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

Podichetty, Anil Kumar; Faust, Andreas; Kopka, Klaus; Wagner, Stefan; Schober, Otmar; Schäfers, Michael; Haufe, Günter

doi:10.1016/j.bmc.2009.02.048

Cited by 49 publications

(41 citation statements)

References 17 publications

(12 reference statements)

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“…This argument is encouraged by our previous finding that the potency of N-alkyl isatins halogenated at the 7-position drops as compared to the corresponding unsubstituted compounds. 9 Thus, increased electron density in the 7-position seems to result in modified receptor-ligand interactions. The n-propyl substituent of compound 9 increases the inhibition potencies against caspases-3 and -7.…”

Section: Caspase Inhibition Potenciesmentioning

confidence: 98%

“…The two different alkyl substituents were chosen because of their favorable properties in regard to inhibition potency and cellular uptake. 7,9 As shown in Scheme 2 we were able to prepare the 5-(1-pyrrolidinylsulfonyl)-7-azaindole derivatives 6 and 7 in a modified four step sequence. In previous protocols usually P2 equiv t-BuLi are used for a complete halogen-lithium exchange reaction.…”

Section: Chemistrymentioning

confidence: 99%

“…5-(1-pyrrolidinylsulfonyl)isatin derivatives. [6][7][8][9][10][11] Mainly, side chains with different functionality were introduced either at position N1 of isatin or at position 2 of the pyrrolidine leading to highly selective inhibitors with K i (or IC 50 ) values in the low nanomolar range.…”

Section: Introductionmentioning

confidence: 99%

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Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Waldmann

Hermann

Faust

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Caspase Inhibition Potenciesmentioning

confidence: 98%

Section: Chemistrymentioning

confidence: 99%

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Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Waldmann

Hermann

Faust

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Furthermore, recent reports described the utility of [ 18 F]-radiolabeled isatins as probes for PET imaging of apoptosis (10)(11)(12)(13)(14), one of them using an experimental rat model of drug-induced liver apoptosis (15). To date, no study has however reported imaging of tumor models by this strategy.…”

mentioning

confidence: 99%

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [ ¹⁸ F]-labeled isatin sulfonamide

Nguyen

Smith

Glaser

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

152

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Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [ 18 F]ICMT-11 for further evaluation on the basis of subnanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In this present study, we have demonstrated that [ 18 F]ICMT-11 binds to a range of drug-induced apoptotic cancer cells in vitro and to 38C13 murine lymphoma xenografts in vivo by up to 2-fold at 24 h posttreatment compared to vehicle treatment. We further demonstrated that the increased signal intensity in tumors after drug treatment, detected by whole body in vivo microPET imaging, was associated with increased apoptosis. In summary, we have characterized [ 18 F]ICMT-11 as a caspase-3/7 specific PET imaging radiotracer for the assessment of tumor apoptosis that could find utility in anticancer drug development and the monitoring of early responses to therapy.cell death ͉ response to treatment ͉ small animal imaging

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“…The PET-labeled agents 18 F-ML10 (4-6), 18 F-C2A (7), 18 F-annexin-V (8-10), and 18 F-FBnTP (11,12) detect key apoptotic pathways involved in membrane imprints (13), membrane blebbing, or mitochondrial membrane potential but do not specifically target members of the caspase family. A separate class of PET imaging agents based on the small-molecule isatin scaffold has been developed including 18 F-AF-110 (14), 18 F-ICMT-11 (15,16), 11 C-WC-98, 18 F-WC-II-89, and 18 F-WC-IV-3 (14,(17)(18)(19). The utility of these 18 F-radiolabeled isatins as PET apoptosis imaging agents has been described previously (15,16,(19)(20)(21).…”

mentioning

confidence: 99%

Biodistribution and Radiation Dosimetry of ¹⁸F-CP-18, a Potential Apoptosis Imaging Agent, as Determined from PET/CT Scans in Healthy Volunteers

et al. 2013

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F18-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)- 24-isopropyl-18-methyl-17,20,23,26, 29-pentaoxo-4,7,10,13-tetraoxa-16,19,22,25,28-pentaazadotriacontane-1,32-dioicacid, is being evaluated as a tissue apoptosis marker for PET imaging. The purpose of this study was to determine the biodistribution and estimate the normal-organ radiation-absorbed doses and effective dose from 18 F-CP-18. Methods: Successive wholebody PET/CT scans were obtained at approximately 7, 45, 90, 130, and 170 min after intravenous injection of 18 F-CP-18 in 7 healthy human volunteers. Blood samples and urine were collected between the PET/CT scans, and the biostability of 18 F-CP-18 was assessed using high-performance liquid chromatography. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on the biodistribution of the tracer. Results: 18 F-CP-18 was 54% intact in human blood at 135 min after injection. The tracer cleared rapidly from the blood pool with a half-life of approximately 30 min. Relatively high 18 F-CP-18 uptake was observed in the kidneys and bladder, with diffuse uptake in the liver and heart. The mean standardized uptake values (SUVs) in the bladder, kidneys, heart, and liver at around 50 min after injection were approximately 65, 6, 1.5, and 1.5, respectively. The calculated effective dose was 38 6 4 mSv/MBq, with the urinary bladder wall having the highest absorbed dose at 536 6 61 mGy/MBq using a 4.8-h bladder-voiding interval for the male phantom. For a 1-h voiding interval, these doses were reduced to 15 6 2 mSv/MBq and 142 6 15 mGy/MBq, respectively. For a typical injected activity of 555 MBq, the effective dose would be 21.1 6 2.2 mSv for the 4.8-h interval, reduced to 8.3 6 1.1 mSv for the 1-h interval. Conclusion: 18 F-CP-18 cleared rapidly through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both the effective dose and the bladder dose can be reduced by frequent voiding. From the radiation dosimetry perspective, the apoptosis imaging agent 18 F-CP-18 is suitable for human use.

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

Cited by 49 publications

References 17 publications

Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [ ¹⁸ F]-labeled isatin sulfonamide

Biodistribution and Radiation Dosimetry of ¹⁸F-CP-18, a Potential Apoptosis Imaging Agent, as Determined from PET/CT Scans in Healthy Volunteers

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

Cited by 49 publications

References 17 publications

Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [ 18 F]-labeled isatin sulfonamide

Biodistribution and Radiation Dosimetry of 18F-CP-18, a Potential Apoptosis Imaging Agent, as Determined from PET/CT Scans in Healthy Volunteers

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Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [ ¹⁸ F]-labeled isatin sulfonamide

Biodistribution and Radiation Dosimetry of ¹⁸F-CP-18, a Potential Apoptosis Imaging Agent, as Determined from PET/CT Scans in Healthy Volunteers