Warheads depsipeptides

The Depsipeptide Natural Products with a Thiol Warhead... 

The total syntheses and SAR studies, notably by Ganesan with FK228 and Williams with largazole, have identified the key features within depsipeptide HDAC inhibitors that are required for HDAC inhibition (Figure 4.17). The macrocyclic backbone is essential as linear uncyclized compounds are inactive. Within the macrocycle, the zinc binding thiol warhead needs to be of D-stereochemistry and the epimer is virtually inactive, while the other amino acid residues present can be varied without loss in activity. The... 

Figure 4.18 Synthesis of an analogue 52 of the depsipeptide natural products with an isosteric substitution of the zinc binding warhead.

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