220509-74-0

Usage

Biological Activity

caspase-3/7 inbibitor i is a potent, reversible, isatin sulfonamide-based inhibitor of caspase-3 (ki(app) = 60 nm) and caspase-7 (ki(app) = 170 nm). is a weaker inhibitor of caspase-9 (ki(app) = 3.1 mm). it has only a trivial effect (ki(app) >25 mm) on the activities of caspase-1, caspase-2, caspase-4, caspase-6, and caspase-8. it has been shown to inhibit apoptosis in camptothecin treated jurkat cells (ic50 ~50 μm). also it has been reported to inhibit apoptosis in chondrocytes (44% inhibition at 10 μm and 98% inhibition at 50 μm). selectivity for caspases-3 and 7 involves unique hydrophobic residues in the s2 pocket surrounding the catalytic cysteine residue. [1] [2] in some systems inhibition of caspases-3 and -7 can prevent apoptosis and may therefore have important therapeutic implications. [3]a potent, cell-permeable, and specific, reversible inhibitor of caspase-3 (ki = 60 nm) and caspase-7 (ki = 170 nm).

references

1. lee, d., et al. 2001. j. med. chem. 44, 2015. 2. lee, d., et al. 2000. j. biol. chem. 275, 16007. 3. clements, k. m., burton‐wurster, n., nuttall, m. e., & lust, g. (2005). caspase‐3/7 inhibition alters cell morphology in mitomycin‐c treated chondrocytes. journal of cellular physiology, 205(1), 133-140.

Upstream product

• 63126-47-6 (2S)-2-(methoxymethyl)-1-pyrrolidine 
• 132898-96-5 5-chlorosulfonylisatin 
• 93783-15-4 3,3-dichloro-2-oxoindoline-5-sulfonyl chloride 
• 220428-23-9 (S)-3,3-dichloro-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)indolin-2-one 
• 80789-74-8 5-isatinsulfonic acid sodium salt 
• 23356-96-9 (S)-1-Pyrrolidin-2-yl-methanol 
• 91-56-5 indole-2,3-dione 
• 69610-40-8 N-(tert-butoxycarbonyl)-L-prolinol 
• 916049-16-6 2-methoxymethylpyrrolidine-1-carboxylic acid tert-butyl ester 

Downstream Products

• 1160524-51-5 (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]-1-[4-(oxiran-2-ylmethoxy)benzyl]isatin 
• 1160524-33-3 (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]-1-(undec-10-enyl)isatin 
• 1160524-34-4 (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]-1-(4-vinylbenzyl)isatin 
• 1160524-35-5 (S)-1-[4-(allyloxy)benzyl]-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin 
• 1160524-50-4 (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]-1-[4-(oxiran-2-yl)benzyl]isatin 
• 1292809-57-4 (S)-1-((1-(biphenyl-4-yl)-1H-1,2,3-triazol-5-yl)methyl)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)indoline-2,3-dione 
• 1292809-49-4 (S)-1-((1-(biphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)indoline-2,3-dione 
• 1292809-58-5 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-5-yl)methyl)indoline-2,3-dione 
• 1292809-50-7 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione 
• 1292809-51-8 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione 
• 1292809-59-6 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)indoline-2,3-dione 
• 1292809-60-9 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-5-yl)methyl)indoline-2,3-dione 
• 1292809-52-9 (S)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)-1-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione 
• 1292809-54-1 (S)-1-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(methoxymethyl)pyrrolidin-1-ylsulfonyl)indoline-2,3-dione 

Relevant academic research and scientific papers

Isatin 1,2,3-triazoles as potent inhibitors against caspase-3

Sixteen disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3. The two most potent inhibitors were found to be (S)-1-((1-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl) sulfonyl)indoline-2,3-dione (7f) and (S)-1-((1-benzyl-1H-1,2,3-triazol-5-yl) methyl)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (8g) with IC50-values of 17 and 9 nM, respectively. Lineweaver-Burk plots revealed that these two triazoles show competitive inhibitory mechanism against caspase-3.

3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3

Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.

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.

Pyrimidoindolones and methods for using same

Novel pyrimidoindolone compounds are disclosed. Methods of using the pyrimidoindolone compounds and compositions containing the compounds in the treatment and/or prevention of disease and other conditions related to inflammation, neurodegeneration, osteoarthritis and apoptosis are also disclosed.

Potent and selective nonpeptide inhibitors of caspases 3 and 7

5-Dialkylaminosulfonylisatins have been identified as potent, nonpeptide inhibitors of caspases 3 and 7. The most active compound within this series (34) inhibited caspases 3 and 7 in the 2-6 nM range and exhibited approximately 1000-fold selectivity for caspases 3 and 7 versus a panel of five other caspases (1, 2, 4, 6, and 8) and was at least 20-fold more selective versus caspase 9. Sequence alignments of the active site residues of the caspases strongly suggest that the basis of this selectivity is due to binding in the S2 subsite comprised of residues Tyr204, Trp206, and Phe256 which are unique to caspases 3 and 7. These compounds inhibit apoptosis in three cell-based models: human Jurkat T cells, human chondrocytes, and mouse bone marrow neutrophils.