydrate) amino acids, carbohydrate scaffolds for nonpeptidal peptidomimetics of cyclic peptides, cyclodextrin functionalized peptides, and carboproteins, i.e., carbohydrate-based proteinmimetics. These successful applications demonstrate the general utility of carbohydrates in peptide and protein architecture. #

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Sugar Amino Acid Containing Somatostatin Analogues that Induce Apoptosis in Both Drug-Sensitive and Multidrug-Resistant Tumor Cells

Cited by 57 publications

References 26 publications

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Origin of problems related to Staudinger reduction in carbopeptoid syntheses

Carbohydrates in peptide and protein design

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