Synthesis of potent Ins(1,4,5)P3 5-phosphatase inhibitors by modification of myo-inositol 1,3,4,6-tetrakisphosphate.
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)P(3) 5-phosphatase, 3-kinase and for Ca(2+) release at the Ins(1,4,5)P(3) receptor, only weak activity was observed for Ca(2+) 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 Ca(2+) and devised conditions for quick, clean and inexpensive sulfoxidation of inositol polyphosphite intermediates.
Mills
Stephen J
SJ
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, BA2 7AY, Bath, UK.
Potter
Barry V L
BV
D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007295:Inositol Phosphates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000072181:Inositol Polyphosphate 5-Phosphatases; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; C081653:inositol-1,3,4,6-tetrakisphosphate; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D002118:Calcium