Synthesis of potent Ins(1,4,5)P3 5-phosphatase inhibitors by modification of myo-inositol 1,3,4,6-tetrakisphosphate

Add time:08/26/2019    Source:sciencedirect.com

Three myo-inositol tetrakisphosphate analogues were synthesised based upon myo-inositol 1,3,4,6-tetrakisphosphate: 2,5-di-O-methyl myo-inositol-1,3,4,6-tetrakisphosphate 19 and its phosphorothioate derivative 22, together with myo-inositol 1,3,4,6 tetrakisphosphorothioate 25. These compounds were prepared by phosphitylating 2,5-di-O-methyl-myo-inositol and 2,5-di-O-benzyl-myo-inositol followed by oxidation with t-butylhydroperoxide or sulfoxidation at room temperature using sulfur in a mixed solvent of DMF and pyridine. Sulfoxidation was complete within 15 min; however, without DMF, the reaction was much slower, and required overnight. When evaluated against Ins(1,4,5)P3 5-phosphatase, 3-kinase and for Ca2+ release at the Ins(1,4,5)P3 receptor, only weak activity was observed for Ca2+ release. 22 and 25 are potent 5-phosphatase inhibitors and 25 is a moderate inhibitor of 3-kinase. Thus, we have synthesised potent enzyme inhibitors, which do not mobilise Ca2+ and devised conditions for quick, clean and inexpensive sulfoxidation of inositol polyphosphite intermediates.

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