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

Hanae Benelkebir; Sabrina Marie; Annette L. Hayden; Jason Lyle; Paul M. Loadman; Simon J. Crabb; Graham Packham; A Ganesan

doi:10.1016/j.bmc.2011.02.024

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

Hanae Benelkebir, Sabrina Marie, Annette L. Hayden, Jason Lyle, Paul M. Loadman, Simon J. Crabb, Graham Packham, A Ganesan

Research output: Contribution to journal › Article › peer-review

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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 ?5 min) to the thiol which has a half-life of 51 min.

Original language	English
Pages (from-to)	3650-3658
Number of pages	9
Journal	Bioorganic & Medicinal Chemistry
Volume	19
Issue number	12
DOIs	https://doi.org/10.1016/j.bmc.2011.02.024
Publication status	Published - 15 Jun 2011

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10.1016/j.bmc.2011.02.024

Cite this

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

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 ?5 min) to the thiol which has a half-life of 51 min.",

author = "Hanae Benelkebir and Sabrina Marie and Hayden, {Annette L.} and Jason Lyle and Loadman, {Paul M.} and Crabb, {Simon J.} and Graham Packham and A Ganesan",

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AU - Benelkebir, Hanae

AU - Marie, Sabrina

AU - Hayden, Annette L.

AU - Lyle, Jason

AU - Loadman, Paul M.

AU - Crabb, Simon J.

AU - Packham, Graham

AU - Ganesan, A

PY - 2011/6/15

Y1 - 2011/6/15

N2 - 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 ?5 min) to the thiol which has a half-life of 51 min.

AB - 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 ?5 min) to the thiol which has a half-life of 51 min.

U2 - 10.1016/j.bmc.2011.02.024

DO - 10.1016/j.bmc.2011.02.024

M3 - Article

VL - 19

SP - 3650

EP - 3658

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 12

ER -