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 (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. 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 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.
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 (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. 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 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.