Abstract
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 18F-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.
Acknowledgements
Sandra Schröer’s assistance in in vitro enzyme inhibition assays is gratefully acknowledged.
Financial & competing interests disclosure
This study was supported by grants from the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 656 (Projects A3 and B1), University of Münster, Germany, and from Siemens Medical Solutions to the European Institute of Molecular Imaging at the University of Münster, Germany. Anil Kumar Podichetty is grateful to the International NRW Graduate School of Chemistry for a stipend. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.