The design, development and synthesis of secondary binding elements for the construction of polyazamacrocyclic inositol phosphate receptors for use as biological probes of phosphatidylinositol metabolism and therapeutic agents for the treatment of bipolar
Warren, Anthony Wayne
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Significant progress has been made in the design, development and synthesis of compounds able to provide secondary binding elements in the construction of a new class of polyazamacrocyclic inositol phosphate receptors. The secondary binding elements explored were based on a myo-inositol core structure, and were functionalized at the C1 and C4 positions with ether linked extended masked aldehyde groups as cyclization handles. Installation of the extended aldehyde on the inositol ring system was accomp-lished using the Williamson method for ether synthesis and provided consistent yields of about 80% across the gamut of latent aldehydes tested. Several molecules bearing differ-entially protected aldehyde moieties, for the purpose of regioselective macrocyclization into a compound designed to host Ins(1,4)P2 molecules, were synthesized. The three specific molecules holding the most promise for future efforts in this area were (±)1,4-O- Bis(2-[1,3]Dioxanylethoxy)-2,3:5,6-Di-O-cyclohexylidene-myo-inositol, (±)1,4-Di-O-allyl- 2,3:5,6-Di-O-cyclohexylidene-myo-inositol and (±)1,4-Di-O-propargyl-2,3:5,6-Di-O- cyclohexylidene-myo-inositol. The latent aldehyde alkynyl function present in the last compound was successfully unmasked via hydroboration-oxidation chemistry and was readily isolated as a near crystalline compound, following size exclusion chromatography using SX-8 mesh BioBeads.