Total synthesis of largazole and analogues: HDAC inhibition, antiproliferative activity and metabolic stability |
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| Authors: | Benelkebir Hanae Marie Sabrina Hayden Annette L Lyle Jason Loadman Paul M Crabb Simon J Packham Graham Ganesan A |
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| Institution: | School of Chemistry, University of Southampton, Southampton SO17 1BJ, United Kingdom. |
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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. |
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