Synthesis of 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines

Abstract

Dedicated to Professor Antonín Holý on the occasion of his 75th birthday in recognition of his outstanding contributions to the area of nucleic acid chemistry.A method for the synthesis of 7-substituted 3-β-D-ribofuranosyl-3H-imidazo[2,1-i]purines has been devised whereby compounds were prepared in a few steps from a common intermediate, 3-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-3H-imidazo[2,1-i]purine-7-carbaldehyde, obtained from the reaction of 2′,3′-O-isopropylideneadenosine with bromomalonaldehyde. The formyl group of the carbaldehyde was subsequently reductively aminated and the resulting secondary amines were then further derivatized either by acylation, lactamization or reductive alkylation.Purine nucleosides and their congeners have found applications in medicinal research as antivirals 1,2 , antiprotozoal agents 3 , adenosine receptor agonists 4-6 , adenosine kinase inhibitors 7,8 and in the treatment of lymphoid malignancies 9-12 and systemic mastocytosis 13 , just to name a few examples. Although the structural analogs of purine nucleosides have for this reason been the subject of extensive synthetic studies, there is still room for further modifications. We now report on the preparation of 7-substituted 3-(β-D-ribofuranosyl)-3H-imidazo[2,1-i]purines to expand the structural diversity of purine-derived compounds. The rationale for the preparation of these compounds is that whilst the structures closely resemble adenosine, the nitrogen atoms analogous to the N 6 and N-1 atoms in adenosine are blocked. These moieties of adenosine are usually engaged in H-bonding with the target protein. It is hoped that this blocking will lead to improved selectivity, since it is expected that only a limited number of potential targets are able to bind these compounds efficiently as ligands.

New Imidazo[1,2‐c]pyrimidin‐5(6H)‐Ones Derived from Cytosine: Synthesis, Structure, and Cytotoxic Activity

“…Kochetkov and coworkers first reported reaction of 9‐methyladenine and 1‐methylcytosine with chloroacetaldehyde, which produced corresponding ethenoderivatives . Because this type of reaction became an interesting pathway for synthesis of modified nucleic acid bases with useful biological, fluorescence, and base‐pairing properties .…”