62252-24-8

Upstream product

• 67-56-1 methanol 
• 3898-66-6 2-(carboxymethyl)-5-nitrobenzoic acid 
• 36795-25-2 7-nitro-1H-2-benzopyran-1,3(4H)-dione 
• 89-51-0 Homophthalic acid 

Downstream Products

• 62252-25-9 4-chloro-3-methoxy-7-nitroisocoumarin 
• 62252-26-0 JLK 6 

Relevant academic research and scientific papers

Homophthalic Esters: A New Type of Reagents for the Castagnoli-Cushman Reaction

The reactivity pattern of the Castagnoli-Cushman reaction between homophthalic anhydride and imines was completely reproduced by replacing homophthalic anhydride with o-(alkoxycarbonyl)methyl benzoic acids activated by CDI (1,1′-carbonyldiimidazole). This allows obtaining tetrahydroisoquinolonic esters directly and plants the Castagnoli-Cushman chemistry onto a fundamentally new reagent space not requiring the use of cyclic anhydrides.

Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein

The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.

Alkyne derivatives of isocoumarins as clickable activity-based probes for serine proteases

Activity-based probes (ABPs) have found increasing use in functional proteomics studies. Recently, ABPs that can be employed in combination with click chemistry gained particular attention due to their flexible application in vitro and in vivo. Moreover,

Isocoumarin-based inhibitors of pancreatic cholesterol esterase

Pancreatic cholesterol esterase (CEase), which is secreted from the exocrine pancreas, is a serine hydrolase that aids in the bile salt-dependent hydrolysis of dietary cholesteryl esters and contributes to the hydrolysis of triglycerides and phospholipids. Additional roles for CEase in intestinal micelle formation and in transport of free cholesterol to the enterocyte have been suggested. There also are studies that point to a pathological role(s) for CEase in the circulation where CEase accumulates in atherosclerotic lesions and triggers proliferation of smooth muscle cells. Thus, there is interest in CEase as a potential drug target. 4-Chloro-3-alkoxyisocoumarins are a class of haloenol lactones that inhibit serine hydrolases and serine proteases and have the potential to be suicide inhibitors. In the present study, we have developed 3-alkoxychloroisocoumarins that are potent inhibitors of CEase. These inhibitors were designed to have a saturated cycloalkane ring incorporated into a 3-alkoxy substituent. The size of the ring as well as the length of the tether holding the ring was found to be important contributors to binding to CEase. 4-Chloro-3-(4-cyclohexylbutoxy)isocoumarin and 4-chloro-3-(3-cyclopentylpropoxy)isocoumarin were demonstrated to be potent reversible inhibitors of CEase, with dissociation constants of 11 nM and 19 nM, respectively. The kinetic results are consistent with predictions from molecular modeling.

Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease

A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (α-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (H

Effect of the 7-Amino Substituent on the Inhibitory Potency of Mechanism-Based Isocoumarin Inhibitors for Porcine Pancreatic and Human Neutrophil Elastases: A 1.85-Angstroem X-ray Structure of the Complex between Porcine Pancreatic Elastase and 7--4-chloro-...

A series of new acyl, urea, and carbonate derivatives of 7-amino-4-chloro-3-methoxyisocoumarin were synthesized and evaluated as irreversible inhibitors of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE).Inhibition of HNE is directly related to the hydrophobicity of the substituent on the 7-amino group.The N-Tos-Phe derivative (19) is the best HNE inhibitor with a second-order rate constant kobs/ = 200 000 M-1s-1.The closest analogue in this series, the 3,3-diphenylpropionyl derivative 5, had kobs/ = 130 000 M-1s-1 with HNE.In contrast to the Tos-Phe derivative 19, phenylacetyl derivative 2 and carbonates 22 and 25 gave extremely stable enzyme-inhibitor complexes with deacylation half-lives longer than 48 h with both elastases.N-Phenylurea derivative 25 was the best inhibitor for PPE with a second-order rate constant kobs/ = 7300 M-1s-1.The crystal structure of a complex of PPE with N-tosyl-Phe derivative 19 was determined at 1.85 Angstroem resolution and refined to a final R factor of 16.9percent.The isocoumarin forms an acyl enzyme with Ser-195, while His-57 is near the inhibitor, but not covalently linked.The Tos-Phe makes a few hydrophobic contacts with the S' subsites of PPE, but appears to be interacting primarily with itself in the PPE structure.This region of HNE is more hydrophobic and modeling indicates that the inhibitor would probably make additional contacts with the enzyme.