An azumamide C analogue without the zinc-binding functionality

Jesper S Villadsen; Betül Kitir; Kathrine Wich; Tina Friis; Andreas Stahl Madsen; Christian Adam Olsen

doi:10.1039/c4md00252k

An azumamide C analogue without the zinc-binding functionality

Jesper S Villadsen, Betül Kitir, Kathrine Wich, Tina Friis, Andreas Stahl Madsen, Christian Adam Olsen

14 Citationer (Scopus)

Abstract

Histone deacetylase (HDAC) inhibitors have attracted considerable attention due to their promise as therapeutic agents. Most HDAC inhibitors adhere to a general "cap-linker-Zn²⁺-binding group" architecture but recent studies have indicated that potent inhibition may be achieved without a Zn²⁺-coordinating moiety. Herein, we describe the synthesis of an azumamide analogue lacking its native Zn²⁺-binding group and evaluation of its inhibitory activity against recombinant human HDAC1-11. Furthermore, kinetic investigation of the inhibitory mechanism of both parent natural product and synthetic analogue against HDAC3-NCoR2 is reported as well as their activity against Burkitt's lymphoma cell proliferation.

Originalsprog	Engelsk
Tidsskrift	MedChemComm
Vol/bind	5
Sider (fra-til)	1849-1855
ISSN	2040-2503
DOI	https://doi.org/10.1039/c4md00252k
Status	Udgivet - 1 dec. 2014

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10.1039/c4md00252k

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title = "An azumamide C analogue without the zinc-binding functionality",

abstract = "Histone deacetylase (HDAC) inhibitors have attracted considerable attention due to their promise as therapeutic agents. Most HDAC inhibitors adhere to a general {"}cap-linker-Zn2+-binding group{"} architecture but recent studies have indicated that potent inhibition may be achieved without a Zn2+-coordinating moiety. Herein, we describe the synthesis of an azumamide analogue lacking its native Zn2+-binding group and evaluation of its inhibitory activity against recombinant human HDAC1-11. Furthermore, kinetic investigation of the inhibitory mechanism of both parent natural product and synthetic analogue against HDAC3-NCoR2 is reported as well as their activity against Burkitt's lymphoma cell proliferation.",

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doi = "10.1039/c4md00252k",

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T1 - An azumamide C analogue without the zinc-binding functionality

AU - Villadsen, Jesper S

AU - Kitir, Betül

AU - Wich, Kathrine

AU - Friis, Tina

AU - Madsen, Andreas Stahl

AU - Olsen, Christian Adam

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Histone deacetylase (HDAC) inhibitors have attracted considerable attention due to their promise as therapeutic agents. Most HDAC inhibitors adhere to a general "cap-linker-Zn2+-binding group" architecture but recent studies have indicated that potent inhibition may be achieved without a Zn2+-coordinating moiety. Herein, we describe the synthesis of an azumamide analogue lacking its native Zn2+-binding group and evaluation of its inhibitory activity against recombinant human HDAC1-11. Furthermore, kinetic investigation of the inhibitory mechanism of both parent natural product and synthetic analogue against HDAC3-NCoR2 is reported as well as their activity against Burkitt's lymphoma cell proliferation.

AB - Histone deacetylase (HDAC) inhibitors have attracted considerable attention due to their promise as therapeutic agents. Most HDAC inhibitors adhere to a general "cap-linker-Zn2+-binding group" architecture but recent studies have indicated that potent inhibition may be achieved without a Zn2+-coordinating moiety. Herein, we describe the synthesis of an azumamide analogue lacking its native Zn2+-binding group and evaluation of its inhibitory activity against recombinant human HDAC1-11. Furthermore, kinetic investigation of the inhibitory mechanism of both parent natural product and synthetic analogue against HDAC3-NCoR2 is reported as well as their activity against Burkitt's lymphoma cell proliferation.

U2 - 10.1039/c4md00252k

DO - 10.1039/c4md00252k

M3 - Journal article

SN - 2040-2503

VL - 5

SP - 1849

EP - 1855

JO - MedChemComm

JF - MedChemComm

ER -

An azumamide C analogue without the zinc-binding functionality

Abstract

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