Development of ligands active specifically in intracellular Ca^<2+>-mobilizing second messenger system

CADPR类似物可用于证实cADPR介导的钙信号转导途径的机制，也有望成为药物开发的先导结构，因为cADPR已被证明发挥重要的生理作用，如从β-细胞释放胰岛素。我们以前开发了环状ADP-碳环-核糖(CADPcR)，这是一种生物和化学上稳定的cADPR的模拟物。我们计划在cADPcR结构的基础上进一步开发有效的化合物，设计了cADPR的N1-不饱和碳环类似物、4“-支链cADPcR类似物和4”-硫代-cADPR等，并合成了N1-不饱和碳环类似物，表明其在T细胞中具有显著的活性。对于4-硫代类似物的合成，关键步骤是分子内缩合形成大的18元焦磷酸环。因此，在一步脱保护合成完成后，将对其生物活性进行研究。

cADPR analogues can be used in proving the mechanism of cADPR-mediated Ca^<2+> signaling pathways and are also expected to be lead structures for the development of drugs, since cADPR has been shown to play important physiological roles, such as insulin release from β-cells. We previously developed cyclic ADP-carbocyclic-ribose (cADPcR), a biologically and chemically stable mimic of cADPR. We planned to develop further effective compounds based on the structure of cADPcR, and designed the N1-unsaturated carbocyclic analogs of cADPR, 4"-branched cADPcR analogs and 4"-thio-cADPR, etc. The synthesis of the N1-unsaturated carbocyclic analog has been achieved to show that it significantly active in T cells. For the synthesis of the 4-thio analog, the key step, that is intramolecular condensation forming the large 18-membered pyrophosphate ring, has been cleared. Thus, after completion of the synthesis by the one step deprotection, its biological activity will be investigated.