SOLID-PHASE SYNTHESIS OF PEPTIDE NUCLEIC-ACID (PNA) MONOMERS AND THEIR OLIGOMERIZATION USING DISULFIDE ANCHORING LINKERS

A new simple solid-phase method has been developed for synthesizing Bo c-protected peptide nucleic acid (PNA) monomers. An immobilized backbo ne 3 was built on Expansin(R) resin using an ester disulphide handle: 2-hydroxypropyl-dithio-2'-isobutyric acid (HPDI). The base acetic acid s of thymine 5, Z-cytosine 9, Z-adenine 12, and 6-O-benzyl guanine 17 were prepared and coupled to the immoblized backbone. The HPDI handle was cleaved under mild conditions by cyanolysis or assisted hydrolysis with tris(2-carboxyethyl)phosphine (TCEP) to give undamaged PNA monom ers. These monomers were coupled to form oligomers by solid-phase meth od with another disulphide linkage: aminoethyldithio-2-isobutyric acid (AEDI) grafted on an amino-functionalized TentaGel(R) resin, using in situ neutralization and TBTU as activating reagent. Final cleavage of the AEDI linker gave PNA bearing a cysteamide residue that could be u seful for optimizing PNA properties. Oligomers of up to 16 residues lo ng were assembled. (C) 1998 European Peptide Society and John Wiley & Sons, Ltd.