Fluorinated isatin derivatives. Part 3. New side-chain fluoro-functionalized pyrrolidinyl sulfonyl isatins as potent caspase-3 and-7 inhibitors
Fluorinated isatin derivatives. Part 3. New side-chain fluoro-functionalized pyrrolidinyl sulfonyl isatins as potent caspase-3 and-7 inhibitors
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DOI：
10.4155/fmc.09.66
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发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
Haufe, Guenter
中科院分区：
文献类型：
--
作者：
Podichetty, Anil Kumar;Wagner, Stefan;Haufe, Guenter
背景资料：I型程序性细胞死亡（细胞凋亡）的失调导致多种疾病，其中癌症、心血管和神经退行性疾病是最突出和最普遍的。效应物半胱天冬酶如半胱天冬酶-3和半胱天冬酶-7在凋亡信号级联过程中被激活，因此代表了用于诊断和治疗凋亡相关疾病的生物靶标。研究方法：先导化合物（S）-（+）-5-[1-（2-甲氧基甲基吡咯烷基）磺酰基]靛红的有效氟化类似物的合成有助于对F-18-放射性标记的前体候选物进行定向鉴定，从而产生放射性标记的化合物，其可用作示踪剂，用于使用正电子发射断层扫描进行体内细胞凋亡的特异性成像。结论：在一系列新的单，二和三氟甲基化的吡咯烷环类似物的先导化合物，高抑制效力的半胱天冬酶-3和-7的IC 50值分别高达30和37 nM。一种新的氧化脱硫脱硝方案被证明是一种通用的氟掺入技术。
Background: Dysregulation of type I programmed cell death (apoptosis) leads to a variety of diseases, among which cancer, cardiovascular and neurodegenerative disorders are the most prominent and widespread. Effector caspases such as caspases-3 and -7 get activated during the apoptotic signaling cascade and hence represent a biological target for the diagnosis and therapy of apoptosis-associated diseases. Methods: Synthesis of potent fluorinated analogs of the lead compound (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin facilitates the aim-oriented identification of precursor candidates for F-18-radiofluorination resulting in radiolabeled compounds that could be employed as tracers for the specific imaging of apoptosis in vivo, using positron-emission tomography. Conclusion: Within a series of new mono-, di- and trifluoromethylated pyrrolidine ring analogs of the lead compound, high inhibition potencies were found for caspases-3 and -7 with IC50 values up to 30 and 37 nM, respectively. A new oxidative desulfurization fluorination protocol was shown to be a versatile technique for fluorine incorporation.