80640-14-8Relevant articles and documents
Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity
Ali El Damrany Hussein, Hussein,Debnath, Samarpita,Goswami, Falguni,Hussain, Ishtiaq,Karn, Alka,Nakka, Srinuvasu,Nugent, Thomas C.
supporting information, p. 3539 - 3545 (2021/06/12)
Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β-diketones remain unreacted while a ketone moiety undergoes a highly
Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors
Schiefer, Isaac T.,Tapadar, Subhasish,Litosh, Vladislav,Siklos, Marton,Scism, Rob,Wijewickrama, Gihani T.,Chandrasena, Esala P.,Sinha, Vaishali,Tavassoli, Ehsan,Brunsteiner, Michael,Fa', Mauro,Arancio, Ottavio,Petukhov, Pavel,Thatcher, Gregory R. J.
supporting information, p. 6054 - 6068 (2013/09/02)
Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain.
3-Fluoroaspartate and pyruvoyl-dependant aspartate decarboxylase: Exploiting the unique characteristics of fluorine to probe reactivity and binding
De Villiers, Jandre,Koekemoer, Lizbe,Strauss, Erick
experimental part, p. 10030 - 10041 (2011/01/13)
Fluorine-containing amino acids have been used with great success as mechanism-based inhibitors of pyridoxal phosphate (PLP)-dependent enzymes, and the influence of fluorine on the conformation of molecules has also been extensively studied and practically exploited. In this study, we sought to use these unique characteristics to probe the reactivity and binding of aspartate decarboxylase (ADC) enzymes, which are members of the small class of pyruvoyl-dependant decarboxylases. Since ADC activity has been shown to be essential to the virulence of Mycobacterium tuberculosis, information gained in this manner could be used for the development of inhibitors that selectively target pyruvoyl-dependent enzymes such as ADC, without affecting PLP-dependent enzymes in the host. For this purpose, we synthesized the L-erythro and L-threo isomers of 3-fluoroaspartate and tested their ability to act as substrates and/or inhibitors of the M. tuberculosis and Escherichia coli ADC enzymes. Trapping and MS-based binding analysis was additionally used to confirm that both isomers enter the enzymes' active sites. Our studies show that both isomers undergo single turnover decarboxylation and fluorine elimination reactions to give enamine products that can be trapped within the active site. Interestingly, the enamine/ADC complex that forms from the lerythro (but not the L-threo) isomer is sufficiently stable that it can be observed even without any trapping. This finding suggests that the two 3-fluoroaspartates maintain different conformations within the ADC active site, which leads to the enamine products with configurations of different stabilities. Taken together, our results provide new insights for the development of cofactor-specific inhibitors, and confirm the utility of fluorine as a unique tool for probing reactivity and binding profiles within enzymes.
