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Synthesis of 7-halogenated isatin sulfonamides: nonradioactive counterparts of caspase-3/-7 inhibitor-based potential radiopharmaceuticals for molecular imaging of apoptosis.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Nov 26; Vol. 57 (22), pp. 9383-95. Date of Electronic Publication: 2014 Nov 14. - Publication Year :
- 2014
-
Abstract
- N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [(18)F]39 that was produced by (19)F/(18)F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.
- Subjects :
- Caspase 3 chemistry
Caspase 7 chemistry
Chemistry, Pharmaceutical methods
Cytochrome P-450 Enzyme System chemistry
Drug Design
Halogens chemistry
Humans
Inhibitory Concentration 50
Isatin chemistry
Molecular Imaging instrumentation
Molecular Imaging methods
Serum drug effects
Solvents chemistry
Sulfonamides chemistry
Temperature
Time Factors
Apoptosis
Caspase Inhibitors chemistry
Enzyme Inhibitors chemistry
Isatin chemical synthesis
Radiopharmaceuticals chemistry
Sulfonamides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25358116
- Full Text :
- https://doi.org/10.1021/jm500718e