Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity

The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca2+ from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P3R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P3R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P3R, i. e. that a cation–π interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P3.