Synthesis, Acid−Base Behavior, and Binding Properties of 6-Modified myo-Inositol 1,4,5-Tris(phosphate)s

Abstract

myo-Inositol 1,4,5-tris(phosphate) was modified at position 6. The analogues synthesized are reported in this publication are 6-deoxy-myo-inositol 1,4,5-tris(phosphate), 6-fluoro-6-deoxy-myo-inositol 1,4,5-tris(phosphate), epi-inositol 1, 4,5-tris(phosphate), and 6-amino-6-deoxy-myo-inositol 1,4, 5-tris(phosphate). These derivatives showed poor affinity for the Ins(1,4,5)P(3) receptors. The inframolecular acid-base behavior and the cooperative effects between the phosphate groups could help explain the loss of affinity of these 6-modified analogues.

Preparation of azide biosynthetic surrogates of myo-inositol

“…The free C 6 alcohol of epi-inositol 9 was subsequently activated as its triflate 10 using trifluoromethane sulfonic acid anhydride in pyridine. 16 In accordance with the report of Schlewer et al, 15 azide displacement of triflate 10 gave the desired myo-product 11 together with trace amounts of the enol ether side-product 12 via 1,2-anti elimination under the basic conditions. After several methods were explored, global deprotection of 11 in the presence of the azide group was eventually achieved in one step by acetolysis 17 using a mixture of sulphuric acid, acetic anhydride and acetic acid to afford the 4-deoxy-4-azido-myoinositol pentaacetate 4a 5,6 in 65% yield.…”

“…The free alcohol at the C 6 position of the myo-inositol derivative 7 was subsequently oxidised under Dess-Martin periodinane (DMP) conditions to give the desired ketone 8 in excellent yield (93%). Stereoselective reduction of 8 by sodium borohydride produced the epi-alcohol 9 15 exclusively. The free C 6 alcohol of epi-inositol 9 was subsequently activated as its triflate 10 using trifluoromethane sulfonic acid anhydride in pyridine.…”

scyllo‐Inositol Pentakisphosphate as an Analogue of myo‐Inositol 1,3,4,5,6‐Pentakisphosphate: Chemical Synthesis, Physicochemistry and Biological Applications

“…[13] Based on earlier studies of other inositol phosphates, a larger difference between the acid-base properties of Ins(1,3,4,5,6)P 5 and scyllo-InsP 5 might have been expected. For example, marked differences were previously observed between InsA C H T U N G T R E N N U N G (1,4,5)P 3 and epi-InsA C H T U N G T R E N N U N G (1,4,5)P 3 , which has an axially orientated 6-OH group, [27] or InsA C H T U N G T R E N N U N G (1,4,6)P 3 , which has its 2-OH and 3-OH groups in inverted configurations with regard to Ins-A C H T U N G T R E N N U N G (1,4,5)P 3 . [28] However, the physicochemical studies described above show that the protonation pattern of scyllo-InsP 5 parallels that of Ins(1,3,4,5,6)P 5 over the physiological pH range.…”

Regioselective protection of myo-inositol orthoesters – recent developments

“…Although, the 4,6-diether 46 is formed in larger amounts as compared to the 2,4-diether 47 (due to the stabilization of the axial alkoxide 44 due to chelation) the isolated yield of 4,6-di-O-substituted derivative 46 was about 40% or less. 14,20,26,28 We have reported 13 a method for the protection of C-4 and C-6 hydroxyl groups in 1 via the dibenzoate 33 (Scheme 9) in better yields (60-65%). Diacylation of the triols 1 or 2 to obtain the symmetrical diesters is also not a facile process, since the regiospecificity of this reaction is dependent on the nature of the acylating agent, reaction conditions, nature of the base used and the possibility of inter-or intramolecular acyl migration.…”

“…Phosphoinositols and other compounds with interesting properties that have been synthesized starting from myo-inositol orthoesters are shown in Scheme 1. (14) Ins(1,4,5)P 3 (19) Ins(4,6-cyclic-1,5)P 3 (20) Ins(1,3,5)PS 3 (21) Ins(1,3,4,5)P 4 (14,15,16,17) Ins(2,4,5,6)P 4 (18) Ins(1,2,3,5)P 4 (18) Ins(1,3,4,5,6)P 5 (23) PtdIns(3,5)P 2 (24,25) PtdIns(3)P (24,25) PtdIns(5)P (24) 1 and 2. In the present account, results of our efforts towards the synthesis of O-protected inositol derivatives starting from orthoesters of myo-inositol is presented.…”