A Systematic Study of C-Glucoside Trisphosphates as myo-Inositol Trisphosphate Receptor Ligands. Synthesis of β-C-Glucoside Trisphosphates Based on the Conformational Restriction Strategy

β-C-Glucoside trisphosphates having a C2 side chain (3,7-anhydro-2-deoxy-d-glycero-d-gulo-octitol 1,5,6-trisphosphate, 11) and a C3 side chain (4,8-anhydro-2,3-dideoxy-d-glycero-d-gulo-nonanitol 1,6,7-trisphosphate, 12) were designed as structurally simplified analogues of a potent d-myo-inositol 1,4,5-trisphosphate (IP3) receptor ligand, adenophostin A. Construction of the β-C-glucosidic structure, which was the key to their synthesis, was achieved by two different methods based on the conformational restriction strategy: (1) radical cyclization with a temporary connecting silicon tether and (2) silane reduction of glyconolactols having an anomeric allyl substituent. Using these methods, the target β-C-glycoside trisphosphates 11 and 12 were successfully synthesized. A structure−activity relationship was established on a series of C-glucoside trisphosphates, including the previously synthesized related compounds, which were a C-glycosidic analogue 3 of adenophostin A, its uracil congener 5, α-C-glucoside trisphosphates 7−9 having a C1, C2, or C3 side chain, and the β-C-glucoside trisphosphates 10−12 having a C1, C2, or C3 side chain. The O-glycosidic linkage of adenophostin A and its analogues proved to be replaced by the chemically and biologically more stable C-glycosidic linkage. The α-C2-glucoside trisphosphate 8 stimulates Ca2+ release with a potency similar to that of IP3 in spite of its simplified structure, indicating a better fit to the receptor than the β-C-glucoside trisphosphates and also the α-congeners having a shorter or longer C1 side chain, which was supported by molecular modeling using the ligand binding domain of the IP3 receptor.