Inositol phosphates, such as 1D-myo-Inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)], are cellular second messengers with potential roles in
cancer prevention and
therapy. It typically is difficult to attribute specific pharmacological activity to a single
inositol phosphate because they are rapidly metabolized by
phosphatases and
kinases. In this study, we have designed stable analogs of myo-
inositol 4,5-bisphosphate [Ins(4,5)
P(2)] and Ins(1,4,5)P(3) that retain the
cyclohexane scaffold, but lack
hydroxyl groups that might be phosphorylated and have
phosphate groups replaced with
phosphatase-resistant phosphorothioates. An Ins(1,4,5)P(3) analog, 1D-2,3-dideoxy-myo-inositol 1,4,5-trisphosphorothioate, was synthesized from (-)-
quebrachitol, and an Ins(4,5)
P(2) analog, 1D-1,2,3-trideoxy-myo-inositol 4,5-bisphosphorothioate, was prepared from cyclohexenol. The Ins(1,4,5)P(3) analog was recognized by Ins(1,4,5)P(3) receptor with a binding constant (K(d)) of 810 nM, compared with 54 nM for the native
ligand Ins(1,4,5)P(3), and was resistant to dephosphorylation by
alkaline phosphatase under conditions in which Ins(1,4,5)P(3) is extensively hydrolyzed. Analogs developed in this study are potential chemical probes for understanding mechanisms of
inositol phosphate actions that may be elucidated by eliciting specific and prolonged activation of the Ins(1,4,5)P(3) receptor.