Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße 40, D-48149 Münster, Germany.
Future Med Chem. 2009 Aug;1(5):969-89. doi: 10.4155/fmc.09.66.
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.
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 (18)F-radiofluorination resulting in radiolabeled compounds that could be employed as tracers for the specific imaging of apoptosis in vivo, using positron-emission tomography.
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 IC(50) values up to 30 and 37 nM, respectively. A new oxidative desulfurization-fluorination protocol was shown to be a versatile technique for fluorine incorporation.
I 型程序性细胞死亡（细胞凋亡）的失调会导致多种疾病，其中癌症、心血管疾病和神经退行性疾病最为突出和广泛。效应半胱天冬酶（如 caspase-3 和 caspase-7）在凋亡信号级联中被激活，因此成为凋亡相关疾病诊断和治疗的生物靶标。
合成先导化合物（S）-（+）-5-[1-（2-甲氧甲基吡咯烷基）磺酰基]色氨酸的强效氟化类似物，有助于有针对性地鉴定（18）F 放射性氟代前体候选物，从而得到放射性标记化合物，可用于正电子发射断层扫描术（PET）体内特异性成像凋亡。
在一系列新的单、二和三氟甲基化吡咯烷环类似物中，发现对 caspase-3 和 caspase-7 的高抑制效力，IC50 值分别高达 30 和 37 nM。显示新的氧化脱硫-氟化方案是一种多功能的氟化物掺入技术。
