Fluorinated isatin derivatives. Part 1: Synthesis of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins as potent caspase-3 and -7 inhibitors

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Abstract

A series of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives has been synthesized and tested as inhibitors of caspases-3 and -7, which are known to be downstream enzymes critical in the execution of apoptosis. N-Propyl- and N-butyl isatins, as well as the corresponding terminal alcohols and regioisomeric fluorobutyl derivatives were shown to be excellent inhibitors having different binding potencies for caspases-3 and -7. In contrast, the corresponding fluoroethyl and fluoropropyl compounds were about 100–1000 times less active. Fluorinated N-benzyl isatins as well as trifluoroalkyl and difluoroalkyl derivatives were moderate inhibitors. However, isatins bearing different alkylether groups at N-1 are very weak or not active as inhibitors of caspases-3 and -7.

Graphical abstract

A series of new (S)-5-[1-(2-methoxymethylpyrrolinyl)sulfonyl]isatins bearing fluorinated and non-fluorinated N-alkyl- and N-benzyl substituents has been synthesized and their inhibition potencies were assayed for recombinant human caspases-3 and -7. Among the most active inhibitors in this series are the n-propyl- and n-butyl derivatives as well as the corresponding terminal alcohols and fluorides.

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Introduction

Programmed cell death, called apoptosis, is induced by either receptor-mediated mechanisms, where a specific protein binds to a receptor on the cell surface and triggers the cell death signal (death receptor pathway), or direct damage of DNA by for example, toxic substances or radiation, followed by mitochondrial induction of the cell death program (mitochondrial pathway).1 Both mechanisms trigger a complex cell death program—apoptosis—resulting in a complete removal of the concerned cell without inflammatory response. Downstream of the initial cellular process a class of intracellular ‘death enzymes’, caspases (cysteinyl aspartate-specific proteases) is activated.1, 2, 3 Apoptosis is known to be present in many human diseases such as neurodegenerative diseases, cardiovascular diseases and others. Thus, apoptosis is an important target for novel drugs.2, 4 Therapeutic inhibition of caspase-3 and -7 has been indeed shown to prevent cells from apoptosis.5

Since caspases have been identified as suitable biological targets for anti-apoptotic strategies, it is reasonable to synthesize compounds, which specifically bind to the active site of these enzymes with high potency. Besides peptidic inhibitors,6, 7, 8 the low molecular weight pyrrolidinylsulfonyl isatins are known to possess caspase inhibitory activity.9, 10 Recently, the therapeutic action of isatins as caspase inhibitors has been demonstrated.11 It has been shown that the lead structure (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (1) perfectly fits into the active site of caspase-3.5 Recently, we and others have also succeeded in the development of new radiotracers (compounds suitable for application in Positron Emission Tomography, PET) based on the isatin lead structure.12, 13, 14, 15

Here, we report our recent results on the synthesis of a group of new fluorinated and non-fluorinated 5-pyrrolidinylsulfonyl isatins as caspase inhibitors. Some of them have been proven to exhibit excellent inhibitory activity for caspases-3 and -7.

Section snippets

Chemistry

Based on the results of earlier work,5, 12 we initially prepared some basic non-fluorinated N-alkyl isatins 2b2d, some polar variants 2f, 2h and 2i and several potential precursors 2e, 2g and 2j for the preparation of fluorinated analogs 2k2m in order to determine their inhibition activity towards caspases-3 and -7 (Scheme 1, Table 1).

Compounds 1 and 2a have been prepared in previous work.5, 12 Compounds 2b2f and 2i were synthesized by treatment in dry DMF of isatin 1 with the corresponding

Conclusion

A series of fluorinated and non-fluorinated (S)-5-[1-(2-methoxymethylpyrrolidinyl) sulfonyl]isatins has been prepared as potential effector caspase inhibitors. A broad variety of N-substituents are tolerated without loss of caspase-3 and -7 inhibition potency. Among the substituted and unsubstituted alkyl chains, the butyl compounds were shown to be the most active caspase-3 and caspase-7 inhibitors. The 3-fluorobut-1-yl derivative 2n was one of the most active caspase inhibitors and even more

General methods

All the chemicals, reagents and solvents for the synthesis of compounds were analytical grade and used without further purification, unless otherwise specified. 1H NMR (300.13 MHz and 400.13 MHz), 13C NMR (75.5 MHz and 100.63 MHz) and 19F NMR (282.4 MHz) spectra were recorded in CDCl3 with TMS for 1H NMR, CDCl3 for 13C NMR and CFCl3 for 19F NMR as the internal standards. All chemical shift values were recorded in ppm (δ). Exact mass analyses were conducted on a Waters Quattro LC and a Bruker

Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich 656 (projects A3 and B1), University of Münster, Germany and from Siemens Medical Solutions to the European Institute of Molecular Imaging (EIMI). A.K.P. is grateful to the International NRW Graduate School of Chemistry for a stipend. Sandra Schröer’s assistance in in vitro enzyme inhibition assays is gratefully acknowledged.

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