Inositol Phosphates and Derivatives

3 Inositol Phosphates and Derivatives. - A review on the recent developments in the synthesis and application of phosphatidylinositols, and one on the biochemistry and chemical synthesis of myo-inositol 1,4,5-trisphosphate have appeared. 

The oxazoline method and two modifications of the H-phosphonate method have been used to obtain glycosyl phosphatidylinositol derivatives.  

The tritiated inositol derivatives 92 have been prepared as substrates for T. brucei a-o-GLCpNAc-PI de-A -acetylase, and derivatives 93 as inhibitors of the enzyme.  

The synthesis and biology of l-D-3-deoxyphosphatidylinositol 94, a putative antimetabolite of phosphatidyl-3-phosphate and an inhibitor of cancer cell colony formation has been achieved from a l-D-3-deoxyinositol reported in Vol. 27, p. 222, ref. 143.  

A synthesis, in natural chiral form, of 1-D-distearoylphosphatidyl-myo-inositol 3,4,5-tris(dihydrogenphosphate), in which the key step involves a regioselective 1- 

3 Inositol Phophates and Derivatives - Reviews on the preparation and separation of inositol phosphates and on the preparation of inositol polyphosphates from glucose have appeared. 

Both enantiomers of l,2 5,6-di-0-cyclohexylidene-m u-inositol have been prepared by standard kinetic resolution involving a lipase and each converted into 3- 

Twenty inositol phosphodiester derivatives 104 have been prepared by reaction of inositol 1,2-cyclic phosphates with the corresponding alcohol catalysed by phosphatidylinositol-specific phospholipase The heterocycle, quercetin, has been rendered more water soluble by conjugation through a 1-O-succinyl-myo-inositol-L-phosphate linkage.  

A full paper has appeared on the tin-mediated allylation and benzylation of 1,2-0-isopropylidene-myo-inositol (see Vol. 27, p. 219, ref. 126 and Vol. 25, p. 215, ref. 108 for preliminary report) which resulted in the preparation of various protected myo-inositol 1,6-bis-and 1,5,6-tris-phosphates.  

A wide range of myo- (both chiral and ( )) and Jcy//o-tetrakisphosphate derivatives have been prepared by standard means and the importance of their H-bonding with their target proteins probed. Several of the compounds were converted into acetoxymethyl esters in order to increase membrane permeability.  

Lengthy ( 20 step) syntheses of l-0-(l,2-di-0-pentadecanoylphosphatidyl)-D-myo-inositol 3,4- and 4,5-bisphosphates and 3,4,5-trisphosphate starting from L-(—)-quebrachitol have also been reported.  

The myo-inositol acceptor l-0-allyl-2,3,4,5-tetra-0-benzyl-D-myo-inositol was synthesized from meso-2,5-di-0-benzoyl-myo-inositol for use in the total synthesis of a heptaose mimetic, a GPI anchor compound of T. brucei (see Vol. 32, p.71. ref. 156). The inositol was desymmetrized using the bis(spiroketal) protected intermediate 175 to enable the stepwise glycosylation at 0-6 and attachment of a phosphoglyceride moiety at 0-1. Cleavage of the dispoke was effected by oxidizing the thiophenyl substituents with mCPBA and then treating the product disulfone with lithium hexamethyldisilazide in THF. In a similar synthesis 

Reagents i, Et3B-BuC02BEt2, hexane ii, Bu2Sn(acac)2, toluene iii, MntCOCI. NMI 

177 found in Leishmania parasites have been synthesized by coupling an inositol-containing disaccharide with a maimobiosyl donor.  

The antigenic core of the glycoconjugate lipoarabinomannan (LAM) from Mycobacterium tuberculosis, 2,6-dimannosyl-m3 o-inositol 1-phosphate, was synthesized by stepwise regioselective mannosylation at the free C-2- and then at the C-6-hydroxyl in 178. Removal of the 1-acetate provided for phosphorylation at the correct site.  

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Reitz, A. B. (1991) Inositol Phosphates and Derivatives, Synthesis, Biochemistry and Therapeutic Potential, ACS Symposia Series, Washington, D.C. 

Parthasarathy, R., and Eisenberg, F., Jr., 1990, Biochemistry, stereochemistry, and nomenclature of the inositol phosphates, In Reitz, A.B. (ed.), Inositol Phosphates and Derivatives Synthesis, Biochemistry, and Therapeutic Potential. ACS Symposium Series 463. American Chemical Society, Washington, DC, pp. 1-19. 

Buscher, B.A.P., van der Hoeven, R.A.M., Tjaden, U.R., Andersson, E. and van der Greef, J. (1995) Analysis of inositol phosphates and derivatives using capillary zone electrophoresis-mass spectrometry. Journal of Chromatography A 712, 235-243. 

Reitz AB (1990) Inositol Phosphates and Derivatives. American Chemical Society, Washington DC... 

Agranoff BW, Fisher SK (1991) Inositol phosphates and derivatives synthesis, biochemistry, and therapeutic potential. In Reitz AB (ed) ACS Symposium series 463, American Chemical Society, Washington, p 20... 

Inositol Phosphates and Derivatives.-The synthesis of Dwi v-inoatol 3,4,S,6-tetrakisphosphate as previously reported (Vol. 26, p. 206, ref. 154) was in fact of the enantiomer. A novel inositol phosphate, L,L-di-myo-inositoI-l,r-phosphate has been isolated from Pyrococcus woesei and its structure confirmed by synthesis. ... 

Inositol Phosphates and Derivatives.-A monograph on the chemical nthesis and biological significance of inositol phosphates has appeared. ... 

Inositol is an essential molecule found ubiquitously in biological systems. Phosphorylation of the cyclic inositol ring produces two related families of molecules, inositol phosphates and phosphinositides. Research into the roles of inositol and its derivatives has been hampered by the complex and multitudinous interactions of these molecules in multiple cellular pathways. However, the potential rewards of such studies are immense, as inositol phosphates and phosphoinositides (Pis) play a role in numerous human diseases. This review addresses current knowledge of the role of inositol phosphates and Pis in human health and disease. 

In tervalent phosphorus acid chemistry the main area of activity has again been the use of tervalent phosphorus acid derivatives for the preparation of phosphates or modified phosphates of biochemical interest. Apart from the nucleotide field, vide infra), pentavalent phosphorus acid chemistry seems to be mainly in the doldrums exceptions to this are the areas of myo-inositol phosphate and aminoalkylphosphonate chemistry where activity remains high. 

Misek, D.E. and Saltiel, A.R. An inositol phosphate glycan derived from a Trypanosoma brucei glycosyl-phosphatidylinositol mimics some of the metabolic actions of insulin. J. Biol. Chem., 1992, 267, 16266-16273. 

Several review articles and books concerning the synthesis of inositol phosphates and phospholipids are available.14 This text does not cover all reports on the synthesis of inositols but principally deals with synthetic strategies and total synthesis of inositol derivatives which involve selective reactions such as stereoselective and regioselective ones. 

To achieve total synthesis of inositol phosphates and related derivatives, multiple phosphorylation of polyol derivatives is the most crucial step. Use of dianilinophosphoric chloride 8 was the only method of choice for this purpose. However, its reactivity is not satisfactory for perphosphorylation of inositols and furthermore spontaneous deprotection of several dianilinophosphoric esters in the same molecules is quite difficult, while phosphorylation of D-2,3,6-tribenzyl-myo-inositol 9 with the chloride 8 giving 11 in 60% yield was accomplished after exploring proper reaction conditions in the first total synthesis of Ins(l,4,5)P3 (Scheme 2-1).However, the phosphorylation product 12 was not formed at all from 10, a positional isomer of 9 under similar conditions. In 1987, it was reported that the reaction of tetrabenzyl pyrophosphate (TBPP, 13) with alkoxides generated in situ by the action of a strong base such as NaH.l c KH, - or butyllithium b on inositols smoothly gave the desired polyphosphorylated products in good yields. Examples are shown in Scheme 2-1. 

The reaction of 1,2-cyclohexylidene-myo-inositol 47a with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPS-CI2) takes place in a completely regioselective manner to afford the 3,4-disiloxane derivative 76 in quantitative yield. 5- - Compound 76 has been shown to be a very useful synthetic intermediate by the synthesis of various inositol phosphates and phospholipids (Scheme 3-9). The usefulness... 

A review on the preparation and separation of inositol tetrakisphosphates and the establishment of enantiomeric configuration by use of L-iditol dehydrogenase has appeared. The synthesis and biological evaluation of inositol derivatives as inhibitors of phospholipase C (PLC) has been reviewed. A review on the chemistry, preparation and enzymatic reactions of inositol phosphates and a review on the biochemistry, stereochemistry and nomenclature of inositol phosphates has also been reported. A part review on phosphonate analogues of myo-inositol triphosphate has appeared. ... 

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