title: Synthesis of densely phosphorylated bis-1,5-diphospho-myo-inositol tetrakisphosphate and its enantiomer by bidirectional P-anhydride formation.
abstract: The ubiquitous mammalian signaling molecule bis-diphosphoinositol tetrakisphosphate (1,5-(PP)2 -myo-InsP4 , or InsP8 ) displays the most congested three-dimensional array of phosphate groups found in nature. The high charge density, the accumulation of unstable P-anhydrides and P-esters, the lack of UV absorbance, and low levels of optical rotation constitute severe obstacles to its synthesis, characterization, and purification. Herein, we describe the first procedure for the synthesis of enantiopure 1,5-(PP)2 -myo-InsP4 and 3,5-(PP)2 -myo-InsP4 utilizing a C2 -symmetric P-amidite for desymmetrization and concomitant phosphitylation followed by a one-pot bidirectional P-anhydride-forming reaction that combines sixteen chemical transformations with high efficiency. The configuration of these materials is unambiguously shown by subsequent X-ray analyses of both enantiomers after being individually soaked into crystals of the kinase domain of human diphosphoinositol pentakisphosphate kinase 2.
authors.affiliation: Department of Chemistry, University of Zürich (UZH), Winterthurerstrasse 190, 8057 Zürich (Switzerland).
authors.forename: Samanta
authors.initials: S
authors.lastname: Capolicchio
authors.forename: Huanchen
authors.initials: H
authors.lastname: Wang
authors.forename: Divyeshsinh T
authors.initials: DT
authors.lastname: Thakor
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shears
authors.forename: Henning J
authors.initials: HJ
authors.lastname: Jessen
mesh_terms: D000812:Anhydrides; D000818:Animals; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D017905:Phosphites / Q000737:chemistry; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014961:X-Ray Diffraction
chemical_list: D000812:Anhydrides; D017905:Phosphites; C000598229:bis-1,5-diphospho-myo-inositol tetrakisphosphate; D007294:Inositol; D017856:Phosphotransferases (Phosphate Group Acceptor); C562140:PPIP5K2 protein, human
keywords: chiral auxiliaries; inositol; kinases; phosphorylation; second messengers