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Terauchi, M. et al.

A systematic study of C-glucoside trisphosphates as myo-inositol trisphosphate receptor ligands. Synthesis of beta-C-glucoside trisphosphates based on the conformational restriction strategy.

Beta-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 beta-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 beta-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, alpha-C-glucoside trisphosphates 7-9 having a C1, C2, or C3 side chain, and the beta-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 alpha-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 beta-C-glucoside trisphosphates and also the alpha-congeners having a shorter or longer C1 side chain, which was supported by molecular modeling using the ligand binding domain of the IP3 receptor.[1]

References

A systematic study of C-glucoside trisphosphates as myo-inositol trisphosphate receptor ligands. Synthesis of beta-C-glucoside trisphosphates based on the conformational restriction strategy. Terauchi, M., Abe, H., Tovey, S.C., Dedos, S.G., Taylor, C.W., Paul, M., Trusselle, M., Potter, B.V., Matsuda, A., Shuto, S. J. Med. Chem. (2006) [Pubmed]

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