title: Synthesis of new fluorinated, 2-substituted 5-pyrrolidinylsulfonyl isatin derivatives as caspase-3 and caspase-7 inhibitors: nonradioactive counterparts of putative PET-compatible apoptosis imaging agents.
abstract: Downstream caspases-3 and -7 are essential to execute the programmed type I cell death (apoptosis). In order to better understand their role, specific inhibitors of these enzymes are required, which after radiolabeling can be applied to non-invasively visualize and monitor apoptotic pathways in vivo using Positron Emission Tomography (PET). Therefore, 2-methoxyethyl-, 2-methoxypropyl-, 2-ethoxymethyl-, 2-(2-fluoroethoxymethyl)-, and 2-(2,2,2-trifluoroethoxymethyl)pyrrolidinyl analogues of (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (2) were prepared and their in vitro binding affinities towards caspases-1, -3, -6 and -7 were evaluated and compared to that of the lead structure 2. While the inhibition potencies against caspases-1 and -6 were in the micromolar range, all synthesized compounds exhibited excellent and selective inhibition of caspases-3 and -7 in the nanomolar range up to IC50=4.79 nM and 7.47 nM, respectively. These highly potent 2-substituted analogues of 2 might be developed as anti-apoptosis agents and some selected fluorinated inhibitors might be useful as potential PET radiotracers for apoptosis imaging after (18)F-labeling.
authors: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany.
authors: Panupun
authors: P
authors: Limpachayaporn
authors: Michael
authors: M
authors: Schäfers
authors: Otmar
authors: O
authors: Schober
authors: Klaus
authors: K
authors: Kopka
authors: Günter
authors: G
authors: Haufe
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7