A novel method for the synthesis of sulfur substituted-cyclopyrophosphate of cADPR analogs

A facile and efficient protocol for the synthesis of sulfur substituted-cyclopyrophosphate of cIDPRE(P_S~1-cIDPRE) was developed.The key step was the cyclization process which was completed by the sulfur substituted cyclization precursor 1b via the one-pot phosphoramidite strategy.     

Small Molecule CD38 Inhibitors: Synthesis of 8-Amino-N1-inosine 5′-monophosphate,Analogues and Early Structure-Activity Relationship

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the N1-ribosylated, Ca²⁺-mobilizing, second messenger cyclic adenosine 5′-diphosphoribose (cADPR). N1-Inosine 5′-monophosphate (N1-IMP) is a fragment directly related to cADPR. 8-Substituted-N1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the N1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5′-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH₂-N1-IMP is the most potent inhibitor (IC₅₀ = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach.     

环腺苷二磷酸核糖类似物的合成、表征及性质

通过次黄嘌呤N1-位取代及分子内环合等反应, 合成了由带芳基支链的含氮链替代天然北区核糖结构的环腺苷二磷酸核糖(cADPR)类似物cIDPRN. 该化合物与Jurkat T淋巴细胞在37 ℃下孵育18 h后, 经毛细管电泳分析, 结果表明该化合物具有良好的稳定性. 荧光分光光度计测定, 结果表明, 在有钙离子和无钙离子环境下, 该化合物胞外给药后均能引起浓度依赖性的钙离子释放. 由以上结果确定该化合物为具有膜透性的促细胞内钙释放激动剂.