Synthesis and Biological Activity of Metabolically Stabilized Cyclopentyl Trisphosphate Analogues of D-myo-Ins(1,4,5)P3

We describe the synthesis of four novel metabolically stabilized analogues of Ins(1,4,5)P3 based on the known cyclopentane pentaol tris(phosphate) 2: tris(phosphorothioate) 3, tris(methylenephosphate) 4, tris(sulfonamide) 5, and tris(sulfate) 6. Of these analogues, only the tris(phosphorothioate) 3 and parent tris(phosphate) 2 bound to the type I InsP3R construct. In addition, both the tris(phosphorothioate) 3 and parent tris(phosphate) 2 elicited calcium release in MDA MB‐435 breast cancer cells. The Ins(1,4,5)P3 agonist activities of these two compounds can be rationalized on the basis of computational docking of the ligands to the binding domain of the type I InsP3R. Ins(1,4,5)P3 analogues: Four phosphatase‐resistant analogues of Ins(1,4,5)P3 were synthesized and evaluated. Tris(phosphorothioate) 3 and the parent tris(phosphate) bound to an InsP3R construct in vitro and elicited calcium release in breast cancer cells. The agonist activity was rationalized by computational docking of the ligands to the binding domain of the InsP3R.