First derivatives of myo-inositol 1,4,6-trisphosphate modified at positions 2 and 3: structural analogues of D-myo-inositol 1,4,5-trisphosphate.
Novel, structurally modified potential mimics of the second messenger D-myo-inositol 1,4,5-trisphosphate, based on the biologically active regioisomer D-myo-inositol 1,4,6-trisphosphate, were synthesised. DL-5-O-Benzyl-1,4,6-tri-O-p-methoxybenzyl-myo-inositol was the key intermediate for the preparation of the following compounds: DL-3-deoxy-, DL-3-deoxy-2-O-methyl-, DL-3-O-(2-hydroxyethyl)-, DL-3-O-(3-hydroxypropyl)- and DL-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate. DL-1,4,6-Tri-O -allyl-5-O-benzyl-myo-inositol was used to prepare DL-2-O-methyl-myo-inositol 1,4,6-trisphosphate. Deoxy-compounds were prepared by reduction of the corresponding tosylated intermediate using Super Hydride. The hydroxyalkyl groups were introduced at the C-3 of myo-inositol using the corresponding benzyl protected hydroxy alkyl bromide via the cis-2,3-O-dibutylstannylene acetal. Methylation and benzylation at C-2 was accomplished using methyl iodide and benzyl bromide, respectively, in the presence of sodium hydride. Deblocking of p-methoxybenzyl groups was accomplished with TFA in dichloromethane and the allyl groups were removed by isomerisation to the cis-prop-1-enyl derivative, which was hydrolysed under acidic conditions to give the corresponding 1,4,6-triol. The 1,4,6-triols were phosphitylated with the P(III) reagent bis(benzyloxy)(diisopropylamino)phosphine in the presence of 1H-tetrazole then oxidised with 3-chloroperoxybenzoic acid followed by deblocking by hydrogenolysis to give DL-2-O-methyl-, DL-3-O-deoxy-, DL-3-O-deoxy-2-O-methyl-, DL-3-O-(2-hydroxyethyl)-, DL-3-O-(3-hydroxypropyl)- and DL-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate, respectively.
Horne
Graeme
G
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Mills
Stephen J
SJ
Potter
Barry V L
BV
D001593:Benzyl Compounds / Q000737:chemistry; D006847:Hydrocarbons, Iodinated / Q000737:chemistry; D006865:Hydrogenation; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008745:Methylation; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D014269:Trifluoroacetic Acid / Q000737:chemistry
D001593:Benzyl Compounds; D006847:Hydrocarbons, Iodinated; C086878:inositol 1,4,6-trisphosphate; D015544:Inositol 1,4,5-Trisphosphate; C014055:methyl iodide; D014269:Trifluoroacetic Acid; C038682:benzyl bromide