The preparation of a dendritic graft polymer by a very efficient synthesis of polyglycerol directly on a polystyrene resin is presented. This one-step process can be performed on a multigram scale to provide a chemically stable polymeric support. The resulting hybrid polymers were fully characterized by diverse analytical methods (NMR, IR, ESEM, UV detection of cleaved protecting groups, and mass-spectrometric methods). They combine a high loading capacity (up to 4.3 mmol g(-1)) with good swelling properties in a wide range of solvents (including water), which is the major drawback for many existing solid phase supports. In comparison to the widely employed PEGylated resins, these hybrid materials offer a 10-fold higher loading capacity. Their suitability as supports for organic synthesis and for the immobilization of reagents has been demonstrated. These materials also swell in water, and consequently, it should be possible to use these new hybrid materials for synthesis in protic solvents.

A library system was developed for the discovery of bioactive peptides. Library synthesis and peptide sequencing was performed on a solid support while the screening for bioactivity was done with peptides in solution. The peptides were synthesized by split and mix one-bead-one-peptide library synthesis, using a Tentagel S-NH2 solid support with a loading of approximately 100 pmol/bead. The major part of the peptide was connected to the support by a single acid-labile linker and a minor part of the peptide was acid-stabile attached to the polymer. The percentage of acid-stabile attached peptides could easily be controlled during modification of the amino functionalities of the resin at the start of the process. The cleavage rate of the acid-labile attached peptide from the resin depends on the composition of the cleavage mixture. When cleavage conditions were carefully controlled, a three-step partial cleavage protocol allowed for convergent bioactivity screening on peptide libraries using only one type of acid-labile linker. The partial cleavage and convergent screening procedure was repeated three times, after which the bead containing the bioactive peptide was sequenced. As such a bead still contained acid-stabile attached peptide, the Edman sequencing was straightforward and repetitive yields were excellent because the immobilized peptide was not washed out. (C) 1998 European Peptide Society and John Wiley & Sons, Ltd.

Polyethyleneglycol (PEG) chain mobility in gelatineous microbeads is investigated by means of dynamic excimer formation. Pyrenebutyric acid (PYB) is covalently linked to the chain ends as probe molecule. Excimer formation is monitored by steady-state and time-resolved fluorescence spectroscopy in the presence of a series of liquid phases and in the dry state. PYB concentration in the beads is varied over three orders of magnitude up to c = 6·10 −2 M . The concentration is derived from absorption measurements in stirred bead suspensions, considering the deviations from Lambert–Beer's law in heterogeneous systems. Excimer formation is found to be a dynamic process in the presence of liquid phases which solvate both the polymer and the fluorophore. The collisional rate constant, k DM , is of the order of k DM -values of PYB in homogeneous solutions, indicating a high translational mobility. Excimer-to-monomer intensity ratios are in general accordance with the solvation capacity of the liquid phase. In the dry state excimer formation is found only at high PYB concentrations, c ≈ 3·10 −2 M . It is concluded that this excimer emission arises from aggregated PYB, since corresponding fluorescence response curves show no rise time.

A novel strategy for solid-phase synthesis of hydantoins with high optical purity is described using a thermal pH-neutral cyclization and simultaneous release from resin. Hereby even hydantoins bearing a pH-sensitive side chain (protection) are available. The reaction conditions are well screened applying the parallel organic synthesizer APOS 1200.

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Porous microbeads of low cross-linked polystyrene (PS) grafted with poly(ethylene glycol) chains (PEG) are labeled at the free chain ends with 3-(1,6-diphenyl-1,3,5-hexatrienyl)propionic acid (DPH-PA) and 1-(dimethylamino)naphthalene-5-sulfonic acid (DANS), which probe the polarizability, polarity, and viscosity of their environments. The beads are investigated in a series of pure liquid phases and in acetonitrile/water mixtures by electronic absorption and steady state as well as time-resolved fluorescence spectroscopy. The extent of solvation in the polymer/liquid interphase is characterized from spectral shifts by introducing a solvation fraction which quantifies the relative amount of polymer and liquid in the solvation shell. The rotational mobility of DPH-PA is derived from time-resolved fluorescence anisotropy measurements. Depending on the liquid phase, the rotational correlation times vary strongly between tau(R)=500 ps and 100 ns. The shortest tau(R)-values are found in liquids which are able to solvate both the fluorophore and the polymer, e.g. toluene and acetonitrile. Long correlation times are observed in the presence of aliphatic hydrocarbons, which do not solvate the bead and therefore cannot penetrate into the polymeric frame, and in presence of water, which solvates PEG but not PS and DPH. In contrast, water is able to weakly solvate DANS chemically bound to the polymeric frame.

Zeitaufwendige Abspaltungs‐ und Isolierungsschritte werden durch die Methode der Suspensions‐1H‐Magic‐Angle‐Spinning(MAS)‐NMR‐Spektroskopie überflüssig, die eine Synthesekontrolle an einer einzelnen Harzpartikel im Nanoliterdetektionsbereich ermöglicht. Am Beispiel einer Hydantoin‐Reaktionssequenz wurde dieses für die kombinatorische Chemie effiziente Verfahren erprobt.

A new method has been developed to raise antibodies against synthetic peptides. A multiple antigenic peptide system (MAP) containing a branched oligolysine was synthesized on a beaded polystyrene polyoxyethylene graft copolymer resin, which acts as a synthetic hapten carrier for use in immunization. The peptides, already attached to the carrier, can be used directly after final deprotection without any further purification steps. The utility of this peptide-carrier conjugate is highlighted by its additional application for affinity purification of antibodies generated.

The diffusion process of a solvent (dioxane) in samples of different cross-linked polystyrenes can be monitored by combined NMR imaging and solid-state NMR techniques. NMR imaging data reveal a strong dependence of the diffusion behavior upon the cross-link density: in the case of lowest cross-linking (1 %), a case II diffusion process takes place, whereas in the case of highest cross-linking (5 %), Fickian diffusion occurs. The 2.5 % cross-linked polystyrene shows intermediate behavior. Solid-state NMR relaxation parameters indicate great differences between the unswollen and the swollen state. Whereas the relaxation data obtained in the unswollen state are almost independent of the degree of cross-linking, great differences are observed between the 1 % and 5 % cross-linked polymers in the swollen state, with both the highest overall mobility and, in particular, a high mobility of the phenyl group in the case of the 1 % cross-linked material. This behavior can be directly related to the different types of diffusion, suggesting that the strong interaction of the highly mobile phenyl groups with the dioxane in the low cross-linked material favors case II diffusion. In the 5 % cross-linked materials, with a lower overall mobility and no predominant high phenyl group motion, Fickian diffusion occurs. Increased cross-linking corresponds to increasing T1rhoC and T1C values, thus indicating reduced mobility.

Large scale quantities of phosphodiester and phosphorothioate oligonucleotides are synthesized on an aminopolyethyleneglycol derivatized polystyrene (TentaGel) support. Efficient, automated synthesis up to 1 mmole scale is achieved with phosphoramidite nucleoside monomers and 5-ethylthiotetrazole activator.

Polystyrene-polyethyleneglycol tentacle polymers (PS–PEG) are a novel class of graft copolymer beads based on a polystyrene matrix grafted with a brush-like layer of polyoxyethylene tentacles [9-12]. Immunogenic materials were obtained by synthesizing on tentacle polymer-bound amino derivatives as a solid support the following haptens: The C-terminal sequence 187—211 KPKAA KPKAA KPKAA KPKAA KPKKA APKKK and the N-terminal sequence 3-31 APAAP AAAPP AEKTP VKKKA AKKPA GA of histone H 1 (calf thymus), as well as the sequences 93-116 of the horse liver alcohol dehydrogenase EE (FTPQC GKCRV CKHPE GNFCL KNDL) and SS (FIPQC GKCSV CKHPE GNLCL KNSL) isozymes (Jörnvall (1970) Eur. J. Biochem. 16, 41-49), respectively. These materials proved to be efficient immunogens both in vivo and in vitro, showing excellent biocompatibility compared to other solid hapten carriers. Tentacle-based immunogens are generally available by standard synthetic procedures either by in situ synthesis of hapten molecules on or by covalent attachment of available antigens or haptens to the beads. Advantageous is the possibility to synthesize the peptide on the tentacle polymer, and to use the solid phase bound peptide directly as hapten. The beads serve as carriers, and no separate splitting off the peptide and binding to another carrier is necessary.

Kinetics and cleavage conditions of peptide amide synthesis were studied using the anchor molecules 5-(4'-aminomethyl-3',5'-dimethoxyphenoxy)valeric acid (4-ADPV-OH) and 5-(2'-aminomethyl-3',5'-dimethoxyphenoxy)valeric acid (2-ADPV-OH). Unexpectedly the anchor amide alanyl-4-ADPV-NH2 was isolated and characterized as an intermediate during the cleavage with trifluoroacetic acid (TFA) of alanyl-4-ADPV-alanyl-aminomethyl-polystyrene to yield the alanine amide. As a matter of fact the NH-CH-alpha bond of the alanyl spacer has to be cleaved to form this intermediate. Using TFA-dichloromethane (1:9) alanyl-4-ADPV-NH2 was obtained as a cleavage product in 50% yield within 60 min, whereas the isomeric alanyl-2-ADPV-NH2 was formed more slowly under these mild conditions. At high TFA concentration no difference between the 2- and 4-ADPV anchor was observed in the rate of formation of the free alanine amide. The presence of tryptophan amide in the cleavage mixture resulted in an anchor alkylated tryptophan amide, which remains stable in acidic solution but disappears rapidly in the presence of the resin. A low TFA/high TFA cleavage procedure is recommended for peptide amid synthesis applying the ADPV anchor.