UNIT 14.1 Synthesis of Acyclic Analogs of Adenosine

This unit describes preparation of two groups of chiral acyclic nucleosides that are N-alkyl derivatives of adenine with hydroxyl group(s) on the alkyl chain. As an example of the neutral group, the synthesis is presented for (S)-(2,3,dihydroxypropyl)adenine (DHPA), a compound with multiple biological effects in proliferating systems. Its synthesis consists of alkylation of adenine with a suitable chiral synthon based on 1,2-O-isopropylideneglycerol. Another group of structurally related biologically active compounds are the 9-alkyladenines bearing both hydroxyl and carboxyl functions. Large-scale cyanohydrin reaction of the adenine-containing acetaldehyde intermediate yields 3-(adenin-9-yl)-2-hydroxypropanoic acid (AHPA). Lastly, one of the alternative syntheses of its homolog, the nucleoside antibiotic eritadenine (with a d-erythro-2,3-dihydroxybutanoic acid side-chain) is described starting from d-ribose. Procedures for preparation of all intermediates as well as the purification of the resulting crude material are described in detail. All these adenine derivatives inhibit SAM-dependent methylation reactions via inhibition of SAH hydrolase.

Keywords: acyclic nucleoside analogs; adenine derivatives; methylation inhibitors; DHPA; AHPA; eritadenine