d- myo-Inositol-1,4,5-trisphosphate and Adenophostin Mimics: Importance of the Spatial Orientation of a Phosphate Group on the Biological Activity

• Published in: Bioorganic & medicinal chemistry 2002-03, Vol.10 (3), p.759-768
• Main Authors: Roussel, Fabien, Moitessier, Nicolas, Hilly, Mauricette, Chrétien, Françoise, Mauger, Jean-Pierre, Chapleur, Yves
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Animals; Binding Sites; Binding, Competitive; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Calcium Channel Agonists - chemical synthesis; Calcium Channel Agonists - chemistry; Calcium Channel Agonists - pharmacology; Calcium Channels - chemistry; Calcium Channels - metabolism; Hepatocytes - metabolism; Inositol 1,4,5-Trisphosphate - chemical synthesis; Inositol 1,4,5-Trisphosphate - chemistry; Inositol 1,4,5-Trisphosphate - pharmacology; Inositol 1,4,5-Trisphosphate Receptors; Medical sciences; Microsomes; Molecular Conformation; Molecular Mimicry; Pharmacology. Drug treatments; Phosphates - chemistry; Rats; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Second Messenger Systems - drug effects; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00329-7

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. Two diastereoisomeric analogues of inositol 1,4,5,-trisphoshate and adenophostins have been prepared. The 2( S) isomer is a potent agonist of InsP 3R and the 2( R) isomer is only weak agonist.