- Synthesis of rigid tryptophan mimetics by the diastereoselective Pictet-Spengler reaction of β3-homo-tryptophan derivatives with chiral α-amino aldehydes
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The Pictet-Spengler (PS) cyclizations of β3-hTrp derivatives as arylethylamine substrates were performed with L-α-amino and D-α-amino aldehydes as carbonyl components. During the PS reaction, a new stereogenic center was created, and the mixtur
- Slupska, Marta,Pulka-Ziach, Karolina,Deluga, Edyta,Sosnowski, Piotr,Wilenska, Beata,Kozminski, Wiktor,Misicka, Aleksandra
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- Synthesis of a β-tetrapeptide analog as a mother compound for the development of matrix metalloproteinase-2-imaging agents
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Matrix metalloproteinase-2 (MMP-2) is an attractive target for the diagnosis of cancer and atherosclerosis in nuclear imaging. A cyclic decapeptide, cCTTHWGFTLC (cCTT), has been used as the mother compound for the development of MMP-2-imaging agents with high potency and selectivity. Most of radiolabeled derivatives of cCTT currently developed for in vivo studies of MMP-2, however, suffer from low accumulation in the target tissues, such as tumors. For enhanced in vivo stability and tissue penetration, we designed a linear β-tetrapeptide analog, H-β3-Phe-β-Ala- β3-Trp-β3-His-OH (1), to mimic cCTT. The component β-amino acids were prepared by reduction of N-protected α-amino acid methyl esters to the alcohols, followed by conversion into the cyanides, and subsequent hydrolysis. Compound 1 was obtained from these β-amino acids by the conventional solution method. In MMP-2 inhibition assay, compound 1 displayed desirably significant inhibition, which was comparable to cCTT. These findings suggest that compound 1 may serve as a mother compound in the design and development of in vivo MMP-2-imaging agents.
- Mukai, Takahiro,Suganuma, Noriko,Soejima, Kenta,Sasaki, Junichi,Yamamoto, Fumihiko,Maeda, Minoru
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p. 260 - 265
(2008/09/21)
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- Endomorphin-1 analogues containing β-proline are μ-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance
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In this paper we describe the synthesis and affinity toward the μ-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH2 (1), by substituting each amino acid in turn with its homologue. The ability to bind μ -opioid receptors depends on the β-amino acid, and in particular 4, which contains β-L-Pro, has a KI, in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the μ-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as μ-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential μ-opioid receptor agonists.
- Cardillo, Giuliana,Gentilucci, Luca,Qasem, Ahmed R.,Sgarzi, Fabio,Spampinato, Santi
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p. 2571 - 2578
(2007/10/03)
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- The cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp): Synthesis, NMR structure in methanol solution, and affinity for human somatostatin receptors
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The known solid-state structure (Fig. 1, top) of cyclo(β-HAla)4 was used to model the structure of the title compound 1 as a prospective somatostatin mimic (Fig. 1, bottom). The synthesis started with the N-protected natural amino acids Boc-Phe-OH, Boc-Trp-OH, Boc-Lys(2-Cl-Z)-OH, and Boc-Thr(OBn)-OH, which were homologated to the corresponding β-amino-acid derivatives (Scheme 1) and coupled to the β-tetrapeptide Boc-β-HTrp-β-HPhe-β-HThr(OBn)-β-HLys(2-Cl-Z)-OMe (16); the (N-Me)-β-HThr-(N-Me)-β-HPhe analog 17 was also prepared. C- and N-terminal deprotection and cyclization through the pentafluorophenyl ester gave the insoluble β-tetrapeptide with protected Thr and Lys side chains (18). Solubilization and debenzylation could only be effected in LiCl-containing THF (ca. 10% yield; with ca. 55% recovery). HPLC Purification provided a sample of the title compound 1, the structure of which, as determined by NMR-spectroscopy (Fig. 2, left) was drastically different from the 'theoretical' model (Fig. 1). There is a transannular H-bond dividing the macrocyclic 16-membered ring, thus forming a ten- and a twelve-membered H-bonded ring, the former mimicking, or actually being superimposable on, an α-peptidic so-called β-turn. Still, the four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the 'original'. The cyclo-β-tetrapeptide has micromolar affinities to the human somatostatin receptors (hsst 1-5). Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small β-peptide. Furthermore, we have discovered a simple way to construct the ubiquitous β-turn motif with β-peptides (which are known to be stable to mammalian peptidases).
- Gademann, Karl,Ernst, Martin,Seebach, Dieter,Hoyer, Daniel
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- Synthesis and biological evaluation of a cyclo-β-tetrapeptide as a somatostatin analogue
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Short β-peptides can mimic natural peptide hormones, as has been shown with a cyclo-β-tetrapeptide (1) that displays micromolar affinity to human somatostatin receptors. β-Peptides are thus a promising new class of peptidomimetics with potential high bioa
- Gademann, Karl,Ernst, Martin,Hoyer, Daniel,Seebach, Dieter
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p. 1223 - 1226
(2007/10/03)
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