The IPL are conjugates of an inositol moiety that is regio- and stereo-specifically linked by a phosphodiester bridge to a lipid moiety. Natural IPL generally have structures based on 1D-1-myo-inositol; however, structures based on uncommon inositol isomers, for example scyllo-inositol, are known. Two structural parents in the myo-inositol series are the glycerolipid-based PI wherein the lipid residue is a 1,2-diacylglyceryl-moiety, and, the sphingolipid-based ceramide-phosphoinositols (Cer-PI) wherein the lipid residue is an N-fattyacyl-sphingosine moiety. Cellular PI belong to the 1D-1-myo-inositol series and have the 1D-1-(1-fattyacyl1-2-fattyacyl2-sn-glycero-3-phospho)-myo-inositol absolute stereochemical structure shown. The cellular Cer-PI commonly have the 1D-1-myo-inositol stereochemical structure conjugated to ceramide moiety with a D-erythro-sphingosine stereostructure. Representative structural parent IPL are shown in FIG. 1. These absolute stereo-structures are susceptible to change during physico-chemical processing.
PI, their radyl analogues with alkylether in place of fattyacyl, Cer-PI, and, their derivatives carrying fattyacyl, glycosyl, and phosphate groups covalently linked to the inositol residue, occur as minor components of biological cells. As the name signifies, synthetic IPL, their structural and stereochemical analogues, and their respective derivatives and congeners, are prepared by synthesis.
The IPL are biological and biocompatible amphiphilic materials with diverse roles and uses. The cellular IPL have critical physicochemical, biochemical and physiological functional roles; in particular, PI and derived mono-, di-, and tris-phosphates, the so-called phosphoinositides, are transducers in vital intracellular and nuclear signaling and related processes. The natural, as well as the synthetic products are useful, broadly, as biochemical reagents in studies on the structure and function of cell membranes and mechanisms of intracellular signaling, as reference compounds for analysis of cellular IPL, as substrates in assays and diagnostics kits for enzymes involved in signaling via the IPL, as lead compounds for the design and development of novel drugs for the treatment of disorders caused by aberrant signaling including diabetes and some cancers, as nutraceuticals and drugs for central nervous system disorders and cardiac arterial diseases, for bio-delivery of specific pharmacodynamic fattyacyls covalently incorporated in the phosphoinositide structure, as the lipid component in liposomal delivery vehicles for cytotoxic drugs, bioactive peptides, proteins and polynucleotides, and in cosmetics formulations.
The embodiments of the present invention particularly provide novel IPL materials and compositions, more particularly, PI and structural and stereochemical analogues, and their respective derivatives including but not limited to phosphate derivatives. The invention embodiments additionally provide methods for isolation and purification of IPL, particularly PI, from natural lipid sources, and, further provide a novel process approach for low cost preparation and large-scale production comprising synthesis using natural IPL as starting materials. The present methods of isolation, purification and synthesis uniquely are designed and validated to ensure that the IPL products of the invention retain the core structure and absolute stereochemistry of the natural IPL, in both the myo-inositol and the lipid residues; for PI, this is the 1D-1-(1-fattyacyl1-2-fattyacyl2-sn-glycero-3-phospho)-myo-inositol absolute stereochemical structure.
USPTO Backgrounds
USPTO Backgrounds