Jens Buchardt

A chemically inert hydrophilic resin for solid phase organic synthesis

Abstract A new mechanically stable and chemically inert resin for solid phase organic synthesis is described. The resin, POEPS-3 (1), is prepared by bulk and inverse suspension radical polymerisation of macromonomers consisting of polyethylene glycol 1500 partially derivatised with 3-(4-vinylphenyl)propyl groups. Synthesis of the macromonomer (4) is described as well as the properties of the resin which show compatibility with Lewis acids and solvents ranging from toluene to water in polarity.

Phosphinic Peptide Matrix Metalloproteinase‐9 Inhibitors by Solid‐Phase Synthesis Using a Building Block Approach

Substrates of matrix metalloproteinase-9 (MMP-9) having Gly and Leu in the P1and P1′ position can be converted into highly potent inhibitors by incorporation of a phosphinic -GΨ{P(O)OHCH2}L- moiety (see figure). This was shown for an array of phosphinic peptide inhibitors which were prepared by solid-phase peptide synthesis using a building block to introduce the phosphinic moiety.

Phosphinic peptide inhibitors of macrophage metalloelastase (MMP-12). Selectivity and mechanism of binding.

Pseudopeptide inhibitors of MMP-12 with a phosphinic dipeptide G psi[PO(2)H-CH(2)]L covering the P1-P1- positions originating from a combinatorial solid phase library have been identified and kinetically analysed with respect to binding mechanism and selectivity towards MMP-7, MMP-9, MMP-13 and MMP-14. One compound with a low nanomolar dissociation constant for MMP-12 showed significantly lower affinity towards all other MMPs tested compared to MMP-12. Two compounds showed selectivity against MMP-9, MMP-13 and MMP-14. One additional compound showed selectivity against MMP-7. The selectivity of these compounds could partly be rationalized by analysis of homology models of the enzymes. Truncated versions of one inhibitor spanning P2 to P2, P3 to P2 or P2 to P3 showed that interactions on both the prime and the non-prime side are important for binding. A two-step binding mechanism, with a rate limiting second step, was shown for binding of a tryptophane containing inhibitor to MMP-12 by transient state analysis, using the tryptophane residue of the inhibitor as fluorescent probe.

Novel methodology for the solid-phase synthesis of phosphinic peptides

A novel, versatile strategy for the solid phase synthesis of phosphinic peptides is developed in which the phosphorus–carbon bond is formed on a polymer support during peptide synthesis. The formation of bis(trimethylsilyl) 1-(allyloxycarbonylamino)ethylphosphonite from 1-(allyloxycarbonylamino)ethylphosphinic acid is investigated, as well as the Michael addition of the former to a resin-bound acrylate. Conditions are also established for the clean, quantitative conversion of a resin-bound, N-terminus acryloylated peptide with bis(trimethylsilyl) 1-(allyloxycarbonylamino)ethylphosphonite. Conventional peptide synthesis is then employed to obtain a phosphinic undecapeptide in high yield and purity.