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

Abstract

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.

Inositol Trisphosphate Receptor Ca2+Release Channels

“…AdA, a fungal glyconucleotide metabolite (448), and its many analogs (1,23,51,102,290,388,397,398,420,444,465) were discovered as agonists of the InsP 3 R. Although their molecular structures are significantly different from those of InsP 3 and its analogs (198), they activate the channel by interacting with the InsP 3 binding site (157). AdA binds InsP 3 R with substantially higher affinity and is significantly more potent in stimulating InsP 3 Rmediated Ca 2ϩ release than its natural agonist InsP 3 .…”

A Concise and Efficient Synthesis of Dapagliflozin

“…The next step, entailing the reduction of ethyl C -aryl glycoside 9 , was also optimized. In general, the reduction of tetra-O-protected methyl C -aryl glycosides to the corresponding β- C -aryl glycosides with a Lewis acid and silane proceeds with high diastereoselectivity. − Wang et al found that tetra-O-unprotected methyl C -aryl glycosides could be successfully reduced using AlCl 3 or BF 3 ·Et 2 O and Et 3 SiH with very high diastereoselectivity (β:α > 99:1) . Therefore, the direct reduction of tetra-O-unprotected ethyl C -aryl glycoside 9 was investigated.…”

Inositol polyphosphates, diphosphoinositol polyphosphates and phosphatidylinositol polyphosphate lipids: Structure, synthesis, and development of probes for studying biological activity

“…191 Recently, numerous analogs, including C-glycosides (such as 55) and compounds modified at the nucleotide backbone (such as 56), have been designed, synthesized and evaluated by Potter and co-workers to enhance InsP 3 R binding and elucidate the details of the interaction. [192][193][194][195][196][197] Since the InsP 3 receptors contain multiple binding domains (see Fig. 3), another strategy for enhancing binding has involved the development of tethered dimeric InsP 3 derivatives.…”