Preparation and applications of polyethylene glycol-polystyrene graft resin supports for solid-phase peptide synthesis

Abstract

Heterobifunctional polyethylene glycol (PEG) derivatives BocNH(CH 2CH 2O) nCONHCH 2CO 2H were attached cleanly onto aminomethyl copoly(styrene-1% divinylbenzene) (PS) resins by oxidation-reduction couplings mediated by tri- n-butylphosphine plus 2,2′-dipyridyl disulfide. The amount of PEG incorporated into the resultant PEG-PS graft resins can be controlled through the degree of aminomethylation of the starting cross-linked PS and/or by use of PEG derivatives of different molecular weight ( i.e., ∼ 2000 for n = 45 ; ∼ 4000 for n = 90 ). The new PEG-PS supports, which have good swelling properties in an extended range of solvents, were evaluated as supports for stepwise solid-phase peptide synthesis (SPPS) using tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) or dithiasuccinoyl (Dts) for N α-amino protection, along with compatible anchoring handles for the C-terminal residue. Several peptide syntheses were carried out in parallel in order to compare PEG-PS supports with the corresponding parent PS resins; reproducible advantages were observed with PEG-PS. In addition, PEG-PS supports were shown to be uniquely suited for SPPS using acetonitrile as the solvent for all coupling steps and washes.