A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

Claus G. Bang; Jakob F. Jensen; Emil O'Hanlon Cohrt; Lasse B. Olsen; Saba G. Siyum; Kim T. Mortensen; Tine Skovgaard; Jens Berthelsen; Liang Yang; Michael Givskov; Katrine Qvortrup; Thomas E. Nielsen

doi:10.1021/acscombsci.7b00068

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

Claus G. Bang, Jakob F. Jensen, Emil O'Hanlon Cohrt, Lasse B. Olsen, Saba G. Siyum, Kim T. Mortensen, Tine Skovgaard, Jens Berthelsen, Liang Yang, Michael Givskov, Katrine Qvortrup^*, Thomas E. Nielsen

^*Corresponding author for this work

3 Citations (Scopus)

Abstract

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.

Original language	English
Journal	ACS Combinatorial Science
Volume	19
Issue number	10
Pages (from-to)	657-669
Number of pages	13
ISSN	2156-8952
DOIs	https://doi.org/10.1021/acscombsci.7b00068
Publication status	Published - Oct 2017

Keywords

HDAC inhibitor
hydroxamic acid
linker
solid-phase synthesis

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10.1021/acscombsci.7b00068

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Bang, C. G., Jensen, J. F., O'Hanlon Cohrt, E., Olsen, L. B., Siyum, S. G., Mortensen, K. T., Skovgaard, T., Berthelsen, J., Yang, L., Givskov, M., Qvortrup, K., & Nielsen, T. E. (2017). A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors. ACS Combinatorial Science, 19(10), 657-669. https://doi.org/10.1021/acscombsci.7b00068

@article{0bb1121eb07c435fab21fc87348560f9,

title = "A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors",

abstract = "We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.",

keywords = "HDAC inhibitor, hydroxamic acid, linker, solid-phase synthesis",

author = "Bang, {Claus G.} and Jensen, {Jakob F.} and {O'Hanlon Cohrt}, Emil and Olsen, {Lasse B.} and Siyum, {Saba G.} and Mortensen, {Kim T.} and Tine Skovgaard and Jens Berthelsen and Liang Yang and Michael Givskov and Katrine Qvortrup and Nielsen, {Thomas E.}",

year = "2017",

month = oct,

doi = "10.1021/acscombsci.7b00068",

language = "English",

volume = "19",

pages = "657--669",

journal = "ACS Combinatorial Science",

issn = "2156-8952",

publisher = "ACS Publications",

number = "10",

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TY - JOUR

T1 - A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

AU - Bang, Claus G.

AU - Jensen, Jakob F.

AU - O'Hanlon Cohrt, Emil

AU - Olsen, Lasse B.

AU - Siyum, Saba G.

AU - Mortensen, Kim T.

AU - Skovgaard, Tine

AU - Berthelsen, Jens

AU - Yang, Liang

AU - Givskov, Michael

AU - Qvortrup, Katrine

AU - Nielsen, Thomas E.

PY - 2017/10

Y1 - 2017/10

N2 - We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.

AB - We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.

KW - HDAC inhibitor

KW - hydroxamic acid

KW - linker

KW - solid-phase synthesis

U2 - 10.1021/acscombsci.7b00068

DO - 10.1021/acscombsci.7b00068

M3 - Journal article

C2 - 28746804

AN - SCOPUS:85030788051

SN - 2156-8952

VL - 19

SP - 657

EP - 669

JO - ACS Combinatorial Science

JF - ACS Combinatorial Science

IS - 10

ER -

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

Abstract

Keywords

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