Use In Solid-phase Synthesis Research Articles

An Optimized Synthesis of Fmoc-l-Homopropargylglycine-OH.

An efficient multigram synthesis of alkynyl amino acid Fmoc-l-homopropargylglycine-OH is described. A double Boc protection is optimized for high material throughput, and the key Seyferth-Gilbert homologation is optimized to avoid racemization. Eighteen grams of the enantiopure (>98% ee) noncanonical amino acid was readily generated for use in solid phase synthesis to make peptides that can be functionalized by copper-assisted alkyne-azide cycloaddition.

Nucleoside Analogues with a Seven-Membered Sugar Ring: Synthesis and Structural Compatibility in DNA-RNA Hybrids.

Herein we describe results on the pairing properties of synthetic DNA and RNA oligonucleotides that contain nucleotide analogues with a 7-membered sugar ring (oxepane nucleotides). Specifically, we describe the stereoselective synthesis of a set of three oxepane thymine nucleosides (OxT), their conversion to phosphoramidite derivatives, and their use in solid-phase synthesis to yield chimeric OxT-DNA and OxT-RNA strands. The different regioisomeric OxT phosphoramidites allowed for positional variations of the phosphate bridge and assessment of duplex stability when the oxepane nucleotides were incorporated in dsDNA, dsRNA, and DNA-RNA hybrids. Little to no destabilization was observed when two of the three regioisomeric OxT units were incorporated in the DNA strand of DNA-RNA hybrids, a remarkable result considering the dramatically different structure of oxepanes in comparison to 2'-deoxynucleosides. Extensive molecular modeling and dynamics studies further revealed the various structural features responsible for the tolerance of both OxT modifications in DNA-RNA duplexes, such as base-base stacking and sugar-phosphate H-bond interactions. These studies suggest that oxepane nucleotide analogues may find applications in synthetic biology, where synthetic oligonucleotides can be used to create new tools for biotechnology and medicine.

Synthesis and Structure of [М(DMF)6][B10H10] (M = Zn(II), Cd(II)) as Precursors for Solid-Phase Synthesis of Trischelate Complexes [М(L)3][B10H10

The reactivity of the decahydro-closo-decaborate anion in the complexation of metals being among intermediates acids in the concept of the Pearson’s theory of hard and soft acids and bases is studied systematically in the presence of competitive ligands L. In continuing these studies, we have synthesized Zn(II) and Cd(II) complexes of the composition [М(DMF)6][B10H10] (M = Zn(II), Cd(II)) and studied them by physicochemical analyses (IR and UV spectroscopy, X-ray powder diffraction). The possibility of their use in solid-phase synthesis of the corresponding trischelate complexes [M(Bipy)3][B10H10] has been found. Complexes [М(DMF)6][B10H10] are formed by the reaction between triethylammonium closo-decaborate with metal nitrates in DMF. The compounds are isostructural with the corresponding Co(II) and Ni(II) complexes [М(DMF)6][B10H10]. Specific interactions have been found between the BH groups of the boron clusters and CH groups of the DMF molecules. According to the data of IR and UV spectroscopy, the complexes contain specific B–H···C–H interactions. The corresponding tris-chelate complexes of the metals [M(Bipy)3][B10H10] are also isostructural.

TEM investigation of semipolar GaN layers grown on Si(001) offcut substrates

We present the results of a conventional and high-resolution electron microscopy investigation of thick (up to 15 μm) semipolar GaN layers grown on Si(001) offcut substrates with 3C-SiC and AlN buffer layers. GaN and AlN layers have been grown by chloride vapor phase epitaxy. The silicon carbide buffer layers were produced by a new method of solid-phase synthesis on 4 and 7° offcut Si(001) substrates. It is shown that the use of solid-phase synthesis for the formation of SiC layer allows one to grow a semipolar GaN layer. The asymmetrical defect structure of the semipolar layer is revealed.

Orthogonally Protected Furanoid Sugar Diamino Acids for Solid-Phase Synthesis of Oligosaccharide Mimetics.

Sugar diamino acids (SDAs), which differ from the widely used sugar amino acids in the presence of a second amino group connected to the carbohydrate core, share structural features of both amino acids and carbohydrates. They can be used for the preparation of linear and branched amide-linked oligosaccharide mimetics. Such oligomers carry free amino groups, which are positively charged at neutral pH, in a spatially defined way and, thus, represent a potential class of aminoglycoside mimetics. We report here the first examples of orthogonally protected furanoid SDAs and their use in solid-phase synthesis. Starting from d-glucose, we developed a divergent synthetic route to three derivatives of 3,5-diamino-3,5-dideoxy-d-ribofuranose. These building blocks are compatible with solid-phase peptide synthesis following the 9-fluorenylmethoxycarbonyl (Fmoc) strategy, which we demonstrate by the synthesis of an SDA tetramer.

Nucleoside triphosphates--from synthesis to biochemical characterization.

The traditional strategy for the introduction of chemical functionalities is the use of solid-phase synthesis by appending suitably modified phosphoramidite precursors to the nascent chain. However, the conditions used during the synthesis and the restriction to rather short sequences hamper the applicability of this methodology. On the other hand, modified nucleoside triphosphates are activated building blocks that have been employed for the mild introduction of numerous functional groups into nucleic acids, a strategy that paves the way for the use of modified nucleic acids in a wide-ranging palette of practical applications such as functional tagging and generation of ribozymes and DNAzymes. One of the major challenges resides in the intricacy of the methodology leading to the isolation and characterization of these nucleoside analogues. In this video article, we present a detailed protocol for the synthesis of these modified analogues using phosphorous(III)-based reagents. In addition, the procedure for their biochemical characterization is divulged, with a special emphasis on primer extension reactions and TdT tailing polymerization. This detailed protocol will be of use for the crafting of modified dNTPs and their further use in chemical biology.

Solid Phase Synthesis of a Functionalized Bis-Peptide Using "Safety Catch" Methodology

In 1962, R.B. Merrifield published the first procedure using solid-phase peptide synthesis as a novel route to efficiently synthesize peptides. This technique quickly proved advantageous over its solution-phase predecessor in both time and labor. Improvements concerning the nature of solid support, the protecting groups employed and the coupling methods employed over the last five decades have only increased the usefulness of Merrifield's original system. Today, use of a Boc-based protection and base/nucleophile cleavable resin strategy or Fmoc-based protection and acidic cleavable resin strategy, pioneered by R.C. Sheppard, are most commonly used for the synthesis of peptides1. Inspired by Merrifield's solid supported strategy, we have developed a Boc/tert-butyl solid-phase synthesis strategy for the assembly of functionalized bis-peptides2, which is described herein. The use of solid-phase synthesis compared to solution-phase methodology is not only advantageous in both time and labor as described by Merrifield1, but also allows greater ease in the synthesis of bis-peptide libraries. The synthesis that we demonstrate here incorporates a final cleavage stage that uses a two-step "safety catch" mechanism to release the functionalized bis-peptide from the resin by diketopiperazine formation. Bis-peptides are rigid, spiro-ladder oligomers of bis-amino acids that are able to position functionality in a predictable and designable way, controlled by the type and stereochemistry of the monomeric units and the connectivity between each monomer. Each bis-amino acid is a stereochemically pure, cyclic scaffold that contains two amino acids (a carboxylic acid with an α-amine)3,4. Our laboratory is currently investigating the potential of functional bis-peptides across a wide variety of fields including catalysis, protein-protein interactions and nanomaterials.

Solid Phase Synthesis of a Functionalized Bis-Peptide Using "Safety Catch" Methodology

In 1962, R.B. Merrifield published the first procedure using solid-phase peptide synthesis as a novel route to efficiently synthesize peptides. This technique quickly proved advantageous over its solution-phase predecessor in both time and labor. Improvements concerning the nature of solid support, the protecting groups employed and the coupling methods employed over the last five decades have only increased the usefulness of Merrifield's original system. Today, use of a Boc-based protection and base/nucleophile cleavable resin strategy or Fmoc-based protection and acidic cleavable resin strategy, pioneered by R.C. Sheppard, are most commonly used for the synthesis of peptides(1). Inspired by Merrifield's solid supported strategy, we have developed a Boc/tert-butyl solid-phase synthesis strategy for the assembly of functionalized bis-peptides(2), which is described herein. The use of solid-phase synthesis compared to solution-phase methodology is not only advantageous in both time and labor as described by Merrifield(1), but also allows greater ease in the synthesis of bis-peptide libraries. The synthesis that we demonstrate here incorporates a final cleavage stage that uses a two-step "safety catch" mechanism to release the functionalized bis-peptide from the resin by diketopiperazine formation. Bis-peptides are rigid, spiro-ladder oligomers of bis-amino acids that are able to position functionality in a predictable and designable way, controlled by the type and stereochemistry of the monomeric units and the connectivity between each monomer. Each bis-amino acid is a stereochemically pure, cyclic scaffold that contains two amino acids (a carboxylic acid with an α-amine)(3,4). Our laboratory is currently investigating the potential of functional bis-peptides across a wide variety of fields including catalysis, protein-protein interactions and nanomaterials.

The use of solid phase synthesis for the preparation of monoadducts of fullerene C60

The method of solid phase synthesis was proposed for the preparation of monoadducts of fullerene C60 using 3′H-cyclopropa[1,9](C60-Ih)[5,6]fullerene-3′-carboxylic acid as an example.

ChemInform Abstract: Guanylated Diamines, Triamines, and Polyamines: Chemistry and Biological Properties

AbstractReview: 251 refs.

Novel preloaded resins for solid-phase biotinylation of carboxylic acids

Use of solid-phase synthesis for the derivatization of carboxylic acids with biotinylated spacers consisting of ethylenoxy units is described. An aminomethylated resin provided with an acid-labile aldehyde linker is used as the polymer support and three different systems with a reactive amino group are introduced. Acylation of each system was tested with a set of model carboxylic acids and afforded crude products of excellent purity. The preloaded resins are similar to the Biotin-PEG-NovaTagTM resin but offer several advantages including simple elongation of the spacer arm. The protocols described represent a very efficient way of modifying compounds to obtain ligands for affinity chromatography studies.

Guanylated Diamines, Triamines, and Polyamines: Chemistry and Biological Properties

Naturally occurring polyamines (PAs) play a pivotal role in the life of all organisms from bacteria to man. The human PAs putrescine, spermidine, and spermine are fundamental for cell viability, having a multitude of in vivo functions, and their study is an expanding field of research. The polycationic nature of these polyamines is important for their biological activities and for their in vivo interaction with macromolecules such as enzymes or the polyanionic nucleic acids. Several reviews have been reported so far on the chemistry, synthesis, and biological properties of polyamines. However, a particular class of polyamines, namely, the guanylated polyamines, attracted the attention of many chemists and biologists in the last decades. A guanylated polyamine is a polyamine with one or more of its amino moieties as part of a guanidine function. These compounds can be sometimes referred to as polyaminoalkylguanidines. Replacement of an amino group in a biologically active polyamine compound by the strongly basic guanidinium results often in a significant increase of its potency and/or selectivity. In fact, the guanidine group is a common structural key element in a variety of natural and synthetic compounds, which show interesting biological properties or chemical behavior and have therefore found important applications in medicinal, bioorganic, supramolecular chemistry, and, most recently, asymmetric synthesis. A guanidinium group is commonly used by proteins and enzymes to recognize and bind anions through ion pairing and hydrogen bonding. The specific patterns of hydrogen bonding recognition together with the high basicity (pKa ≈ 13.5) makes the guanidium group able to play several key roles in recognition, electrophilic catalysis, and biological activity in many enzymes. As a consequence, guanylated polyamines may possess biochemical and biophysical properties amplified with respect to their parent polyamines. Moreover, being strictly related to natural bioamines and amino acids, the guanylated polyamines often have high solubility in water and bioavailability, which makes them excellent drugs or lead compounds. Guanylated polyamines (in particular guanylated diamines and triamines) play important roles in biological processes and might be produced directly by plants, animals, and humans. However, despite their simple chemical structures, these compounds showed difficulties from a synthetic point of view, mostly due to the nature of guanidine moiety, which makes these compounds highly polar and hard to handle and to purify. In addition, the presence of two or more nitrogens or guanidine moieties represents an additional issue: for instance, the regioselctive guanylation of polyamines still represents a big challenge for chemists. Different synthetic methodologies have been reported to overcome these issues such as the shrewd use of a protecting group strategy or the use of solid-phase synthesis. Moreover, possessing these compounds different reactive moieties, side reactions sometimes constitute a problem. This review will cover systematically the preparation methodologies and chemical properties of guanylated diamines, triamines, and, more generally, polyamines. Finally, a description of their most important biological properties will be reported.

Deglycobleomycin A 6 analogues modified in the methylvalerate moiety

Previous studies have indicated that the methylvalerate subunit of bleomycin (BLM) plays an important role in facilitating DNA cleavage by BLM and deglycoBLM. Eleven methylvalerate analogues have been synthesized and incorporated into deglycoBLM congeners by the use of solid-phase synthesis. The effect of the valerate moiety in the deglycoBLM analogues has been studied by comparison with the parent deglycoBLM A 5 using supercoiled DNA relaxation and sequence-selective DNA cleavage assays. All of the deglycoBLM analogues were found to effect the relaxation of the plasmid DNA. Those analogues having aromatic C4-substituents exhibited cleavage efficiency comparable to that of deglycoBLM A 5. Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage.

Dimeric Building Blocks for Solid-Phase Synthesis of α-Peptide-β-Peptoid Chimeras

Recently, a novel type of antimicrobial and proteolytically stable peptidomimetic oligomers having an α-peptide-β-peptoid chimeric backbone was reported. The present paper describes efficient protocols for the preparation of a wide range of dimeric building blocks, displaying different types of side-chains, for use in solid-phase synthesis (SPS) of libraries of this type of oligomers. The β-peptoid monomers were obtained by microwave-assisted aza-Michael additions to acrylic esters. Subsequent solution-phase peptide coupling with suitably protected α-amino acids afforded dimeric intermediates. Even sluggish peptide couplings, involving sterically hindered N-alkyl-β-alanines or amino acids with bulky side-chains, gave high yields on multigram-scale when using microwave (MW) irradiation. Protecting group and side-chain manipulations were performed as one-pot solution-phase procedures to afford ten different building blocks in good to excellent yields. Finally, the efficiency of SPS oligomerization of a representative dimer was demonstrated by preparing 10- to 16-residue homomers and by the assembly of four different building blocks to give a diversely functionalized octamer.

A new colorimetric test for detection of hydroxyl groups in solid-phase synthesis

A new colorimetric test (methyl red-DIC test) for monitoring the presence of hydroxyl groups on resins for use in solid-phase synthesis was developed. The resin became orange-red when the carboxyl group of methyl red formed ester linkages with the resin’s hydroxyl groups. This new test can be used not only for qualitative analysis but also quantitative analysis by using pictures of the relationship between color depth and hydroxy loading rates.

Poly(vinyl alcohol)-graft-poly(ethylene glycol) resins and their use in solid-phase synthesis and supported TEMPO catalysis

New poly(vinyl alcohol)-graft-poly(ethylene glycol) (PVA-g-PEG) resins with various PEG chain lengths, which have high loadings and good swelling both in water and organic solvents, have been prepared via an anionic polymerization of ethylene oxide onto PVA beads and applied in solid-phase synthesis, supported TEMPO catalysis and in HR-MAS 1H NMR spectral analysis.

Synthesis of cationic porphyrin modified amino acids

Derivatives of amino acids bearing a porphyrin moiety on a side chain were synthesized by coupling a porphyrin to a glutamic acid side chain; the utility of these compounds was demonstrated by their use in solid-phase synthesis of a peptide bearing a cationic porphyrin and by studying its DNA-binding properties.

AMPA receptor ligands: synthetic and pharmacological studies of polyamines and polyamine toxins.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular polyamines are known to modulate the function of these receptors in vivo. In this study, recent developments in the medicinal chemistry of polyamine-based ligands are given, particularly focusing on the use of solid-phase synthesis (SPS) as a tool for the facile generation of libraries of polyamine toxin analogues. Moreover, the recent development of highly potent and very selective AMPAR ligands is described. Additionally, we provide a detailed account on the mechanism and site of action of AMPAR blockade by polyamine-based ligands, including examples of how these ligands are used as tools to study AMPAR, and a comparison with their action on other ionotropic receptors.

Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases Plasmepsin I and II. Use of Solid-Phase Synthesis to Explore Novel Statine Motifs

Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 microM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

Solid-phase synthesis of peptide ribonucleic acids (PRNA)

The range of available peptide ribonucleic acid (PRNA) monomers was fully expanded for the use in solid-phase synthesis of PRNA oligomers, which were designed to reversibly control the recognition and complexation behavior of the complementary DNA/RNA by external factors. A couple of PRNA 12-mers with desired purine–pyrimidine mixed sequences were prepared indeed in high yields by the solid-phase synthesis.