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The synthesis of a series of adenophostin A analogues modified at C-6 and C-2 of adenine is described. The target compounds were synthesized by a convergent route involving a modified Vorbrüggen condensation of either 6-chloropurine or 2,6-dichloropurine with a protected disaccharide, yielding two versatile intermediates capable of undergoing substitution with a range of nucleophiles. The new analogues showed a range of abilities to mobilize Ca(2+) from the intracellular stores of permeabilized hepatocytes and are among the first totally synthetic compounds to approach the activity of adenophostin A. In agreement with the biological results, docking studies of adenophostin A using the recently reported X-ray crystal structure of the type 1 Ins(1,4,5)P(3) receptor binding core suggested that, in likely binding modes of adenophostin A, the area around N(6) may be relatively open, identifying this region of the adenophostin A molecule as a promising target for further elaboration. The docking results also point to specific interactions involving residues within the binding domain of the Ins(1,4,5)P(3) receptor that may be involved in the molecular recognition of the adenophostins.

Original publication

DOI

10.1021/jm030883f

Type

Journal article

Journal

J Med Chem

Publication Date

06/11/2003

Volume

46

Pages

4860 - 4871

Keywords

Adenosine, Animals, Binding Sites, Calcium, Calcium Channels, Hepatocytes, In Vitro Techniques, Inositol 1,4,5-Trisphosphate Receptors, Models, Molecular, Molecular Mimicry, Purines, Rats, Receptors, Cytoplasmic and Nuclear, Structure-Activity Relationship