Tetrakisphosphates and bispyrophosphates of myo-inositol derivatives as allosteric effectors of human hemoglobin: Synthesis, molecular recognition, and oxygen release.

Various 2,5- and 1,4-substituted and unsubstituted myo-inositol tetrakisphosphates and bispyrophosphates were prepared following a general synthetic pathway. All final compounds were tested for their capability to induce oxygen release from human hemoglobin. Most of these proved to be efficient allosteric effectors, with similar affinities for hemoglobin to that of myo-inositol hexakisphosphate, which is one of the best known allosteric effectors of hemoglobin. The efficacy was found to be higher for free phosphates than pyrophosphates. As allosteric Hb effectors, these compounds enable enhanced oxygen release. These effects increase with the strength of Hb binding and correspond primarily to electrostatic interactions. Stereochemical and steric factors also play a significant but secondary role in molecular recognition. In view of the central role played by hypoxia in numerous types of diseases, the exploration of myo-inositol phosphate derivatives represents an important avenue in the search for substances which act on the oxygenation status of tissues and may have significant potential in the discovery and development of novel drug candidates.