Studies on the application of Ugi reaction for the synthesis of biologically active tripeptides and peptoids

Michał Mroczkiewicz

Abstract

The main matter of the thesis Studies on the application of Ugi reaction for the synthesis of biologically active tripeptides and peptoids was the elaboration of the methodology for the synthesis of tripeptides with C-terminal aldehyde group possessing arbitrary absolute configuration at stereogenic centers. For the construction of peptide skeletons multicomponent Ugi reaction was applied. As a substrates amine A, aldehyde B and chiral, non-racemic carboxylic acids C and isocyanides D were used. Diastereoisomeric products of Ugi reaction E were subjected to the subsequent reactions: (a) removal of amide bond protecting group R2, (b) resolution of diastereoisomeric mixtures, and (c) functionalisation of aldehyde precursor group X leading to the final compounds F. Developed methodology was applied for the synthesis of all stereoisomers of the known proteasome inhibitor MG-132 possessing a structure of tripeptide aldehyde Cbz-Leu-Leu-Leu-al. Biological studies confirmed a high proteasome inhibitory activity of peptides possessing amino acids with non-natural absolute configuration. In this way it was shown that activity of compounds is highly dependent on their spatial structure. In the thesis were also presented results of the studies on the synthesis of tripeptides with α,α-disubstituted amino acids and other than aldehyde C-terminal functional groups as well as dipeptide aldehydes with non-peptidyl N-terminal groups. Ugi reaction was also used for the synthesis of peptoids having the N-substituted oligoclycine structure. It was found that appropriate form of formaldehyde used as formyl substrate of multicomponent reaction is paraformaldehyde. A method of peptoid synthesis with the application of Ugi reaction was used for the preparation of a group of pentapeptoids with a variety of N-protection of amide bonds. Generally in the thesis a wide application of Ugi reaction for the synthesis of peptides and their various analogues was shown.
Diploma typeDoctor of Philosophy
Author Michał Mroczkiewicz (FC)
Michał Mroczkiewicz,,
- Faculty of Chemistry
Title in EnglishStudies on the application of Ugi reaction for the synthesis of biologically active tripeptides and peptoids
Languagepl polski
Certifying UnitFaculty of Chemistry (FC)
Disciplinechemistry / (chemical sciences domain) / (physical sciences)
Defense Date29-01-2010
End date23-02-2010
Supervisor Ryszard Ostaszewski (FC)
Ryszard Ostaszewski,,
- Faculty of Chemistry

Internal reviewers Michał Fedoryński (FC / IBC / DDTB)
Michał Fedoryński,,
- Department Of Drug Technology And Biotechnology
External reviewers Piotr Kiełbasiiński
Piotr Kiełbasiiński,,
-
Pages202
Keywords in Englishxxx
Abstract in EnglishThe main matter of the thesis Studies on the application of Ugi reaction for the synthesis of biologically active tripeptides and peptoids was the elaboration of the methodology for the synthesis of tripeptides with C-terminal aldehyde group possessing arbitrary absolute configuration at stereogenic centers. For the construction of peptide skeletons multicomponent Ugi reaction was applied. As a substrates amine A, aldehyde B and chiral, non-racemic carboxylic acids C and isocyanides D were used. Diastereoisomeric products of Ugi reaction E were subjected to the subsequent reactions: (a) removal of amide bond protecting group R2, (b) resolution of diastereoisomeric mixtures, and (c) functionalisation of aldehyde precursor group X leading to the final compounds F. Developed methodology was applied for the synthesis of all stereoisomers of the known proteasome inhibitor MG-132 possessing a structure of tripeptide aldehyde Cbz-Leu-Leu-Leu-al. Biological studies confirmed a high proteasome inhibitory activity of peptides possessing amino acids with non-natural absolute configuration. In this way it was shown that activity of compounds is highly dependent on their spatial structure. In the thesis were also presented results of the studies on the synthesis of tripeptides with α,α-disubstituted amino acids and other than aldehyde C-terminal functional groups as well as dipeptide aldehydes with non-peptidyl N-terminal groups. Ugi reaction was also used for the synthesis of peptoids having the N-substituted oligoclycine structure. It was found that appropriate form of formaldehyde used as formyl substrate of multicomponent reaction is paraformaldehyde. A method of peptoid synthesis with the application of Ugi reaction was used for the preparation of a group of pentapeptoids with a variety of N-protection of amide bonds. Generally in the thesis a wide application of Ugi reaction for the synthesis of peptides and their various analogues was shown.
Thesis file
Mroczkiewicz.pdf 1.85 MB

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