An efficient protocol for the synthesis of arylphosphonate diesters via a palladium-catalyzed cross-coupling of H-phosphonate diesters with aryl electrophiles, promoted by acetate ions, was developed. A significant shortening of the cross-coupling time in the presence of the added acetate ions was achieved for bidentate and monodentate supporting ligands, and for different aryl electrophiles (iodo, bromo and triflate derivatives). The reaction conditions were optimized in terms of amount of the catalyst, supporting ligands, and source of the acetate ion used. Various arylphosphonates, including those of potential biological significance, were synthesized using this newly developed protocol. Some mechanistic aspects of the investigated reactions are also discussed.
The RNA components of small nuclear ribonucleoproteins (U snRNPs) possess a characteristic 59-terminal 2,2,7-trimethyl-guanosine CAP structure (m 3 G-CAP). This cap is an important component of the nuclear localization signal of U snRNPs. Here we report synthesis of four m 3 G-CAP constructs and the effective attachment of these onto oligonucleotides (ONs) using Cu(I) [3 + 2] cycloaddition (''click chemistry''). The four constructs (1-4, Fig. 1) are equipped with a handle that in principle allows for universal conjugation to any cargo and differ in their complexity starting from m 3 GpppA (linker) to m 3 GpppA (OMe) U (OMe) A (linker) that resembles the native m 3 G-CAP followed by the 29-O-methylated sequence AUA. The four m 3 G-CAP containing constructs are equipped with an azide linker and by taking advantage of initial attachment of a novel activated triple bond donor p-aminomethyltoluic acid (PATA) to ONs on solid support we were able to synthesize novel bioconjugates equipped with different constructs carrying the m 3 G-CAP Nuclear Localisation Signal (NLS) for the investigation of nuclear delivery.
A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles, to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety.
An efficient method for the synthesis of multiply functionalized oligonucleotides (ONs) utilizing a novel H-phosphonate alkyne-based linker for multiple functionalization (LMF) is developed. The strategy allows for the conjugation of various active entities to oligonucleotide through the postsynthetic attachment of LMF at the 5'-terminus of ONs using H-phosphonate chemistry followed by conjugation of various entities via [3 + 2] copper(I) catalyzed cycloaddition in a stepwise manner. Each cycle is composed of attachment of the LMF followed by a click reaction with azido-containing units. Sequential solid-phase synthesis of oligonucleotide conjugates containing three attached entities was performed using an acetylated form of MIF peptide conjugated to azido linker, achieving high conversions at each unit addition. In addition, to show the versatility of the method, oligonucleotide conjugates with several different classes of compounds were synthesized. Each conjugate containing three different entities, whose structure and function varied (e.g., sugars, peptides, fluorescent labels, and mG-Caps).
An efficient method for the synthesis of β-hydroxy and β-amino ketones from allylic alcohols catalyzed by Ru(η 5 -C 5 Ph 5 )(CO) 2 Cl is described. The influence of the stereoelectronic properties of the catalyst on the reaction outcome has been studied. Optimization of the reaction conditions supressed the formation of undesired side products such as saturated ketones, benzyl alcohols, and α,β-unsaturated ketones.
Biotin is an important molecule for modern biological studies including, e.g., cellular transport. Its exclusive affinity to fluorescent streptavidin/avidin proteins allows ready and specific detection. As a consequence methods for the attachment of biotin to various biological targets are of high importance, especially when they are very selective and can also proceed in water. One useful method is Hüisgen dipolar [3+2]-cycloaddition, commonly referred to as “click chemistry”. As we reported recently, the activated triple bond donor p-(N-propynoylamino)toluic acid (PATA) gives excellent results when used for conjugations at submicromolar concentrations. Thus, we have designed and synthesized two biotin linkers, with different lengths equipped with this activated triple bond donor and we proceeded with biotinylation of oligonucleotides and C-myc peptide both in solution and on solid support with excellent yields of conversion.
We have developed a new, efficient method for the synthesis of benzylphosphonate and benzylphosphonothioate diesters via a palladium(0)-catalyzed cross-coupling reaction between benzyl halides and H-phosphonate or H-phosphonothioate diesters, using Pd 2 (dba) 3 (CHCl 3 ) as a palladium source and Xantphos as a supporting ligand. Some mechanistic aspects of these reactions were investigated using 31 P NMR spectroscopy.
Achieving higher nuclear concentrations by active transport may give potent therapeutic effects at lower doses for many drugs. A method of increasing nuclear uptake is use of naturally existing Nuclear Localization Signals (NLS) by conjugating NLS structures to the cargo. We have synthesized a set of 2,2,7-trimethylguanosine cap (m 3 G-CAP)-containing structures (and their biotin conjugates) as artificially attached analogs of a naturally found NLS. The origin of a naturally found NLS is uridine rich, small nuclear ribonucleoproteins (U snRNPs) that employ Snurportin1 as a nuclear transport protein. In this report the NLS activity of various m 3 G-CAP biotin constructs was studied. We have shown that a minimal requirement for nuclear uptake is the inclusion of a trinucleotide sequence between the m 3 G-CAP and the artificial linker. CAP Product m/z calc/found CAP Product m/z calc/foundMinimal requirement for Snurportin based nuclear uptake is the inclusion of a trinucleotide sequence between the m 3 G-CAP and the artificial linker.
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