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 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.
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Institut für Pharmazie, Fachbereich Chemie, Universität Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany.
Bressi
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JC
Van Calenbergh
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Gelb
M H
MH
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D000818:Animals; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism*; D010271:Parasites / Q000201:enzymology*; D011108:Polymers
D003839:Deoxyadenosines; D011108:Polymers; D009243:NAD