Terauchi Masaru, Abe Hiroshi, Tovey Stephen C, Dedos Skarlatos G, Taylor Colin W, Paul Michael, Trusselle Melanie, Potter Barry V L, Matsuda Akira, Shuto Satoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
J Med Chem. 2006 Mar 23;49(6):1900-9. doi: 10.1021/jm051039n.
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.
具有C2侧链（3,7-脱水-2-脱氧-D-甘油-D-古洛-辛糖醇1,5,6-三磷酸酯，11）和C3侧链（4,8-脱水-2,3-二脱氧-D-甘油-D-古洛-壬糖醇1,6,7-三磷酸酯，12）的β-C-葡萄糖苷三磷酸酯被设计为强效D-肌醇1,4,5-三磷酸酯（IP3）受体配体腺嘌呤磷素A的结构简化类似物。β-C-葡萄糖苷结构的构建是其合成的关键，通过基于构象限制策略的两种不同方法实现：（1）用临时连接的硅链进行自由基环化，以及（2）对具有异头烯丙基取代基的糖醛酸内酯进行硅烷还原。使用这些方法，成功合成了目标β-C-糖苷三磷酸酯11和12。在一系列C-葡萄糖苷三磷酸酯上建立了构效关系，包括先前合成的相关化合物，即腺嘌呤磷素A的C-糖苷类似物3、其尿嘧啶同系物5、具有C1、C2或C3侧链的α-C-葡萄糖苷三磷酸酯7-9，以及具有C1、C2或C3侧链的β-C-葡萄糖苷三磷酸酯10-12。腺嘌呤磷素A及其类似物的O-糖苷键被证明可被化学和生物学上更稳定的C-糖苷键取代。尽管结构简化，但α-C2-葡萄糖苷三磷酸酯8刺激Ca2+释放的效力与IP3相似，这表明它比β-C-葡萄糖苷三磷酸酯以及具有较短或较长C1侧链的α-同系物与受体的契合度更好，这得到了使用IP3受体配体结合域的分子建模的支持。
