Discovery and development of inhibitors selective for human constitutive proteasome and immunoproteasome active sites

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Discovery and development of inhibitors selective for human constitutive proteasome and immunoproteasome active sites

Type: Doctoral Thesis
Title: Discovery and development of inhibitors selective for human constitutive proteasome and immunoproteasome active sites
Author: Xin, B.
Issue Date: 2017-09-27
Keywords: Proteasome inhibitor
ABP
Abstract:  This thesis describes the design and development of subunit‐selective inhibitors of particular catalytically active subunits of human constitutive proteasomes and immunoproteasomes. Most existing proteasome inhibitors are oligopeptides composed of 2‐4 amino acid residues, N‐terminally capped and with the C‐terminus adapted to give an electrophilic trap. Such compounds are also at the basis of the research described in this Thesis. Attention was directed to substitute specific amino acid residues by either synthetic, non‐canonical amino acid derivatives (with a review on the synthesis of such items given in Chapter 2) or dipeptide isosteres. Alternatively, modifications of the electrophilic trap, specifically, the epoxyketone moiety, were investigated. In this way, and by the synthesis of focused libraries, in which in each case a number of structural analogues, rather than a single one, inhibitors selective for β5c, β2c and β2i were discovered, and a number of two‐step activity‐based probes for probing these activities in vitro and in situ were identified.
Promotor: Supervisor: Overkleeft H.S., Marel G.A. van der Co-Supervisor: Florea B.I.
Faculty: Science
University: Leiden
Handle: http://hdl.handle.net/1887/55958
 

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application/pdf Title page_Table of contents 261.8Kb View/Open
application/pdf Chapter 1 General introduction 484.9Kb View/Open
application/pdf Chapter 2 1.612Mb View/Open
application/pdf Chapter 3 787.9Kb View/Open Full text at publisher site
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application/pdf Chapter 5 2.744Mb Under embargo Full text at publisher site
application/pdf Chapter 6 1.975Mb Under embargo until 2019-03-27
application/pdf Chapter 7 2.413Mb Under embargo until 2019-03-27
application/pdf Chapter 8 1.273Mb View/Open
application/pdf Chapter 9 Summary and future perspectives 639.9Kb View/Open
application/pdf Summary in Chinese 323.0Kb View/Open
application/pdf Curriculum Vitae_List of publications 287.1Kb View/Open
application/pdf Propositions+Acknowledgements 169.6Kb View/Open

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