Conformational study of the natural iron chelator myo-inositol 1,2,3-trisphosphate using restrained/flexible analogues and computational analysis

• Published in: Tetrahedron 2010-11, Vol.66 (46), p.8949-8957
• Main Authors: Mansell, David, Veiga, Nicolás, Torres, Julia, Etchells, Laura L., Bryce, Richard A., Kremer, Carlos, Freeman, Sally
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Chair conformation; Chemistry; Computational analysis; Coordination compounds; Exact sciences and technology; Inorganic chemistry and origins of life; Inositol phosphates; Iron chelation; myo-Inositol 1,2,3-trisphosphate; Organic chemistry; Preparations and properties
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2010.09.033

myo-Inositol 1,2,3-trisphosphate [Ins(1,2,3)P 3], a component in mammalian cells, possesses the correct chemical properties of an intracellular iron transit ligand. Here we have examined the conformation of the Ins(1,2,3)P 3–Fe 3+ complex. The synthesis and antioxidant properties of 4,6-carbonate- myo-inositol 1,2,3,5-tetrakisphosphate [4,6-carbonate Ins(1,2,3,5)P 4], which is locked in the unstable penta-axial chair conformation and 1,2,3-trisphosphoglycerol, a flexible acyclic analogue of Ins(1,2,3)P 3, are reported. 4,6-Carbonate Ins(1,2,3,5)P 4 caused complete inhibition of iron-catalysed hydroxyl radical (HO ) formation at 100 μM, thereby resembling Ins(1,2,3)P 3 and supporting a penta-axial chair binding conformation. In contrast, 1,2,3-trisphosphoglycerol was shown to have incomplete antioxidant properties. In support of experimental observations, we have applied high-level density functional calculations to the binding of Ins(1,2,3)P 3 to iron. This study provides evidence that Fe 3+ binds tightly to the less stable penta-axial conformation of Ins(1,2,3)P 3 using terminal and bridging phosphate oxygens, thought to also contain a tightly bound water molecule or hydroxyl ligand in the complex. [Display omitted]