title: Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity.
abstract: 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 Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 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)P(3)R, i. e. that a cation-pi 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)P(3).
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK BA2 7AY.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Borissow
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Black
authors.forename: Michael
authors.initials: M
authors.lastname: Paul
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Tovey
authors.forename: Skarlatos G
authors.initials: SG
authors.lastname: Dedos
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000225:Adenine / Q000737:chemistry*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D006860:Hydrogen Bonding; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D012996:Solutions / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D012996:Solutions; C085029:adenophostin A; D000225:Adenine; D000241:Adenosine; D002118:Calcium