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Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability

Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability
The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ?5min) to the thiol which has a half-life of 51min.
epigenetics, histone deacetylase, enzyme inhibitors, natural products, depsipeptide
0968-0896
3650-3658
Benelkebir, Hanae
6b4a6913-02de-4700-aba3-939968130c51
Marie, Sabrina
62391d09-1a3e-4ad1-b854-566a12088d83
Hayden, Annette L.
80301564-d83f-404c-abd0-0f8acf6c2e60
Lyle, Jason
ee76cd66-cf67-4913-8461-b0aad0d2a344
Loadman, Paul M
359e4b0a-e487-456e-9f35-97b31807c22d
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9
Benelkebir, Hanae
6b4a6913-02de-4700-aba3-939968130c51
Marie, Sabrina
62391d09-1a3e-4ad1-b854-566a12088d83
Hayden, Annette L.
80301564-d83f-404c-abd0-0f8acf6c2e60
Lyle, Jason
ee76cd66-cf67-4913-8461-b0aad0d2a344
Loadman, Paul M
359e4b0a-e487-456e-9f35-97b31807c22d
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Ganesan, A.
62aa5a87-9308-4383-8686-99726b6bcfb9

Benelkebir, Hanae, Marie, Sabrina, Hayden, Annette L., Lyle, Jason, Loadman, Paul M, Crabb, Simon J., Packham, Graham and Ganesan, A. (2011) Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability. Bioorganic & Medicinal Chemistry, 19 (12), 3650-3658. (doi:10.1016/j.bmc.2011.02.024). (PMID:21420302)

Record type: Article

Abstract

The total synthesis of largazole and four analogues is reported. All analogues were nanomolar HDAC inhibitors. The antiproliferative activity is driven by lipophilicity and cell permeability. In murine liver homogenates, largazole is rapidly metabolized (half-life ?5min) to the thiol which has a half-life of 51min.

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More information

e-pub ahead of print date: 17 February 2011
Published date: 15 June 2011
Keywords: epigenetics, histone deacetylase, enzyme inhibitors, natural products, depsipeptide
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 180089
URI: https://eprints.soton.ac.uk/id/eprint/180089
ISSN: 0968-0896
PURE UUID: 0eabcc84-8b50-481f-8669-a26add6e1b6d
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

Catalogue record

Date deposited: 06 Apr 2011 14:28
Last modified: 31 Jan 2019 01:37

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