Simple formylacetal (CH2) as a novel linker for saccharide synthesis on soluble-polymer support

Described herein is a new formylacetal (CH₂) linker for immobilization of small molecules onto a soluble-polymer support, poly(ethylene glycol) ω-monomethyl ether (MPEG), and its application to saccharide synthesis. This small linker allows immobilization of a hindered hydroxy group such as the 4-hydroxy group of glucose onto MPEG. The linker is stable under several reaction conditions including glycosylation. Removal of this support was found to be achieved through cleavage of the CH₂ linker either by a Lewis acid (TMSI or Ce(OTf)_x) or a Brønsted acid (trifluoroacetic acid) in moderate to good yields. In combination with solid acid catalyst, simpler operations became possible during the working-up and purification processes.     

Optimization of spiroimidazolidinone derivatives synthesis on solid phase using SynPhase™ Lanterns

We report the synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives from N-benzyl-4-piperidone and N-protected amino acid amides on solid support. We have translated the chemistry from solution to solid phase using a backbone amide linker (BAL) mimic. Using a parallel combinatorial approach, we performed the optimization of the synthesis on SynPhase™ Lanterns.     

2-Bromoethyl glycosides for synthesis of glycoconjugates on solid support

2-Bromoethyl glycosides can easily and in high yields be transformed into sulfones by treatment with a suitable thiol followed by oxidation with mCPBA. The observation that the so formed sulfones were cleaved by treatment with NaOMe/MeOH was used to design a new safety catch linker for synthesis of glycoconjugates on solid support.     

Solid-phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines

The synthesis of imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives by condensation between an α-bromoketone bound to solid support and various 2-aminopyridine or 2-aminopyrimidine derivatives was described. Either an acid labile linker or a base labile linker was used in this study.     

Tricyclic heterocycles as precursors to functionalized spirocyclic oximes

An efficient synthesis of functionalized spirocyclic oximes from tricyclic heterocycles is reported. This novel method accomplishes high diastereoselectivity via an intramolecular 1,3-dipolar cycloaddition with a regenerating Michael linker strategy. Ring opening of the tricyclic N-(trimethylsilyloxy)pyrrolo[3,4-c]isoxazolidine framework was found to be essential for successful N-alkylation of the tertiary amine on the polymer support. β-Elimination of the quaternary salt releases the spirocyclic oximes from the solid support in overall yields of 45–60%.     

Dual linker with a reference cleavage site for information rich analysis of polymer-supported transformations

Two dual linker systems with specific reference cleavage sites were designed and synthesized to accelerate and simplify development and optimization of reaction conditions for solid-phase synthesis. The dual linker allows simple evaluation of cleavage rate of polymer-supported compounds from the linker and, at the same time, ensures that all resin-bound components are cleaved from the solid support. The dual linker 4 was assembled from two Wang linkers connected by a three carbon spacer. The linker 9 was synthesized using the PAL and HMPB linkers.     

Preparation and sorption studies of polyester microsphere copolymers containing β-Cyclodextrin

Polyester copolymer sorbent materials that incorporate β-Cyclodextrin (β-CD) were prepared using water-in-oil (w/o) micro-emulsion conditions at variable β-CD: cross linker mole ratios; where the cross linker units were sebacoyl chloride (SCl) and terephthaloyl chloride (TCl). The copolymers were characterized using TGA, nitrogen adsorption, and NMR/IR spectroscopy. The dye-based sorption properties of the copolymers with p-nitrophenol (PNP) in aqueous solution were evaluated at pH 4.6 and 295 K using UV-Vis spectrophotometry. The uptake of PNP varied from 0.221 to 0.352 mmol/g, according to the nature of the cross linker and the copolymer mole ratio. The sorption capacity of SCl-based copolymers exceed that for TCl-based copolymers, and correlate with the relative swelling properties and hydrated surface areas of the sorbent frameworks. ¹H NMR spectroscopy of copolymers with low levels of linker content (i.e. SCl or TCl) indicate dual sorption sites for PNP (i.e. β-CD inclusion sites and non-inclusion (interstitial) linker domains). The existence of dual sorption sites is similarly concluded for copolymers containing higher levels of cross linker. Inclusion complexes are firstly formed between PNP and the β-CD inclusion sites of the copolymer; thereafter, PNP is adsorbed onto the linker domains of the copolymer sorbent framework.     

Synthesis and characteristics of a chelating resin as an extractant and chromogenic reagent of heavy metal ions in solid phase extraction

A new chelating resin (CPS-DMA-SABA) was synthesized with the chloromethylated cross-linked polystyrene porous beads (CPS) as raw materials, which were bonded with salicylidene-o-aminobenzoic acid (SABA) on the surface via a quaternary ammonium unit as a linker. The results showed that CPS-DMA-SABA would easily change into a zwitterionic chelating resin (CPS-DMA-SABZ) when washed with distilled water. CPS-DMA-SABA was characterized by elemental analysis, infrared spectra and thermo-gravimetric analysis. The ion sorption capacities of CPS-DMA-SABA were found to be 1916 μg/g for Zn²⁺ with pH at 4.5, 1620 μg/g for Cu²⁺ with pH at 6.2, 1291 μg/g for Ni²⁺ with pH at 6.6 and 780 μg/g for Cr³⁺ with pH at 5.5, respectively. The experiments showed CPS-DMA-SABA also changed its color when meeting with the metal ion in the aqueous solution. As a consequence, CPS-DMA-SABA can not only be used as a solid phase extractant but also an indicator for confirming the heavy metal ion in solutions.     

A Novel Oxime‐Derived Solid Support for the Synthesis of 3‐Phosphorylated Oligonucleotides

Oligonucleotides containing terminal phosphate groups serve as useful intermediates for different applications in molecular and cell biology, as well as for diagnostic purposes. The chemical synthesis of these derivatives has been an important topic of oligonucleotide research. We report here a novel polystyrene‐based solid support bearing an α‐hydroxy oximate linker that allows the synthesis of 3′‐phosphorylated oligodeoxynucleotides as well as oligoribonucleotides in high quality. The formation of the phosphorylated oligonucleotides likely proceeds through an eliminative pathway with concurrent nitroso‐ene production.     

Development of solid phase radioimmunoassay system using new polymeric magnetic micro-spheres

Magnetic particles were locally prepared by co-precipitation of Fe²⁺ and Fe³⁺ in an ammonia solution. The prepared microsphere were grafted with polyacrylamide acrylic acid by using gamma irradiation polymerization in presence of MBA as a cross linker. AFP antibody was immobilized on these beads and used as a solid phase in radioimmunoassay technique. The immunoreactivity of the developed assay was found to be influenced by different factors such as solid phase volume, incubation time, incubation temperature and storage period. A comparative study was performed between the developed assay system and others two ones. The maximum binding percent attained the value of 19.5% while the sensitivity was observed to be 1.3 IU/mL. The developed assay displayed acceptable precision estimated by repeated analysis of the quality control samples and the clinical samples analyzed by this assay showed a good correlation with that commercial kit (r = 0.998).     

Solid-phase synthesis of an apoptosis-inducing tetrapeptide mimicking the Smac protein

An approach for the solid-phase synthesis of apoptosis-inducing Smac peptidomimetics is presented. Using a Rink linker strategy, tetrapeptides mimicking the N-4-terminal residue of the Smac protein [(N-Me)AVPF sequence] were synthesized on PEGA resin in excellent purities and yields. Following two synthetic routes, a known tetrapeptide, incorporating a substituted proline, previously shown to exhibit excellent biological activity in vitro as well as low toxicity, was synthesized effectively on a solid support.     

Synthesis of a secretoglobin 3A2 type C (98–139) fragment by Dawson’s native chemical ligation

A secretoglobin 3A2 type C (98–139) peptide was synthesized by native chemical ligation between ¹¹⁵Ile and ¹¹⁶Cys residues using Dawson’s linker. The peptide-N-acyl-benzimidazolinone-glycine amide, a C-terminal thioesters precursor, was provided from 3-amino-4-(methylamino)benzoic acid. In addition, an N-terminal cysteine fragment, the (116–139) peptide, was prepared by ordinary Fmoc-solid phase peptide synthesis. Native chemical ligation of the (98–115) fragment with the Dawson’s linker and the (116–139) peptide smoothly proceeded to give SCGB3A2 type C (98–139) peptide.     

Translational dynamics of a non-degenerate molecular shuttle imbedded in a zirconium metal–organic framework

A new [2]rotaxane molecular shuttle linker based on the binding of a 24-crown-8 ether macrocycle at a benzimidazole recognition site was synthesised. The shuttling dynamics of the linker were studied in solution and the structure confirmed by X-ray crystallography. A multivariate Zr(iv) MOF, UWDM-11, containing the new MIM linker and primary linker tetramethylterphenyldicarboxylate was synthesised and the translational motion of the molecular shuttle studied in the solid state. The use of a ¹³C enriched MIM linker allowed the dynamics of both activated and mesitylene-solvated UWDM-11 to be elucidated by VT ¹³C CPMAS SSNMR. The incorporation of mesitylene into the pores of UWDM-11 resulted in a significant increase in the barrier for thermally driven translation of the macrocycle.

An unsymmetrical molecular shuttle was incorporated into the octahedral cavities of a Zr(iv) MOF. ¹³C SSNMR showed that the presence of mesitylene in the pores results in an increase in the barriers for the thermally driven motion of the macrocycle.     

Enantiomerically pure chiral pyridino-crown ethers: synthesis and enantioselectivity toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate

Seven new enantiomerically pure chiral pyridino-crown ethers (S,S)-4–(R,R)-10 were prepared. Three of them [(S,S)-4, (S,S)-7 and (R,R)-10] contain one, and two of them [(S,S)-5 and (S,S)-8] contain two linker chains with a terminal double bond. These linker chains were connected to the carbon atom at position 9 (opposite the pyridine moiety) of the macrocycle. The terminal double bond of the linker makes it possible to attach these ligands to silica gel to obtain chiral stationary phases (CSPs). The enantioselectivity of the new ligands toward the enantiomers of α-(1-naphthyl)ethylammonium perchlorate (NEA) was also determined by a titration ¹H NMR method.     

Synthesis and structural characterization of metal–organic frameworks with the mellitate linker M2(OH)2[C12O12H2]·2H2O (M = Al,Ga, In) MIL-116

A new series of isostructural MOF-type carboxylates called MIL-116 (M₂(OH)₂[C₁₂O₁₂H₂]·2H₂O), was synthesized from the combination of mellitic acid and trivalent p cations M = Al³⁺, Ga³⁺ or In³⁺. Their structures were analyzed either by single-crystal microdiffraction using the synchrotron radiation beamline (ID13 station at ESRF, Grenoble) or solved from powder X-ray diffraction. The 3D hybrid framework is built up from the connection of infinite straight chains of metal-centered octahedra sharing trans corners linked to each other through the mellitate ligands. Here the ligand acts as octadentate linker with four of the carboxylic groups involved in the M–O–C bondings. The two other carboxylate arms remain non-bonded under their protonated form. This represents a rare case of the occurrence of both non-bonding and bonding organic functionalities in a MOF-type solid. Within the tunnels are located water species that interact with the non-coordinated –COOH groups pointing towards the channel.     

Color Bricks: Building Highly Organized and Strongly Absorbing Multicomponent Arrays of Terpyridyl Perylenes on Metal Oxide Surfaces

Terpyridine‐substituted perylenes containing cyclic anhydrides in the peri position were synthesized. The anhydride group served as an anchor for assembly of the terpyridyl‐crowned chromophores as monomolecular layers on metal oxide surfaces. Further coordination with Zn²⁺ ions allowed for layer‐by‐layer formation of supramolecular assemblies of perylene imides on the solid substrates. With properly selected anchor and linker molecules it was possible to build high quality structures of greater than ten successive layers by a simple and straightforward procedure. The prepared films were stable and had a broad spectral coverage and high absorbance. To demonstrate their potential use, the synthesized dyes were employed in solid‐state dye‐sensitized solar cells, and electron injection from the perylene antennas to titanium dioxide was observed.     

Improved Methodology for the Synthesis of a Cathepsin B Cleavable Dipeptide Linker,Widely Used in Antibody-Drug Conjugate Research

Antibody-drug conjugates (ADCs) represent an emerging class of biopharmaceutical agents that deliver highly potent anticancer agents (payloads) selectively to tumors or components associated with the tumor microenvironment. The linker, responsible for the connection between the antibody and payload, is a crucial component of ADCs. In certain examples the linker is composed of a cleavable short peptide which imparts an additional aspect of selectivity. Especially prevalent is the cathepsin B cleavable Mc-Val-Cit-PABOH linker utilized in many pre-clinical ADC candidates, as well as the FDA approved ADC ADCETRIS^® (brentuximab vedotin). An alternative route for the synthesis of the cathepsin B cleavable Mc-Val-Cit-PABOH linker is reported herein that involved six steps from l-Citrulline and proceeded with a 50% overall yield. In this modified route, the spacer (a para-aminobenzyl alcohol moiety) was incorporated via HATU coupling followed by dipeptide formation. Importantly, this route avoided undesirable epimerization and proceeded with improved overall yield. Utilizing this methodology, a drug-linker construct incorporating a potent small-molecule inhibitor of tubulin polymerization (referred to as KGP05), was synthesized as a representative example.     

Spectroscopic investigation of adsorbed 7-(4-ethyl-1-methyloctyl)-8-quinolinol (kelex 100) and of its gallium(III) complex: Comparison with the behaviours observed in solvent extraction systems

The adsorption of a long hydrocarbon chain oxine derivative, 7-(4-ethyl-1-methyloctyl)-8-quinolinol, on the macromolecular Amberlite XAD-7 support is shown by FT-IR spectroscopy to be the result of only weak extractant-support interactions. It is also shown that the chelation ability of the extractant towards gallium(III) does not suffer from the presence of the solid support. Finally the stereochemistry (fac or mer configuration) of the tris-7-(4-ethyl-1 -methyloctyl)-8-quinolinato gallium(III) complex formed either in solution in an organic diluent or on the support is discussed on the basis of ¹H and ¹³C NMR and FIR data.     

Synthesis of a new hydrophilic o-nitrobenzyl photocleavable linker suitable for use in chemical proteomics

Linkers currently used in solid phase synthesis are generally short and hydrophobic, limiting their usefulness in biological systems. Herein, we describe a facile synthesis of a long, hydrophilic, o-nitrobenzyl photocleavable linker, suitable for constructing affinity supports for use in chemical proteomics. The rates of photolysis of the linker on exposure to UV light emitting diodes are reported.     

Automated Synthesis of Oligosaccharides

The chemical synthesis of oligosaccharides with an automated solid‐phase synthesizer is described. An octenediol linker served to attach the growing oligosaccharide chain to the solid support, and the desired structures were cleaved from the support via olefin metathesis to afford a pentenyl glycoside. The automated syntheses of several important carbohydrates, including a pentarhamnoside, a proteoglycan linkage‐region tetrasaccharide, a phytoalexin elicitor dodecasaccharide, and a branched Leishmania lipophosphoglycan tetrasaccharide, were accomplished in higher overall yield and ca. 20 times faster than with solution‐phase methods.