Small Molecule Analogs of Phospholipid-Metal Ion Binding Sites: Synthesis and Molecular Modeling of Cyclohexane-1,2,4-triol Trisphosphates

Four diastereomeric cyclohexane-1,2,4-triol trisphosphates were synthesized to serve as small molecule analogs of putative phospholipid-metal ion binding sites. The parent cyclehexane-1,2,4-triols were prepared and phosphorylated. Deprotection of the tris(diphenylphosphates) provided four regiochemical isomers: two with the trans-1,2-phosphate moiety, (±)-(1R,2R,4S)- and (±)-(1R,2R,4R)-cyclohexane-1,2,4-triol tris(ammonium hydrogen phosphate), and two with the cis-1,2-phosphate moiety, (±)-(1R,2S,4R)- and (±)-(1R,2S, 4S)-cyclohexane-1,2,4-triol tris(ammonium hydrogen phosphate). Molecular mechanics calculations for each trisphosphate and the Ca(II) and Mg(II) complex were performed using MacroModel. Results from the molecular modeling studies indicate that two of the criteria for the suitability of the trisphosphates as analogs of phospholipid-metal ion binding sites are satisfied: (1) anionic groups which can interactively bind a metal ion and (2) interphosphate distances comparable to the phosphate-phosphate distances of a computational phospholipid surface.