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

开发在细胞内Ca^2-动员第二信使系统中具有特异性活性的配体

• 批准号: 17390027
• 负责人: SHUTO Satoshi
• 金额: $ 7.01万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390027/
• 关键词: cADPR; intracellular signal transduction; calcium; second messenger; 創薬リード

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.

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。

项目成果

Synthesis and biological activity of 4" ,6"-unsaturated cyclic ADP-carbocyclic-ribose

4",6"-不饱和环状ADP-碳环核糖的合成及生物活性

• 发表时间: 2005
• 作者: Natsum Sakaguchi;Takashi Kudoh;Takashi Murayama;Mitsuhiro Arisawa;Satoshi Shuto;工藤 高志
• 通讯作者: 工藤 高志

Synthesis and biological activity of 4", 6"-unsaturatred cyclic ADP-carbocyclic-ribose

4",6"-不饱和环状ADP-碳环核糖的合成及生物活性

• 发表时间: 2005
• 作者: Takashi Kudoh;Takashi Murayama;Akira Matsuda;Satoshi Shuto
• 通讯作者: Satoshi Shuto

Substitution at the 8-position of 3"-deoxy-cyclic ADP-carbocyclic-ribose, a highly potent Ca^<2+>-mobilizing agent, provides partial agonist.

3”-脱氧环ADP-碳环-核糖(一种高效的Ca 2- 动员剂)的8位取代提供了部分激动剂。

• 发表时间: 2007
• 期刊: Bioorg. Med. Chem. 15
• 作者: T. Kudoh.;et. al.
• 通讯作者: et. al.

Synthesis biological activity of cyclic AD.P-carbocyclic-ribose analogs : Structure-activity relationship and conformational analysis of the Nl-carbocyclic-ribose moiety.

环状AD.P-碳环核糖类似物的合成生物活性：N1-碳环核糖部分的结构-活性关系和构象分析。

• 发表时间: 2005
• 期刊: Nucleosides, Nucleotides, and Nucleic Acids 24
• 作者: T.Kudoh.;et al.
• 通讯作者: et al.

Synthesis of 5'-methylenearisteromycin and its 2-fluoro congener with potent antimalarial activity due to inhibition of the parasite S-sdenosylhomocysteine hydrolase.

合成 5-亚甲基马里斯霉素及其 2-氟同源物，由于抑制寄生虫 S-sdenosylhomocysteine 水解酶而具有有效的抗疟活性。

• 期刊: Org.Biomol.Chem. (in press)
• 作者: C.Takagi;et al.
• 通讯作者: et al.