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 synthe sized to serve as small molecule analogs of putative phospholipid-meta l ion binding sites. The parent cyclehexane-1,2,4-triols were prepared and phosphorylated. Deprotection of the tris(diphenylphosphates) prov ided four regiochemical isomers: two with the trans-1,2-phosphate moie ty, (+/-)-(1R,2R,4S)- and (+/-)-(1R,2R,4R)-cyclohexane-1,2,4-triol tri s(ammonium hydrogen phosphate), and two with the cis-1,2-phosphate moi ety, (+/-)-(1R,2S,4R)- and (+/-)-(1R,2S, 4S)-cyclohexane-1,2,4-triol t ris(ammonium hydrogen phosphate). Molecular mechanics calculations for each trisphosphate and the Ca(II) and Mg(II) complex were performed u sing 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) ani onic groups which can interactively bind a metal ion and (2) interphos phate distances comparable to the phosphate-phosphate distances of a c omputational phospholipid surface. (C) 1994 Academic Press, Inc.