Synthesis and application of novel enone-type prostaglandin probes

前列腺素(PG)类似物，具有交叉共轭的二烯酮结构，可抑制氧化应激诱导的神经细胞死亡。我们用不同的衍生物对这种活性进行了构效关系研究，并设计了一种有效的类似物，NEPP11，它显示了增强的活性和较低的毒性。NEPP11对小鼠脑神经细胞的保护作用呈剂量依赖关系，细胞内蛋白和信使RNA的表达水平分析表明，NEPP诱导应激诱导蛋白HO-1的表达是其神经保护作用的重要机制。为了确定与HO-1诱导相关的NEPP的胞内靶分子(受体)，设计并合成了一种连接生物素部分的分子探针。将该探针应用于亲和标记实验，可检测到一些结合蛋白。此外，Seve…合成了更多的新型J-型PG类似物，并对其生物活性进行了测定。PGs对神经细胞死亡的抑制作用类似于NNP，但略弱于NNP。我们还试图开发一种PET示踪剂，用正电子发射断层扫描(PET)分析NEPP在脑中的定位和动态变化，用于活体脑研究。设计了一些含有较长半衰期正电子发射核76Br的候选化合物，并制备了相应的非放射性标记的衍生物。冷化合物在保护神经细胞免受氧化应激方面表现出与NAPP相似的效果。此外，成功地合成了候选PET示踪剂的锡化前驱体，并建立了在低温条件下将溴诱导到该前驱体中的方法学。此外，对IKKβ(一种调节转录因子NF-κB活性的激酶)抑制作用的结构-活性研究，导致了一种有希望的具有更高抑制活性的NEPP类似物的精制。较少

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