A novel solid-phase synthesis of cyclic guanidines

We have developed a robust solid-phase approach to cyclic guanidines based on the Staudinger protocol. The synthetic sequence involves the reaction of the immobilized aza-Wittig reagents derived from the respective azidobenzoic acids with bifunctional amines. Convenient isolation and good yields of the desired products (34-84%) along with the diversity of the targeted molecules are distinctive features of the resultant library.     

Ring-closing metathesis approaches for the solid-phase synthesis of cyclic peptoids

Cyclic peptoids were efficiently synthesized on a solid phase in high yields utilizing ring-closing metathesis (RCM). This method should be a valuable tool for easy access to cyclic peptoid libraries and various cyclic compounds.     

A novel strategy for the solid-phase synthesis of cyclic lipodepsipeptides

A rapid and efficient Fmoc solid-phase synthesis of cyclic lipodepsipeptide analogue 1 to antibiotic fusaricidin A is described. Our synthetic approach includes resin attachment of the first amino acid via side chain, successful use of combination of four quasi-orthogonal removable protecting groups, stepwise solid-phase synthesis of linear peptide analogue, lipid tail attachment followed by depsipeptide bond formation and on-resin head-to-tail cyclization. Undesired O→N acyl shift, which may occur during Fmoc removal, was successfully avoided by the incorporation of the lipid tail into the linear peptide precursor prior to on-resin depsipeptide bond formation and the ring closure.     

Facile solid-phase synthesis of cyclic decapeptide antibiotic streptocidins A-D

Total synthesis of decapeptide antibiotics streptocidins A-D from Streptomyces sp. Tü 6071 was accomplished for the first time by solid-phase peptide synthesis followed by traceless cyclization of the activated linear precursors, without protection of nucleophilic side chain. Synthetic products were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the amphipathic antimicrobial cyclic decapeptide family.     

A solid-phase total synthesis of the cyclic depsipeptide HDAC inhibitor spiruchostatin A

Spiruchostatin A, a potent histone deacetylase inhibitor, was efficiently synthesized from (3S,4R)-4-amino-3-hydroxy-5-methylhexanoic acid utilizing solid-phase peptide elongation with d-cysteine, d-alanine, and (E)-3-hydroxy-7-thio-4-heptenoic acid and solution-phase macrolactonization, followed by intramolecular disulfide formation.     

Traceless solid-phase synthesis of multiple sulfonamide-containing cyclic sulfides exploiting microwave irradiation

In this Letter, a new synthetic method of sulfonamide-containing cyclic sulfides using a microwave-assisted traceless solid-phase approach is described. Using this new method, many highly pure cyclic sulfides were efficiently synthesized based on intramolecular alkylation of the sulfides followed by elimination of the desired products from the generated sulfonium salts.     

Efficient solid-phase synthesis of cyclic RGD peptides under controlled microwave heating

Cyclic RGD peptides are potent antagonists for the α_vβ₃ integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 °C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = d-Phe(p-Br) or d-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity.     

Click chemistry as a macrocyclization tool in the solid-phase synthesis of small cyclic peptides

Despite the vast number of techniques developed for the cyclization of small peptides, cyclization efficiency remains problematic in peptides that lack turn-promoting structures. Here we demonstrate the utility of click chemistry as a macrocyclization tool in the solid-phase synthesis of cyclic tetra-, penta-, hexa-, and heptapeptides. On-resin cyclization is completed at room temperature within 6 h, resulting in predominantly monomer with small amounts of cyclomultimer byproducts.     

Ring-closing metathesis: development of a cyclisation-cleavage strategy for the solid-phase synthesis of cyclic sulfonamides

A series of novel 7-membered cyclic sulfonamides have been synthesised using a solid-phase cyclisation-cleavage RCM strategy. Model solution studies indicated the sulfonamides were suitable substrates for RCM using the Grubbs' catalyst 2. Starting from either 2-carboxyethyl polystyrene (21) or Merrifield resin, various seven-membered sulfonamides were prepared in good to excellent yields at low catalyst loadings (2.5-5 mol%) using a flexible spacer between the polymer and the substrate. In addition, a novel double-armed linker was shown to allow efficient RCM cleavage of sulfonamides with as little as 1 mol% of the ruthenium alkylidene complex 2.     

Mammalian pituitary growth hormone: applications of free flow electrophoresis

We have used free flow electrophoresis (FFE) technology to study the electrophoretic behavior of growth hormone (GH) molecules, GH secretory granules and GH cell subpopulations contained in pituitary glands of humans and rodents. GH activities in different electrophoresis fractions were measured by immunoassay or bioassay, viz., measurement of chondrocyte proliferation in the tibial growth plate of the hypophysectomized rat. Using FFE we discovered a peptide in human post mortem pituitary tissue and cryopoor human plasma that is active in the tibial line bioassay, is inactive in a GH immunoassay, and is neither GH nor a GH fragment. This peptide, called tibial peptide, has high anodal mobility and is readily separable from GH by FFE. Its molecular mass is approximately 5 kD. It is particularly rich in glycine. A partial amino acid sequence (residues 9-25) in the middle region of the peptide shows that 9 of the 16 residues are nonpolar. On the basis of results from other FFE experiments, using either GH-containing secretory granules or GH-producing cells, we believe that the peptide is stored within the secretion granule of a subpopulation of GH cells. On the basis of recent information elucidating the role of C peptide contained in the insulin storage granule of the pancreatic cell, we propose that the tibial peptide serves a similar role in the GH cell. Thus, not only may tibial peptide aid in proper alignment of disulfide bonds between GH monomers in the secretory granule, but, like the C peptide, it also appears to have biologic activity in its own right.     

Original loading and Suzuki conditions for the solid-phase synthesis of biphenyltetrazoles. Application to the first solid-phase synthesis of irbesartan

Biphenyltetrazoles are recognized privileged structures. Among them, the therapeutically important class of sartans displays antagonistic activity on AT1 receptors. We have developed a method for anchoring tetrazole derivatives via the heterocycle on a hydroxylated resin using zinc triflate. New Suzuki-Miyaura cross-coupling conditions are developed for the quantitative formation of the phenyl-phenyl bond. Our straightforward synthesis scheme, starting from the conserved phenyltetrazole moiety and ending with the appending of the structurally variable moiety, is well suited to the preparation of sartans and their analogues at a laboratory scale. We thus describe here the first solid phase synthesis of irbesartan, a marketed AT1 antagonist.     

An efficient synthesis of the plant growth hormone 1-triacontanol

Summary A high yield synthesis of 1-triacontanol was based on the cheap and easily available starting materials 1-octadecanol and 1,12-dodecanediol. The first one was converted to octadecanal using a phase transfer system, whereas the second one after phase transfer bromination and reaction with triphenylphosphine provided 1-hydroxy-12-triphenylphosphonium bromide.Wittig reaction of these two synthons and subsequent hydrogenation furnished the desired product.

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Eine effiziente Synthese des Pflanzenwachstumshormons 1-Triacontanol

Zusammenfassung Eine Synthese von 1-Triacontanol, basierend auf den einfach zugänglichen Edukten 1-Oktadecanol und 1,12-Dodecandiol, die gute Ausbeuten ergibt, wird beschrieben. Ersteres Edukt wurde mit Hilfe eines Phasentransfersystems zu Oktadecanal umgesetzt. Letzteres gab nach Phasentransfer-Bromierung und Umsatz mit Triphenylphosphin 1-Hydroxy-12-triphenylphosphoniumbromid.Wittig-Reaktion dieser beiden Synthone und anschließende Hydrierung lieferte das erwünschte Produkt.

     

Structure-activity relationships of GHRP-6 azapeptide ligands of the CD36 scavenger receptor by solid-phase submonomer azapeptide synthesis

The cluster of differentiation 36 (CD36) class B scavenger receptor binds a variety of biologically endogenous ligands in addition to synthetic peptides (i.e., growth hormone-releasing peptides, GHRPs), which modulate biological function related to anti-angiogenic and anti-atherosclerotic activities. Affinity labeling had previously shown that GHRP-6 analogues such as hexarelin, [2-Me-W(2)]GHRP-6 (1), bind to the lysine-rich domain of the CD36 receptor. Moreover, the azapeptide analogue [aza-F(4)]GHRP-6, 2, exhibited a characteristic β-turn conformation as described by CD and NMR spectroscopy and a slightly higher CD36 binding affinity relative to hexarelin (1.34 and 2.37 μM, respectively), suggesting receptor binding was mediated by the conformation and the aromatic residues of these peptide sequences. Ligand-receptor binding interactions were thus explored using azapeptides to examine influences of side-chain diversity and backbone conformation. In particular, considering that aromatic cation interactions may contribute to binding affinity, we have explored the potential of introducing salt bridges to furnish GHRP-6 azapeptide ligands of the CD36 receptor. Fifteen aza-glutamic acid analogues related to 2 were prepared by submonomer solid-phase synthesis. The azapeptide side chains were installed by novel approaches featuring alkylation of resin-bound semicarbazone with Michael acceptors and activated allylic acetates in the presence of phosphazene base (BTPP). Moreover, certain Michael adducts underwent intramolecular cyclization during semicarbazone deprotection, leading to novel pyrrazoline and aza-pyroglutamate N-terminal residues. Structural studies indicated that contingent on sequence the [aza-Glu]GHRP-6 analogues exhibited CD spectra characteristic of random coil, polyproline type II and β-turn secondary structures in aqueous media. In covalent competition binding studies with the GHRP-6 prototype hexarelin bearing a radiotracer, certain [aza-Glu]GHRP-6 azapeptides retained relatively high (2-27 μM) affinity for the CD36 scavenger receptor.     

Analysis of human pituitary growth hormone and its charge variants by fast-atom bombardment mass spectrometry.

There is evidence that even highly purified preparations of human growth hormone are not homogenous, but contain charge as well as size variants. The charge heterogeneity was suggested to be due to deamidation of the native hormone. To verify this we have applied peptide mapping followed by fast-atom bombardment mass spectrometry (FAB-MS), in order to identify fragments containing the altered amino acids. Growth hormone was purified from human pituitaries and the differently charged forms were separated by column electrophoresis in agarose suspension. The isolated components were treated with trypsin and analysed directly by FAB-MS without prior separation by reversed-phase high-performance liquid chromatography (RP-HPLC). Using this technique, approximately 80% of the hormone structure was recovered and two deamidation sites were found in the fragment T15 (FDTNSHNDDALLK). The results clearly elucidated the potential use of FAB-MS for the fast screening of other variants of the growth hormone which are known to exist.