The synthesis of solid supports carrying base labile linkers to generate 3'-phosphate oligonucleotides.

Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.

Safety-Catch Linkers for Solid-Phase Peptide Synthesis.

Solid-phase peptide synthesis (SPPS) is the preferred strategy for synthesizing most peptides for research purposes and on a multi-kilogram scale. One key to the success of SPPS is the continual evolution and improvement of the original method proposed by Merrifield. Over the years, this approach has been enhanced with the introduction of new solid supports, protecting groups for amino acids, coupling reagents, and other tools. One of these improvements is the use of the so-called "safety-catch" linkers/resins. The linker is understood as the moiety that links the peptide to the solid support and protects the C-terminal carboxylic group. The "safety-catch" concept relies on linkers that are totally stable under the conditions needed for both α-amino and side-chain deprotection that, at the end of synthesis, can be made labile to one of those conditions by a simple chemical reaction (e.g., an alkylation). This unique characteristic enables the simultaneous use of two primary protecting strategies: tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). Ultimately, at the end of synthesis, either acids (which are incompatible with Boc) or bases (which are incompatible with Fmoc) can be employed to cleave the peptide from the resin. This review focuses on the most significant "safety-catch" linkers.

A safety-catch protecting group strategy compatible with Boc-chemistry for the synthesis of peptide nucleic acids (PNAs).

Peptide Nucleic Acids (PNAs) are an intriguing class of synthetic biomolecules with great potential in medicine. Although PNAs could be considered analogs of oligonucleotides, their synthesis is more like that of peptides. In both cases, a Solid-Phase Synthesis (SPS) approach is used. Herein, the advantage using Boc as a temporal protecting group has been demonstrated to be more favored than Fmoc. In this context, a new PNA SPS strategy has been developed based on a safety-catch protecting group scheme for the exocyclic nitrogen of the side-chain bases and the linker. Sulfinyl (sulfoxide)-containing moieties are fully stable to the trifluoroacetic acid (TFA) used to remove the Boc group, but they can be reduced to the corresponding sulfide derivatives, which are labile in the presence of TFA. The efficiency of this novel synthetic strategy has been demonstrated in the synthesis of the PNA pentamer H-PNA(TATCT)-ßAla-OH.

Solid-Phase Peptide Synthesis Using a Four-Dimensional (Safety-Catch) Protecting Group Scheme.

Peptides of importance to both academia and industry are mostly synthesized in the solid-phase mode using a two-dimensional scheme. The so-called Fmoc/tBu strategy, where the groups are removed by piperidine and TFA, respectively, is currently the method of choice for peptide synthesis. However, as the molecular diversity of cyclic and branched peptides becomes a challenging interest, a high level of orthogonal dimensionality is required, such as through triorthogonal protection schemes. Here we present a fourth category of orthogonal protecting groups that are stable under cleavage conditions, including the TFA treatment that removes the tBu-based groups. At the end of the synthetic process and upon some chemical manipulation, the groups in this fourth category were removed with TFA. This new concept of protecting groups could facilitate the synthesis and manipulation of difficult peptides.

Crystal structure, spectroscopic studies and theoretical studies of thiobarbituric acid derivatives: understanding the hydrogen-bonding patterns.

In addition to their wide-ranging applications in the pharmaceutical industry, thiobarbituric acid (TBA) derivatives are also known to possess applications in engineering and materials science. 20 TBA derivatives, with diversity at the N and C-5 positions through acylation, Schiff base formation, Knoevenagel condensation, thioamide and enamine formation, were studied. The absolute configurations for six derivatives, namely 5-acetyl-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H14N2O3S, A01, 1,3-diethyl-5-propionyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H16N2O3S, A02, tert-butyl [1-(1,3-diethyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate, C18H29N3O5S, A06, 1,3-diethyl-4,6-dioxo-2-thioxo-N-(p-tolyl)hexahydropyrimidine-5-carbothioamide, C16H19N3O2S2, A13, 5-(1-aminoethylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C10H15N3O2S, A17, and 5-(1-aminopropylidene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione, C11H17N3O2S, A18, were confirmed by single-crystal X-ray crystallography, which indicates the formation of intramolecular hydrogen bonding in all six cases and intermolecular hydrogen bonding for A17. In A13, the presence of two intramolecular hydrogen bonds was observed. The stabilization of the enol form over the keto form was confirmed by computation. In order to convert the keto form to the enol form, an energy barrier of 55.05 kcal mol-1 needs to be overcome, as confirmed by transition-state calculations.

Exploiting the Thiobarbituric Acid Scaffold for Antibacterial Activity.

Thiobarbituric acid (TBA) has been considered a privileged structure for developing antimicrobial agents. Diversity was obtained at positions N and at C5 through acylation, Schiff base formation, Knoevenagel condensation, and thioamide and enamine formation. The present work describes the synthesis of small libraries based on the TBA moiety and above-mentioned reactions. Preliminary antimicrobial activity screening of the prepared compounds against selected bacteria (both Gram-positive and -negative) showed the best results for the Boc-Phe-TBA derivative. These results could be useful for designing and building libraries based on other amino acids with distinct protecting groups.

Investigation of the N-Terminus Amino Function of Arg10-Teixobactin.

Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity.