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Synthesis of Aldehyde-Functionalized Building Blocks and Their Use for the Cyclization of Peptides: Applications to Angiotensin II
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This study addresses the issue of how to convert peptides into drug-like non- peptides with retained biological activities at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide.

Knowledge of the bioactive conformations of endogenous peptides is invaluable for the conversion of peptides into less peptidic analogues. Effectively constrained cyclic analogues, with retained pharmacological activities, may provide valuable information about the bioactive conformations of the peptide in question.

This thesis describes the development of synthesis for a number of protected, aldehyde-functionalized building blocks for standard solid phase peptide synthesis, and their use for the preparation of cyclic peptide analogues. The effect of variations in the side-chain lengths of the building blocks, on the outcome of the cyclizations was studied. Incorporation of a building block derived from L-aspartic acid afforded bicyclization towards the C-terininal end of the peptide, while for the corresponding L-glutamic acid derived building block, N-terminal directed bicyclization was achieved. A building block derived from L-2-aminoadipic acid was exploited for monocyclization furnishing cis- and trans- vinyl sulfide bridged peptide analogues.

The described cyclization methods have been applied to the synthesis of a number of conformationally constrained Ang II analogues, for which the pharmacological properties have been evaluated. Two of the Ang II analogues synthesized displayed high affinities and full agonist activities at the AT1 angiotensin receptor, and have proven to be useful tools in the search for the bioactive conformation of Ang II.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 69
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 262
Keywords [en]
Pharmaceutical chemistry, Synthesis, Aldehyde, Cyclization, Peptide, Angiotensin II, Ang II, Bioactive Conformation, Solid Phase Peptide Synthesis, Dimethyl Acetal
Keywords [sv]
Farmaceutisk kemi, Syntes, Aldehyd, Cyklisering, Peptid, Bioaktiv konformation, Fast-fas peptidsyntes, Dimetylacetal
National Category
Medicinal Chemistry
Research subject
Organic Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-1623ISBN: 91-554-5211-6 (print)OAI: oai:DiVA.org:uu-1623DiVA, id: diva2:161216
Public defence
2002-02-01, B41, BMC, Uppsala, 10:15
Opponent
Available from: 2002-01-09 Created: 2002-01-09 Last updated: 2018-01-13Bibliographically approved

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Citation style
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