Synthesis and application of novel enone-type prostaglandin probes

新型烯酮型前列腺素探针的合成及应用

• 批准号: 14550824
• 负责人: FURUTA Kyoji
• 金额: $ 2.24万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14550824/
• 关键词: prostaglandin; NEPP; neuroprotection; PET; HO-1; IKKβ; エノン型プロスタグランジン; 神経保護作用; PETトレーサー; NEPP11; 陽電子放射断層画像撮影法; 動態解析

NEPPs, prostaglandin (PG) analogs with a cross-conjugated dienone structure, can suppress the death of neuronal cells induced by oxidative stress. We conducted a structure-activity relationship study on this activity with various derivatives and elaborated a potent analog, NEPP11, which revealed an enhanced activity and lower toxicity. NEPP11 was proved to be effective for the protection of brain neurons against ischemia in mice by a dose-dependent manner.,Analyses of the expression levels of intracellular proteins and messenger RNAs indicated that induction of heme oxygenase-1 (HO-1), a stress-induced protein, by NEPP was highly responsible for the neuroprotective activity. In order to identify the intracellular target molecule (receptor) of NEPP associated with the induction of HO-1, a molecular probe attaching a biotin moiety was designed and synthesized. Application of the probe to an affinity labeling experiment resulted in the detection of some binding proteins. Furthermore, seve … More ral novel J-type PG analogs were synthesized and their biological activities were assayed. The PGs exerted suppressive activities similar to but somewhat weaker than NEPPs against neuronal cell death. We also attempted to develop a PET tracer to' analyze the localization and dynamic ovement of NEPP in brain by positron emission tomography (PET) for in vivo brain researches. Some candidates incorporating 76Br, a positron emitting nucleus with relatively long half-life, were designed and the corresponding non-radio-labeled derivatives were prepared. The cold compounds exhibited similar effects to NEPPs in the protection of neuronal cells against oxidative stress. Moreover, a stannylated precursor of a PET tracer candidate was successfully synthesized and the methodology for the induction of bromine into the precursor was established under cold conditions. In addition, a structure-activity study on the inhibition of IKKβ, a kinase that regulates the activity of a transcription factor NF-κB, resulted in the elaboration of a promising NEPP analog with improved inhibitory activity. Less

NEPPs是一种具有交叉共轭二烯酮结构的前列腺素类似物，能抑制氧化应激诱导的神经细胞死亡。我们用各种衍生物对这种活性进行了构效关系研究，并阐述了一种有效的类似物NEPP 11，它显示出增强的活性和较低的毒性。NEPP 11被证明以剂量依赖的方式对小鼠脑神经元的缺血保护有效。细胞内蛋白和信使RNA表达水平的分析表明，诱导血红素加氧酶-1（HO-1），应激诱导蛋白，NEPP是高度负责的神经保护活性。为了鉴定与HO-1诱导相关的NEPP细胞内靶分子（受体），设计并合成了连接生物素部分的分子探针。将探针应用于亲和标记实验导致检测到一些结合蛋白。此外，SEVE ...更多信息 合成了新型J型PG类似物，并对其生物活性进行了测定。PGs对神经元细胞死亡的抑制活性与NEPPs相似，但稍弱于NEPPs。我们还尝试研制了一种PET示踪剂，利用正电子发射断层扫描（PET）技术分析NEPP在脑内的定位和动态变化，为在体脑研究提供新的思路。设计并合成了一系列具有较长半衰期的正电子发射核76 Br的非放射性标记衍生物。冷化合物在保护神经细胞免受氧化应激方面表现出与NEPPs相似的作用。此外，成功地合成了PET示踪剂候选物的锡烷基化前体，并在冷条件下建立了用于将溴诱导到前体中的方法。此外，对IKKβ（一种调节转录因子NF-κB活性的激酶）的抑制作用的结构-活性研究导致了具有改善的抑制活性的有希望的NEPP类似物的制备。少

项目成果

T.Satoh: "Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress."Eur.J.Neurosci.. 17. 2249-2255 (2003)

T.Satoh：“血红素加氧酶-1 蛋白在氧化应激下环戊烯酮前列腺素衍生物的神经保护作用中的作用。”Eur.J.Neurosci.. 17. 2249-2255 (2003)

T.Satoh: "Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress."Eur.J.Neurosci.. 17・11. 2249-2255 (2003)

T.Satoh：“血红素加氧酶-1 蛋白在氧化应激下环戊烯酮前列腺素衍生物的神经保护作用中的作用。”Eur.J.Neurosci.. 17・11 (2003)。

T.Satoh: "Neurite outgrowth-promoting prostaglandins that act as neuroprotective agents against brain ischemia and may enhance recovery of higher neuronal functions."Strategic Medical Science Against Brain Attack. 78-96 (2002)

T.Satoh：“促进神经突生长的前列腺素可作为针对脑缺血的神经保护剂，并可能促进高级神经元功能的恢复。”针对脑攻击的战略医学科学。

T.Satoh: "Neurite outgrowth-promoting prostaglandins that act as neuroprotective agents against brain ischemia and may enhance recovery of higher neuronal functions"Strategic Medical Science Against Brain Attack. 78-96 (2002)

T.Satoh：“促进神经突生长的前列腺素可作为针对脑缺血的神经保护剂，并可能促进高级神经元功能的恢复”《针对脑攻击的战略医学科学》。