We have investigated the in vitro antimalarial activity of a new series of adenosine derivatives. The results show that N(6)-(1-naphthylmethyl)-5'-deoxy-5'-(amido)adenosines as well as N(6)-(4-phenylbenzyl)-5'-deoxy-5'-(amido)adenosines display significant activity against the malaria-causing parasites, with the sterically demanding bisubstituted species reported being active in most cases in the low-micromolar range. The novel compounds with unusual substitution pattern were obtained applying an efficient convergent polymer-assisted solution-phase (cPASP) synthesis protocol. Thus, we were able to prepare a series of substituted derivatives in parallel that would have been difficult to synthesize by standard techniques. The scope and limitations of the synthetic methodology are discussed.

We have investigated the in vitro antimalarial activity of a new series of adenosine derivatives. The results show that N(6)-(1-naphthylmethyl)-5'-deoxy-5'-(amido)adenosines as well as N(6)-(4-phenylbenzyl)-5'-deoxy-5'-(amido)adenosines display significant activity against the malaria-causing parasites, with the sterically demanding bisubstituted species reported being active in most cases in the low-micromolar range. The novel compounds with unusual substitution pattern were obtained applying an efficient convergent polymer-assisted solution-phase (cPASP) synthesis protocol. Thus, we were able to prepare a series of substituted derivatives in parallel that would have been difficult to synthesize by standard techniques. The scope and limitations of the synthetic methodology are discussed.

In a joint effort with various laboratories we have been aiming at the structure-based design of glycolysis inhibitors as anti-trypanosomal drugs. 2′-Deoxy-2′-(3-methoxybenzamido)-N6-(1-naphtylmethyl)adenosine (1a) was thus revealed as a promising lead structure for the development of selective agents against protozoan parasites. Here we describe the polymer-assisted synthesis of novel amido derivatives of the scaffold 2′-amino-2′-deoxy-N6-(1-naphtylmethyl)adenosine (5a) we reported recently. This building block synthesized in solution was treated with an excess of polymer-supported carboxylic acids leading to chemoselective, practically quantitative conversion of the amine to the desired analogous amides. The best compound (1h) from this series was obtained after on-bead nucleophilic substitution of the carboxylic acid equivalent attached to the Kenner safety catch linker and exhibited an improved inhibitory effect on T. b. brucei blood stream forms with an IC50 of 0.85 μM in vitro

An efficient and simple polymer-assisted approach has been developed to biotinylate multifunctional compounds bearing an amino functionality. Biotin was immobilized on aminomethylated polystyrene via the Kenner safety catch linker, activated and subsequently transferred to the amino function of the target compounds chemoselectively, thus avoiding protecting group operations. This approach holds potential for the introduction of spacer-modified biotin derivatives.

The synthesis of a novel scaffold for the simple and high-yielding polymer-assisted solution phase preparation of arrays of 2′-amido-2′-deoxy-N6-(1-naphthylmethyl)adenosine derivatives 10a–h as analogues of a known inhibitor of trypanosomatid glycosomal glyceraldehyde-3-phosphate dehydrogenase is described.

A polymer-assisted solution-phase (PASP) synthesis of lead structure analogues ready for biological testing without the demand for chromatographic purification is described. Carboxylic acids are coupled to the Kenner or Ellman safety catch linker, respectively, activated by methylation or cyanomethylation and subsequently transferred to the 2'-amino group of the 2'-amino-2'-deoxyadenosine scaffold (5). The chemoselective attack of weakly nucleophilic amino groups on the N-alkylated N-acyl sulfonamide linker allows for the synthesis of amides 6 in high yields without the need for protection of primary and secondary hydroxyl functions. Thus, the use of 4-sulfamylbenzoylaminomethyl 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 parallel format. Biological evaluation of all compounds reported revealed no improvement over known lead structures.