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Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines

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Le Quement, Sebastian Thordal ; Ishoey, Mette ; Petersen, Mette Terp ; Thastrup, Jacob ; Hagel, Grith ; Nielsen, Thomas Kjær. / Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines. I: ACS Combinatorial Science. 2011 ; Bind 13, Nr. 6. s. 667-75.

Bibtex

@article{21d8038b9aaa484d81fb38b57ec5846c,
title = "Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines",
abstract = "Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.",
author = "{Le Quement}, {Sebastian Thordal} and Mette Ishoey and Petersen, {Mette Terp} and Jacob Thastrup and Grith Hagel and Nielsen, {Thomas Kj{\ae}r}",
year = "2011",
doi = "10.1021/co200078u",
language = "English",
volume = "13",
pages = "667--75",
journal = "A C S Combinatorial Science",
issn = "2156-8952",
publisher = "American Chemical Society",
number = "6",

}

RIS

TY - JOUR

T1 - Solid-phase synthesis of smac peptidomimetics incorporating triazoloprolines and biarylalanines

AU - Le Quement, Sebastian Thordal

AU - Ishoey, Mette

AU - Petersen, Mette Terp

AU - Thastrup, Jacob

AU - Hagel, Grith

AU - Nielsen, Thomas Kjær

PY - 2011

Y1 - 2011

N2 - Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.

AB - Apoptotic induction mechanisms are of crucial importance for the general homeostasis of multicellular organisms. In cancer the apoptotic pathways are downregulated, which, at least partly, is due to an abundance of inhibitors of apoptosis proteins (IAPs) that block the apoptotic cascade by deactivating proteolytic caspases. The Smac protein has an antagonistic effect on IAPs, thus providing structural clues for the synthesis of new pro-apoptotic compounds. Herein, we report a solid-phase approach for the synthesis of Smac-derived tetrapeptide libraries. On the basis of a common (N-Me)AVPF sequence, peptides incorporating triazoloprolines and biarylalanines were synthesized by means of Cu(I)-catalyzed azide-alkyne cycloaddition and Pd-catalyzed Suzuki cross-coupling reactions. Solid-phase procedures were optimized to high efficiency, thus accessing all products in excellent crude purities and yields (both typically above 90%). The peptides were subjected to biological evaluation in a live/dead cellular assay which revealed that structural decorations on the AVPF sequence indeed are highly important for cytotoxicity toward HeLa cells.

U2 - 10.1021/co200078u

DO - 10.1021/co200078u

M3 - Journal article

C2 - 21905744

VL - 13

SP - 667

EP - 675

JO - A C S Combinatorial Science

JF - A C S Combinatorial Science

SN - 2156-8952

IS - 6

ER -

ID: 33257393