The synthesis and characterization of gamma-glutamyl aldehydes and epoxides designed as inhibitors of the cysteine protease gamma-glutamyl hydrolase.
Alexander, Matthew D.
2004
Abstract
gamma-Glutamyl peptidyl aldehydes and epoxides were synthesized as potential inhibitors of gamma-glutamyl hydrolase (GH). Two <italic>N</italic>-methyl <italic> p</italic>-aminobenzoyl (<italic>N</italic>-Me-<italic>p</italic>AB)-containing substrate mimics possessing terminal glutamate gamma-semialdehyde residues were synthesized, <italic>N</italic>-Me-<italic>p</italic>AB-Glu-gamma-Glu-gamma-CHO and <italic>N</italic>-Me-<italic>p</italic>AB-(4,4-F<sub>2</sub>)Glu-gamma-Glu-gamma-CHO. The aldehyde moiety of glutamate gamma-semialdehyde-containing peptides was found to undergo intramolecular reaction with the backbone nitrogen of the Glu-gamma-Glu peptide. The resulting cyclic hemiaminal was the predominant form present in solutions of these peptides, while the aldehyde and hydrate forms were barely detectable by NMR. The analysis of these <italic>N</italic>-acyl glutamate gamma-semialdehydes was facilitated by extensive NMR studies with <italic> N</italic>-TFA glutamate gamma-semialdehydes that were synthesized with and without <italic>N</italic>-methyl and methyl ester derivatization. Analysis of the <italic>N</italic>-TFA series indicated the acylal species (from intramolecular cyclization through the alpha-carboxyl) was not present. Chemical reactivity studies with glutamate gamma-semialdehyde-containing peptides showed that while the aldehyde species was barely detectable by NMR, the majority of the compound could be derivatized with the well known aldehyde reagent, dinitrophenylhydrazine, to form the corresponding hydrazone. A glutamate gamma-semialdehyde-containing peptide with <italic>N</italic>-methyl substitution of the Glu-gamma-Glu peptide bond was synthesized and found to exist only as the aldehyde and hydrate forms. The gamma-glutamyl peptidyl epoxides were synthesized using a glutamate gamma-semialdehyde derivative as the key building block. A dipeptidyl terminal epoxide was synthesized through a series of reactions that resulted in formation of an epoxide between the terminal carbons in the methylene homolog of <italic>N</italic>-Me-<italic> p</italic>AB-Glu-gamma-Glu-gamma-CHO to give <italic>N</italic>-Me <italic> p</italic>AB-Glu-gamma-Glu-gamma-epoxide. A truncated analog, <italic> N</italic>-Me-<italic>p</italic>AB-Glu-gamma-epoxide, was synthesized using analogous chemistry. The peptidyl aldehydes and epoxides inhibited the GH-catalyzed hydrolysis of known substrates. However, they also showed alternate substrate activity which contributes to the inhibitory activity and has yet to be quantified. An internal epoxide-containing Glu-gamma-Glu dipeptide mimic was designed and key synthetic steps have been completed. This potential inhibitor is analogous to known substrates, with a <italic>trans</italic> epoxide replacing the Glu-gamma-Glu peptide bond. A stereospecific synthesis of ethyl (<italic>S</italic>)-cyclopent-2-enecarboxylate with further elaboration provided the C-terminal portion of the molecule, a protected glutarate derviative. Julia-Kocienski olefination between this fragment and a suitably protected glutamate-gamma-semialdehyde provided the key <italic>E</italic> olefin intermediate in the synthesis of the internal epoxide target compound.Subjects
Aldehydes Characterization Cysteine Protease Designed Epoxides Glutamyl Hydrolase-gamma Inhibitors Synthesis
Types
Thesis
Metadata
Show full item recordCollections
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.