Polymer-assisted solution-phase synthesis of 2 '-amido-2 '-deoxyadenosine derivatives targeted at the NAD(+)-binding sites of parasite enzymes

A polymer-assisted solution-phase (PASP) synthesis of lead structure analog ues ready for biological testing without the demand for chromatographic pur ification is described. Carboxylic acids are coupled to the Kenner or Ellma n safety catch linker, respectively, activated by methylation or cyanomethy lation and subsequently transferred to the 2'-amino group of the 2'-amino-2 '-deoxyadenosine scaffold (5). The chemoselective attack of weakly nucleoph ilic amino groups on the N-alkylated N-acyl sulfonamide linker allows for t he synthesis of amides 6 in high yields without the need for protection of primary and secondary hydroxyl functions. Thus, the use of 4-sulfamylbenzoy laminomethyl polystyrene is reported for the construction of chemoselective polymer-supported acylating reagents instead of its known use as linker in solid-phase peptide or organic synthesis; This approach is demonstrated to be well suited to obtain 2'-amido-2'-deoxyadenosine derivatives 6 in paral lel format. Biological evaluation of all compounds reported revealed no imp rovement over known lead structures.