5-pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis.
Caspases are the unique enzymes responsible for the execution of the cell death program and may represent an exclusive target for the specific molecular imaging of apoptosis in vivo. 5-Pyrrolidinylsulfonyl isatins represent potent nonpeptidyl caspase inhibitors that may be suitable for the development of caspase binding radioligands (CBRs). (S)-5-[1-(2-Methoxymethylpyrrolidinyl)sulfonyl]isatin (7) served as a lead compound for modification of its N-1-position. Corresponding pairs of N-1-substituted 2-methoxymethyl- and 2-phenoxymethylpyrrolidinyl derivatives were examined in vitro by biochemical caspase inhibition assays. All target compounds possess high in vitro caspase inhibition potencies in the nanomolar to subnanomolar range for caspase-3 (Ki=0.2-56.1 nM). As shown for compound (S)-1-(4-(2-fluoroethoxy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (35), the class of N-1-substituted 5-pyrrolidinylsulfonyl isatins competitively inhibits caspase-3. All caspase inhibitors show selectivity for the effector caspases-3 and -7 in vitro. The 2-methoxymethylpyrrolidinyl versions of the isatins appear to possess superior caspase inhibition potencies in cellular apoptosis inhibition assays compared with the 2-phenoxymethylpyrrolidinyl inhibitors.
Kopka
Klaus
K
Department of Nuclear Medicine, University Hospital of the Westfälische Wilhelms-Universität, Münster, Germany. kopka@uni-muenster.de
Faust
Andreas
A
Keul
Petra
P
Wagner
Stefan
S
Breyholz
Hans-Jörg
HJ
Höltke
Carsten
C
Schober
Otmar
O
Schäfers
Michael
M
Levkau
Bodo
B
D017209:Apoptosis; D053148:Caspase 3 / Q000737:chemistry; D053179:Caspase 7 / Q000737:chemistry; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D002478:Cells, Cultured; D006801:Humans; D007457:Iodine Radioisotopes; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007553:Isotope Labeling; D007700:Kinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
C516218:1-(4-(2-fluoroethoxy)benzyl)-5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin; D061945:Caspase Inhibitors; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases