D-myo-inositol-1,4,5-trisphosphate and adenophostin mimics: importance of the spatial orientation of a phosphate group on the biological activity.
Three different routes for the synthesis of heterocyclic analogues of the second messenger D-myo-inositol-1,4,5-trisphosphate (InsP(3)) and the natural adenophostins, starting from allyl D-xyloside are described. The two diastereoisomers at C-2 of new compounds, which we named xylophostins, were obtained. The preliminary biological studies shows that the presence of the adenine residue has a beneficial effect on the affinity for the receptor. The low potency of one of the two diastereoisomeric compounds shows that the configuration of the carbon bearing the non-vicinal phosphate group is an important requirement for a high affinity to the receptor. These results provide evidence for the existence of a binding pocket for the adenine ring nearby the InsP(3) binding site. The consequence of these stabilizing interactions should be to place the phosphate group in a suitable position to perfectly mimic InsP(3) in the more active diastereoisomer. Obviously, in the other diastereoisomer, the phosphate cannot accommodate the same orientation, thus explaining the low affinity. The existence of such a binding pocket for adenine is in line with the high potency of adenophostins.
Roussel
Fabien
F
Groupe SUCRES, UMR 7565, CNRS-Université Henri Poincaré Nancy 1, BP 239, F-54506 Vandoeuvre, France.
Moitessier
Nicolas
N
Hilly
Mauricette
M
Chrétien
Françoise
F
Mauger
Jean-Pierre
JP
Chapleur
Yves
Y
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002120:Calcium Channel Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008861:Microsomes; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010710:Phosphates / Q000737:chemistry; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010710:Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; C085029:adenophostin A; C085030:adenophostin B; D015544:Inositol 1,4,5-Trisphosphate; D000241:Adenosine